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Accueil > Personnels > HAMZE Abdallah

HAMZE Abdallah

Paris-Sud University

Tél : 01 46 83 54 98 Fax : 01 46 83 58 28

:contact : abdallah.hamze universite-paris-saclay.fr

Abdallah Hamze received his Ph.D. in Organic and Medicinal Chemistry in 2003 from the University of Montpellier-France, under the supervision of Pr. J. Martinez and Dr. J. F. Hernandez. After conducting research as a Post-doctoral fellowship - Sanofi in the research group of Pr. H. Vial and Pr. M. Calas on the Synthesis of new antimalarial prodrugs (2003-04). In 2006, He joined the University of Paris Sud, Department of Medicinal and Organometallic Chemistry as associate Professor and obtained his Habilitation diploma in 2011. In 2016, he obtained the National Scientific Qualification as Associate Professor in Medicinal Chemistry. Since 2017, he is a Professor for Medicinal Chemistry at the University of Paris Sud.

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Highlights

  • Synthetic methodology, including organometallic chemistry (Pd, Pt, Sn, Si, B)
  • New catalytic reactions for C-C, and C-N bond reactions
  • Medicinal chemistry (cancer, malaria, bioconjugate...)

Active-Learning Exercises in Medicinal Chemistry Course

QCM
http://wims.u-psud.fr/wims/wims.cgi?module=U2/chemistry/qcmmedchem.fr

Synthesis
https://wims.universite-paris-saclay.fr/wims/wims.cgi?lang=fr&+module=U2/chemistry/oefmedsynthese.fr

News


02.06.2022

Recent Developments in the Photochemical Synthesis of Functionalized Imidazopyridines.


10.04.2022

 ! Congrats to Jun


02.03.2022


18.02.2022

Congratulation to Jun for his first paper.


18.01.2022


15.12.2021

ABDALLAH HAMZE REÇOIT LE PRIX MICHEL DELALANDE DE L’ACADÉMIE NATIONALE DE PHARMACIE
https://www.pharmacie.universite-pa...


18.06.2021

Congratulation to Shannon for this nice work.


06.05.2021

Fantastic work ! Congratulations Kena !


06.04.2021


01.12.2020

Félicitations à Diana pour le Prix de la Chancellerie
Congratulations to Diana for Chancellery Award


06.11.2020

Our article on the cover ! congratulations to Diana.


23.10.2020

Congratulations to Diana and co-workers for this nice work !


09.10.2020


06.10.2020

Our collaborative paper about the Identification of Cyclic Bridged analogs of isoCA-4 : Design, Synthesis and Biological Evaluation has been accepted in Eur. J. Med. Chem. Congratulation to Shannon

10.07.2020


Congratulation to Kena for this nice work.


11.05.2020

Our collaborative paper about the Identification of a new series of flavopiridol-like structures as kinase inhibitors with high cytotoxic potency has been accepted in Eur. J. Med. Chem.


25.02.2020


29.01.2020

Developments of iso Combretastatin A-4 derivatives as highly cytotoxic agents


17.10.2019


10.10.2019


23.03.2019


22.03.2019
Hydrostannation of Alkynes https://pubs.acs.org/doi/10.1021/acscatal.9b00482#.XJTdoIvjAdo.twitter


04.03.2019


04.01.2019


17.12.2018


5.12.2017

Met Cat.


84. Naret, T. ; Retailleau, P. ; Bignon, J. ; Brion, J. D. ; Alami, M. ; Hamze, A., Palladium‐Catalyzed One‐Pot Synthesis of 5‐(1‐Arylvinyl)‐1H‐benzimidazoles : Overcoming the Limitation of Acetamide Partners. Adv. Synth. Catal. 2016, 358, 1833. [>http://onlinelibrary.wiley.com/wol1/doi/10.1002/adsc.201600173/abstract]
This article was selected as an Adv. Synth. Catal. Front cover of issue 11 of the journal by the Editorial Team.


83.Bzeih, T. ; Naret, T. ; Hachem, A. ; Jaber, N. ; Khalaf, A. ; Bignon, J. ; Brion, J.-D. ; Alami, M. ; Hamze, A., A general synthesis of arylindoles and (1-arylvinyl)carbazoles via a one-pot reaction from N-tosylhydrazones and 2-nitro-haloarenes and their potential application to colon cancer. Chem. Commun. 2016, 52, 13027.
[>http://pubs.rsc.org/en/content/articlelanding/2016/cc/c6cc07666a#!divAbstract]


82. Aziz, J. ; Brion, J.-D. ; Alami, M. ; Hamze, A., Synthesis of benzofulvenes through chemoselective Sonogashira and Barluenga couplings of ortho ethynyl-N-tosylhydrazones and cycloisomerization. RSC Adv. 2015, 5, 74391. [>http://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra14459k#!divAbstract]


81.Lawson, M. ; Bignon, J. ; Brion, J.-D. ; Hamze, A. ; Alami, M., Transition-Metal-Free Synthesis of Polysubstituted Cyclopropane Derivatives from N-Tosylhydrazones and their Cytotoxic Activities. Asian J. Org. Chem. 2015, 4 (10), 1144. [>http://onlinelibrary.wiley.com/doi/10.1002/ajoc.201500289/abstract]


80.Roche, M. ; Salim, S. M. ; Bignon, J. ; Levaique, H. ; Brion, J.-D. ; Alami, M. ; Hamze, A., Palladium-Catalyzed One-Pot Reaction of Hydrazones, Dihaloarenes, and Organoboron Reagents : Synthesis and Cytotoxic Activity of 1,1-Diarylethylene Derivatives. J. Org. Chem. 2015, 80 (13), 6715. DOI : 10.1021/acs.joc.5b00880


79. Bruneau, A. ; Roche, M. ; Hamze, A. ; Brion, J.-D. ; Alami, M. ; Messaoudi, S., Stereoretentive Palladium-Catalyzed Arylation, Alkenylation, and Alkynylation of 1-Thiosugars and Thiols Using Aminobiphenyl Palladacycle Precatalyst at Room Temperature. Chem. Eur. J. 2015, 21 (23), 8375.
[>http://onlinelibrary.wiley.com/doi/10.1002/chem.201501050/abstract]


78. Aziz J. ;Frison, G. ; Gómez, M. ; Brion, J-D. ; Hamze, A. ; Alami. M. Copper-Catalyzed Coupling of N-Tosylhydrazones with Amines : Synthesis of Fluorene Derivatives. ACS Catal. 2014 ; 4, 4498-4503. DOI : 10.1021/cs5014877

Abstract

An original formation of one C–N bond and one C–C bond on the same carbenic center has been developed. This approach involves a copper-catalyzed cross-coupling reaction between 2′-bromo-biaryl-N-tosylhydrazones and different amines leading to 9H-fluoren-9-amine derivatives. This reaction proceeds under mild conditions in glycerol, an inexpensive and environmentally friendly solvent, without adding any external ligand.


77. Tréguier, B. ; Lawson, M. ; Bernadat, G. ; Bignon, J. ; Dubois, J. ; Brion, J-D. ; Alami, M. ; Hamze, A. Synthesis of a 3-(alpha-Styryl)benzo[b]-thiophene Library via Bromocyclization of Alkynes and Palladium-Catalyzed Tosylhydrazones Cross-Couplings : Evaluation as Antitubulin Agents. ACS Comb. Sci. 2014  ; 16, 702-710. DOI : 10.1021/co500115b

Abstract

A library of functionalized 3-(α-styryl)-benzo[b]thiophenes, endowed with a high level of molecular diversity, was efficiently synthesized by applying a synthetic sequence that allowed introduction of various substituents on aromatic A, B, and C-rings. The strategy developed involves the synthesis of 3-bromobenzo[b]thiophene derivatives through a bromocyclization step of methylthio-containing alkynes using N-methylpyrrolidin-2-one hydrotribromide reagent (MPHT). Further coupling of 3-bromobenzothiophenes under palladium-catalysis with N-tosylhydrazones efficiently furnished 2-aryl-3-(α-styryl)benzo[b]thiophene derivatives. The antiproliferative properties of target compounds were studied. Among them, compound 5m has demonstrated submicromolar cytotoxic activity against HCT-116 cell line, and inhibited the polymerization of tubulin at micromolar level comparable to that of CA-4.


76. Roche, M. ; Bignon, J. ; Brion, J-D. ; Hamze, A. ; Alami, M. Tandem One-Pot Palladium-Catalyzed Coupling of Hydrazones, Haloindoles, and Amines : Synthesis of Amino-N-vinylindoles and Their Effect on Human Colon Carcinoma Cells. J. Org. Chem. 2014  ; 79, 7583-7592. DOI : 10.1021/jo501315q

Abstract

The synthesis of amino-substituted N-vinylazoles was achieved by a new palladium-assisted tandem catalytic reaction involving N-tosylhydrazones, halo-substituted azoles, and amines. Accordingly, two Csp2–N bonds were formed through two mechanistically distinct reactions using a single PdII/Pd0 catalyst system in a one-pot fashion. This work paves the way for the design of biological relevant compounds in an amino-substituted N-vinylindole series. Among several polyoxygenated derivatives evaluated, compounds 5e and 5u were found to exhibit good antiproliferative activity.


75. Aziz, J. ; Messaoudi, S. ; Alami, M. ; Hamze, A. Sulfinate derivatives : dual and versatile partners in organic synthesis. Org. Biomol. Chem. 2014 , 12, 9743-9759.DOI : 10.1039/c4ob01727g

Abstract

Sulfinic acids and their salts have recently emerged as versatile coupling partners to efficiently access a wide variety of hetero- and carbocyclic compounds, under relatively mild conditions. Their growing importance is attributable to their dual capacity for acting as nucleophilic or electrophilic reagents. This report summarizes recent advances in the preparation and use of sulfinates in organic synthesis.


74. Aziz, J. ; Frison, G. ; Le Menez, P. ; Brion, J.-D. ; Hamze, A. ; Alami, M. Gold versus Palladium : A Regioselective Cycloisomerization of Aromatic Enynes. Adv. Synth. Catal. 2013  ; 355, 3425-3436. DOI : 10.1002/adsc.201300746

Abstract

Aromatic enynes can be transformed into arylnaphthalenes or benzofulvenes depending on the reaction conditions. Under gold(I) catalysis, exclusive or major 6-endo-dig cyclization took place leading to arylnaphthalenes. However, a catalytic system based on palladium iodide/1,3-bis(diphenylphosphino)propane, in the presence of cesium carbonate as a base was necessary to furnish exclusively 5-exo-dig cyclization pattern, regardless of the electronic effects of the substituents. In the latter transformation, a mechanistic study (kinetic isotopic effect, density functional theory) involving a C[BOND]H activation is suggested for the exclusive formation of benzofulvenes.


73. Aziz, J. ; Brion, J.-D. ; Hamze, A. ; Alami, M., Copper Acetoacetonate [Cu(acac)2]/BINAP-Promoted Csp3-N Bond Formation via Reductive Coupling of N-Tosylhydrazones with Anilines. Adv. Synth. Catal. 2013 , 355 (11-12), 2417-2429. DOI : 10.1002/adsc.201300466

Abstract

We report the the copper(II) acetoacetonate [Cu(acac)2]/BINAP-catalyzed synthesis of arylamines from N-tosylhydrazones and anilines. A fine tuning of the reaction conditions was required to accomplish the cross-coupling successfully, including the ligands effect and the addition of small amounts of water. The characteristic feature of this protocol is its functional group compatibility and its chemoselectivity when various aminophenol derivatives were used. Taking into consideration the interest for this copper-reductive coupling in which no stoichiometric metal hydride reagent is employed, this can be considered as an alternative to the conventional reductive amination.


72. Roche M, Frison G, Brion J-D, Provot O, Hamze A, Alami M. Csp2–N Bond Formation via Ligand-Free Pd-Catalyzed Oxidative Coupling Reaction of N-Tosylhydrazones and Indole Derivatives. J Org Chem. 2013  ; 78:8485-95. DOI : 10.1021/jo401217x

Abstract

In a fresh approach to the synthesis of N-vinylazoles, a ligand-free palladium catalytic system was found to promote the Csp2–N bond-forming reaction utilizing N-tosylhydrazones and N-H azoles. This process shows functional group tolerance ; di-, tri-, and tetrasubstituted N-vinylazoles were obtained in high yields. Under the optimized conditions, the reaction proceeds with high stereoselectivity depending on the nature of the coupling partners.


71. Lawson, M. ; Hamze, A. ; Peyrat, J.-F. ; Bignon, J. ; Dubois, J. ; Brion, J.-D. ; Alami, M. An efficient coupling of N-tosylhydrazones with 2-halopyridines : synthesis of 2-alpha-styrylpyridines endowed with antitumor activity.
Org. Biomol. Chem. 2013, 11, 3664-73. DOI : 10.1210/me.2012-1328

Abstract

The synthesis of 2-α-styrylpyridines has been carried out by using the coupling of polyoxygenated N-tosylhydrazones with various 2-halopyridines. We demonstrated that the use of a catalytic amount of PdCl2(MeCN)2 in combination with a bidentate ferrocene DPPF or a monodentate alkyl phosphine tBu2MeP-HBF4 constitutes an efficient protocol for this coupling, providing 2-α-styrylpyridines 2 in satisfactory to good yields. Among several polyoxygenated derivatives 2 evaluated, compound 2aa was found to exhibit excellent antiproliferative and antimitotic activities comparable to that of the reference compound isoCA-4.


70. Roche, M. ; Hamze, A. ; Provot, O. ; Brion, J.-D. ; Alami, M. Synthesis of Ortho/Ortho′-Substituted 1,1-Diarylethylenes through Cross-Coupling Reactions of Sterically Encumbered Hydrazones and Aryl Halides.
J. Org. Chem. 2013, 78, 445-454. DOI : 10.1021/jo3023268

Abstract

The reactivity of sterically hindered N-tosylhydrazones 2 featuring ortho/ortho′-substituents on the aromatic ring with various ortho-, meta-, and para-substituted aryl halides 3 was investigated. To accomplish successfully this challenging coupling, fine-tuning of the reaction conditions were required. The newly established PdCl2(MeCN)2/Xphos/NaO-t-Bu/F-benzene system in a sealed tube is compatible with a broad spectrum of both coupling partners, regardless of their electronic and steric nature. This protocol has been applied successfully to the synthesis of a xanthene derivative.


69. Roche, M. ; Hamze, A. ; Brion, J.-D. ; Alami, M. Catalytic Three-Component One-Pot Reaction of Hydrazones, Dihaloarenes, and Amines.
Org. Lett. 2013, 15, 148–151. DOI : 10.1021/ol303194s

Abstract

A new three-component assembly reaction between N-tosylhydrazones, dihalogenated arenes, and various primary and secondary amines was devised, producing nitrogen-containing 1,1′-diarylethylenes in good yields. The two C–C and C–N bonds formed through this coupling have been catalyzed by a single Pd-catalyst in a one-pot fashion.


68. Hamze, A. ; Brion, J.-D. ; Alami, M.
Synthesis of 1,1-Diarylethylenes via Efficient Iron/Copper Co-Catalyzed Coupling of 1-Arylvinyl halides with Grignard Reagents.
Org. Lett. 2012, 14, 2782–2785. DOI : 10.1021/ol3010112

Highlighted in Organic Chemistry Portal
http://www.organic-chemistry.org/abstracts/lit3/663.shtm

Abstract

An efficient access to 1,1-diarylethylenes of biological interest by coupling functionalized aryl Grignard reagents and 1-arylvinyl halides in the presence of FeCl3/CuTC is described. This bimetallic system proved to be superior to the use of Fe or Cu catalyst alone. The synthetic utility of this protocol is illustrated in the field of steroid chemistry.


67. Rasolofonjatovo, E. ; Treguier, B. ; Provot, O. ; Hamze, A. ; Brion, J. D. ; Alami, M., A One-Pot Three-Step Synthesis of Z-Trisubstituted Olefins from Arylalkynes and Their Cyclization into 4-Aryl-2H-chromenes.
Eur. J. Org. Chem. 2012, (8), 1603-1615. DOI : 1615.10.1002/ejoc.201101735.

Abstract

Rapid and versatile access to (Z)-trisubstituted olefins 2 and their cyclization into 4-aryl-2H-chromenes 1 starting from arylalkynes 3 is described. In a one-pot fashion, alkynes 3 were first hydrated, then transformed into N-tosylhydrazones, and finally coupled with ortho-substituted aryl halides under palladium catalysis to give trisubstituted olefins 2 in good yields and very high to total Z selectivity. 1,1-Diarylolefins 2 having an ortho-OMOM (methoxymethoxy) substituent underwent rapid cyclization in the presence of p-toluensulfonic acid to give a variety of 4-aryl-2H-chromenes in good to excellent yields. This methodology was also successfully applied to the preparation of 5-aryl-2,3-dihydrobenzo[b]oxepine 4 from the required arylbutynol 3b.


66.Hamze, A. ; Treguier, B. ; Brion, J.-D. ; Alami, M. Copper-catalyzed reductive coupling of tosylhydrazones with amines : A convenient route to [small alpha]-branched amines.
Org. Biomol. Chem. 2011, 9, 6200-6204. DOI : 10.1039/C1OB05664F.

OBC 2011

This article was selected as an OBC HOT article, and was featured in the top 10% of the most highly cited articles published in the latest Impact Factor window (2011-2012)

Abstract

A general procedure for the reductive coupling of N-tosylhydrazones with amines in the presence of Cu(acac)2 and Cs2CO3 has been developed. The protocol is very effective and chemoselective with various primary and secondary aliphatic amines, aminoalcohols as well as azole derivatives to give α-branched amines in good yields.


65. Brachet, E. ; Hamze, A. ; Peyrat, J-F. ; Brion, J-D. ; Alami, A. Pd-Catalyzed Reaction of Sterically Hindered Hydrazones with Aryl Halides : Synthesis of Tetra-Substituted Olefins Related to isoCombretastatin A4.
Org. Lett. 2010, 4042–4045. DOI : 10.1021/ol101639g

Highlighted in Organic Chemistry Portal
http://www.organic-chemistry.org/abstracts/lit3/025.shtm

hydrazone etienne

Abstract

PdCl2(MeCN)2 in combination with dppp proved to be a powerful and efficient catalyst for the coupling of sterically hindered N-arylsulfonylhydrazones with aryl halides, thus providing a flexible and convergent access to tetrasubstituted olefins related to iso-combretastatin A4 in good yields. This new protocol has been applied successfully to the formal synthesis of biphenylisopropylidene 4-pyridine CYP17 inhibitor, 12b, of biological interest.


64. Rasolofonjatovo, E. ; Treguier, B. ; Provot, O. ; Hamze, A. ; Morvan, E. ; Brion, J. D. ; Alami, M. Palladium-catalyzed coupling of N-tosylhydrazones with ortho substituted aryl halides : synthesis of 4-arylchromenes and related heterocycles.
Tetrahedron Lett. 2011, 52, 1036-1040. doi:10.1016/j.tetlet.2010.12.093

Abstract

A convenient and efficient procedure for the synthesis of 4-arylchromenes, thiochromenes, and related heterocycles via a four step-sequence has been developed. The first three steps, which involve hydration of alkynes, hydrazones formation, and their Pd-coupling with ortho substituted aryl halides, furnished stereoselectively Z-trisubstituted olefins without any purification of the intermediates generated in each stage. These latter proved to be suitable precursors, in the last step, for the synthesis of the desired heterocycles of biological interest.


63. Tréguier B. ; Hamze, A. ; Provot O. ; Brion J-D. ; Alami M. Expeditious synthesis of 1,1-diarylethylenes related to isocombretastatin A-4 (isoCA-4) via palladium-catalyzed arylation of N-tosylhydrazones with aryl triflates.
Tetrahedron Lett. 2009, 6549-52. doi:10.1016/j.tetlet.2009.09.046

otf hydrazone

Abstract

A quick and efficient entry to 1,1-diarylethylenes via the reaction of polyoxygenated aryl N-tosylhydrazones with aryl triflates is described. The reaction employs the catalytic system Pd(OAc)2/XPhos, tBuOLi as the base and dioxane as the solvent. A variety of substituents on both the coupling partners’ hydrazones and triflates are tolerated. This procedure provides a complementary route to the existing methods for the access to 1,1-diarylethylenes of biological interest.

Med. Chem.

Front cover of issue 3 Org. Biomol. Chem. 2013, 11, 430-442. DOI : 10.1039/C2OB26253C


38. Lamaa, D. ; Lin, H.-P. ; Zig, L. ; Bauvais, C. ; Bollot, G. ; Bignon, J. ; Levaique, H. ; Pamlard, O. ; Dubois, J. ; Ouaissi, M. ; Souce, M. ; Kasselouri, A. ; Saller, F. ; Borgel, D. ; Jayat-Vignoles, C. ; Al-Mouhammad, H. ; Feuillard, J. ; Benihoud, K. ; Alami, M. ; Hamze, A. Design and Synthesis of Tubulin and Histone Deacetylase Inhibitor Based on iso-Combretastatin A-4. J. Med. Chem. 2018, 61, 6574-6591.
https://doi.org/10.1021/acs.jmedchem.8b00050

Abstract

Designing multitarget drugs have raised considerable interest due to their advantages in the treatment of complex diseases such as cancer. Their design constitutes a challenge in antitumor drug discovery. The present study reports a dual inhibition of tubulin polymerization and HDAC activity. On the basis of 1,1-diarylethylenes (isoCA-4) and belinostat, a series of hybrid molecules was successfully designed and synthesized. In particular compounds, 5f and 5h were proven to be potent inhibitors of both tubulin polymerization and HDAC8 leading to excellent antiproliferative activity.


37. Alami, M ; Brion, J-D ; Hamze, A ; Composés « multi-cibles » à activité inhibitrice des histone-désacétylases et de la polymérisation de la tubuline pour son utilisation dans le traitement du cancer. PCT/FR 2017/050032. PCT Int. Appl. (2017), WO 2017118822 A2 20170713


36. Naret, T. ; Bignon, J. ; Bernadat, G. ; Benchekroun, M. ; Levaique, H. ; Lenoir, C. ; Dubois, J. ; Pruvost, A. ; Saller, F. ; Borgel, D. ; Manoury, B. ; Leblais, V. ; Darrigrand, R. ; Apcher, S. ; Brion, J.-D. ; Schmitt, E. ; Leroux, F. R. ; Alami, M. ; Hamze, A. A fluorine scan of a tubulin polymerization inhibitor isocombretastatin A-4 : Design, synthesis, molecular modelling, and biological evaluation. Eur. J. Med. Chem. 2018, 143, 473-490.
https://doi.org/10.1016/j.ejmech.2017.11.055

Abstract

A novel series of tubulin polymerization inhibitors, based on fluorinated derivatives of isocombretastatin A-4 was synthesized with the goal of evaluating the effect of these compounds on the proliferative activity. The introduction of fluorine atom was performed on the phenyl ring or at the linker between the two aromatic rings. The modification of isoCA-4 by introduction of difluoromethoxy group at the para-position (3i) and substitution of the two protons of the linker by two fluorine atoms (3m), produced the most active compounds in the series, with IC50 values of 0.15–2.2 nM (3i) and 0.1–2 nM (3m) respectively, against a panel of six cancer cell lines. Compounds 3i and 3m had greater antiproliferative activity in comparison with references CA-4 or isoCA-4, the presence of fluorine group leads to a significant enhancement of the antiproliferative activity. Molecular docking studies indicated that compounds 3i and 3m occupy the colchicine binding site of tubulin. Evaluation of cytotoxicity in Human noncancer cells indicated that the compounds 3i and 3m were practically ineffective in quiescent peripheral blood lymphocytes, and may have a selective antiproliferative activity against cancer cells. Analyses of cell cycle distribution, and morphological microtubules organization showed that compound 3m induced G2/M phase arrest and, dramatically disrupted the microtubule network.


35. Khelifi, I. ; Naret, T. ; Renko, D. ; Hamze, A. ; Bernadat, G. ; Bignon, J. ; Lenoir, C. ; Dubois, J. ; Brion, J.-D. ; Provot, O. ; Alami, M., Design, synthesis and anticancer properties of IsoCombretaQuinolines as potent tubulin assembly inhibitors. Eur. J. Med. Chem. 2017, 127, 1025-1034.
http://dx.doi.org/10.1016/j.ejmech.2016.11.012

Abstract

The synthesis and evaluation of a new series of IsoCombretaQuinolines (IsoCoQuines) 2 with a 2-substituted-quinoline in place of the 3,4,5-trimethoxyphenyl ring present in isoCA-4 and CA-4 are described. Most of these compounds displayed a potent cytotoxic activity (IC50 < 10 nM) against a panel of five human cancer cell lines and inhibited tubulin assembly at a micromolar level. The most potent analogue 2b, having a 3-hydroxy-4-methoxyphenyl as B-ring, led to cell cycle arrest in G2/M phase. Docking studies indicate that 2b showed a binding mode comparable to those previously observed with quinazoline analogous (IsoCoQ) and with isoCA-4 at the colchicine binding site of tubulin.


34. Pautus, S. ; Alami, M. ; Adam, F. ; Bernadat, G. ; Lawrence, D. A. ; De Carvalho, A. ; Ferry, G. ; Rupin, A. ; Hamze, A. ; Champy, P. ; Bonneau, N. ; Gloanec, P. ; Peglion, J.-L. ; Brion, J.-D. ; Bianchini, E. P. ; Borgel, D., Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1. Sci Rep. 2016, 6, 36462.

Abstract

Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of the tissue type and urokinase type plasminogen activators. High levels of PAI-1 are correlated with an increased risk of thrombotic events and several other pathologies. Despite several compounds with in vitro activity being developed, none of them are currently in clinical use. In this study, we evaluated a novel PAI-1 inhibitor, annonacinone, a natural product from the Annonaceous acetogenins group. Annonacinone was identified in a chromogenic screening assay and was more potent than tiplaxtinin. Annonacinone showed high potency ex vivo on thromboelastography and was able to potentiate the thrombolytic effect of tPA in vivo in a murine model. SDS-PAGE showed that annonacinone inhibited formation of PAI-1/tPA complex via enhancement of the substrate pathway. Mutagenesis and molecular dynamics allowed us to identify annonacinone binding site close to helix D and E and β-sheets 2A.


33. Lawson, M. ; Rodrigo, J. ; Baratte, B. ; Robert, T. ; Delehouzé, C. ; Lozach, O. ; Ruchaud, S. ; Bach, S. ; Brion, J.-D. ; Alami, M. ; Hamze, A., Synthesis, biological evaluation and molecular modeling studies of imidazo[1,2-a]pyridines derivatives as protein kinase inhibitors.Eur. J. Med. Chem. 2016, 123, 105. http://dx.doi.org/10.1016/j.ejmech.2016.07.040

Abstract

We report here the synthesis, the biological evaluation and the molecular modeling studies of new imidazo[1,2-a]pyridines derivatives designed as potent kinase inhibitors. This collection was obtained from 2-aminopyridines and 2-bromoacetophenone which afforded final compound in only one step. The bioactivity of this family of new compounds was tested using protein kinase and ATP competition assays. The structure-activity relationship (SAR) revealed that six compounds inhibit DYRK1A and CLK1 at a micromolar range. Docking studies provided possible explanations that correlate with the SAR data. The most active compound 4c inhibits CLK1 (IC50 of 0.7 μM) and DYRK1A (IC50 of 2.6 μM).


32. Esber, N. ; Cherbonnier, C. ; Resche-Rigon, M. ; Hamze, A. ; Alami, M. ; Fagart, J. ; Loosfelt, H. ; Lombes, M. ; Chabbert-Buffet, N., Anti-Tumoral Effects of Anti-Progestins in a Patient-Derived Breast Cancer Xenograft Model. Horm. Cancer 2016, 7 (2), 137-147. DOI : 10.1007/s12672-016-0255-4

Abstract

Breast cancer is a hormone-dependent disease in which estrogen signaling targeting drugs fail in about 10 % due to resistance. Strong evidences highlighted the mitogen role of progesterone, its ligands, and the corresponding progesterone receptor (PR) isoforms in mammary carcinoma. Several PR antagonists have been synthesized ; however, some of them are non-selective and led to side or toxic effects. Herein, we evaluated the anti-tumor activity of a commercially available PR modulator, ulipristal acetate (UPA), and a new selective and passive PR antagonist “APR19” in a novel preclinical approach based on patient-derived breast tumor (HBCx-34) xenografted in nude mice. As opposed to P4 that slightly reduces tumor volume, UPA and APR19 treatment for 42 days led to a significant 30 % reduction in tumor weight, accompanied by a significant 40 % retardation in tumor growth upon UPA exposure while a 1.5-fold increase in necrotic areas was observed in APR19-treated tumors. Interestingly, PR expression was upregulated by a 2.5-fold factor in UPA-treated tumors while APR19 significantly reduced expression of both PR and estrogen receptor α, indicating a potential distinct molecular mechanism among PR antagonists. Cell proliferation was clearly reduced in UPA group compared to vehicle conditions, as revealed by the significant reduction in Ki-67, Cyclin D1, and proliferating cell nuclear antigen (PCNA) expression. Likewise, an increase in activated, cleaved poly(ADP-ribose) polymerase (PARP) expression was also demonstrated upon UPA exposure. Collectively, our findings provide direct in vivo evidence for anti-progestin-mediated control of human breast cancer growth, given their anti-proliferative and pro-apoptotic activities, supporting a potential role in breast cancer therapy.


31. Renko, D. ; Provot, O. ; Rasolofonjatovo, E. ; Bignon, J. ; Rodrigo, J. ; Dubois, J. ; Brion, J.-D. ; Hamze, A. ; Alami, M., Rapid synthesis of 4-arylchromenes from ortho-substituted alkynols : A versatile access to restricted isocombretastatin A-4 analogues as antitumor agents. Eur. J. Med. Chem. 2015, 90, 834-844.
>http://www.sciencedirect.com/science/article/pii/S0223523414011337]

Abstract

Potent anticancer 4-arylchromene agents 6, as restricted isoCA-4 analogues, were prepared with excellent yields by a rapid and versatile synthetic pathway. First, in the presence of PTSA in EtOH, a variety of arylalkynols 9 were transformed into substituted 4-chromanones 10 in a one pot procedure which include regioselective arylalkynols hydration, alcohol etherification, MOM-cleavage, and cyclization. Further palladium coupling reactions, using aryl halides and N-tosylhydrazones 11 gave access to a small library of functionalized 4-arylchromenes 6 with good yields. From this series of 4-arylchromenes, we have identified compound 6s which inhibit tubulin assembly at a micromolar level and demonstrate a remarkable nanomolar level of cytotoxicity against four human cancer cell lines. Docking studies showed that isoCA-4 and its restricted chromene analogue 6s adopt a similar positioning in the colchicine binding-site of tubulin.


30. Maksimenko, A ; Alami, M ; Zouhiri, F ; Brion, J.D ; Pruvost, A ; Mougin, J ; Hamze, A ; Boissenot, T ; Provt, O ; Desmaele, D ; Couvreur, P ; Therapeutic Modalities of Squalenoyl Nanocomposites in Colon Cancer : An Ongoing Search for Improved Efficacy. Acs Nano 2014, 8, 2018-2032. [DOI : 10.1021/nn500517a >http://pubs.acs.org/doi/abs/10.1021/nn500517a]

Abstract

Drug delivery of combined cytotoxic and antivascular chemotherapies in multidrug nanoassemblies may represent an attractive way to improve the treatment of experimental cancers. Here we made the proof of concept of this approach on the experimental LS174-T human colon carcinoma xenograft nude mice model. Briefly, we have nanoprecipitated the anticancer compound gemcitabine conjugated with squalene (SQ-gem) together with isocombretastatin A-4 (isoCA-4), a new isomer of the antivascular combretastatin A-4 (CA-4). It was found that these molecules spontaneously self-assembled as stable nanoparticles (SQ-gem/isoCA-4 NAs) of ca. 142 nm in a surfactant-free aqueous solution. Cell culture viability tests and apoptosis assays showed that SQ-gem/isoCA-4 NAs displayed comparable antiproliferative and cytotoxic effects than those of the native gemcitabine or the mixtures of free gemcitabine with isoCA-4. Surprisingly, it was observed by confocal microscopy that the nanocomposites made of SQ-gem/isoCA-4 distributed intracellularly as intact nanoparticles whereas the SQ-gem nanoparticles remained localized onto the cell membrane. When used to deliver these combined chemotherapeutics to human colon cancer model, SQ-gem/isoCA-4 nanocomposites induced complete tumor regression (by 93%) and were found superior to all the other treatments, whereas the overall tolerance was better than the free drug treatments. This approach could be applied to other pairs of squalenoylated nanoassemblies with other non-water-soluble drugs, thus broadening the application of the “squalenoylation” concept in oncology.


29. Farhat, M. ; Poissonnier, A. ; Hamze, A. ; Ouk-Martin, C. ; Brion, JD. ; Alami, M. ; Feuillard, J. ; Jayat-Vignoles, C. Reversion of apoptotic resistance of TP53-mutated Burkitt lymphoma B-cells to spindle poisons by exogenous activation of JNK and p38 MAP kinases. Cell Death & Disease 2014, 5, e1201. DOI : 10.1038/cddis.2014.150

Abstract

Defects in apoptosis are frequently the cause of cancer emergence, as well as cellular resistance to chemotherapy. These phenotypes may be due to mutations of the tumor suppressor TP53 gene. In this study, we examined the effect of various mitotic spindle poisons, including the new isocombretastatin derivative isoNH2CA-4 (a tubulin-destabilizing molecule, considered to bind to the colchicine site by analogy with combretastatin A-4), on BL (Burkitt lymphoma) cells. We found that resistance to spindle poison-induced apoptosis could be reverted in tumor protein p53 (TP53)-mutated cells by EBV (Epstein Barr virus) infection. This reversion was due to restoration of the intrinsic apoptotic pathway, as assessed by relocation of the pro-apoptotic molecule Bax to mitochondria, loss of mitochondrial integrity and activation of the caspase cascade with PARP (poly ADP ribose polymerase) cleavage. EBV sensitized TP53-mutated BL cells to all spindle poisons tested, including vincristine and taxol, an effect that was systematically downmodulated by pretreatment of cells with inhibitors of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. Exogenous activation of p38 and JNK pathways by dihydrosphingosine reverted resistance of TP53-mutated BL cells to spindle poisons. Dihydrosphingosine treatment of TP53-deficient Jurkat and K562 cell lines was also able to induce cell death. We conclude that activation of p38 and JNK pathways may revert resistance of TP53-mutated cells to spindle poisons. This opens new perspectives for developing alternative therapeutic strategies when the TP53 gene is inactivated.


28. Provot, O ; Hamze, A ; Peyrat, J-Fr ; et al. Discovery and Hit to Lead Optimization of Novel Combretastatin A-4 Analogues : Dependence of C-Linker Length and Hybridization. Anti-Cancer Agents Med. Chem. 2013, 13, 1614-1635. http://www.ingentaconnect.com/conte...

Abstract

We have synthesized a large variety of CA-4 analogues having a non-isomerizable C-linker between the A-and B-aromatic rings. Most of them displayed a nanomolar level of cytotoxicity against a panel of human cancer cell lines and inhibited tubulin polymerization at a micromolar level. Among all these compounds, the most interesting compounds were undoubtedly isoCA-4 and structural analogues 18-20 as well as benzil derivatives 11 which displayed a comparable level of activity than that of CA-4. Moreover, it has been demonstrated that these drugs arrested cancer cells in the G(2)/M phase of cellular cycle and induced apoptosis at very low concentrations. In vitro antivascular effects and the binding mode of the most active compounds was also investigated.


27. Aziz, J. ; Brachet, E. ; Hamze, A. ; Peyrat, J.F ; Bernadat, G. ; Morvan, E. ; Bignon, J. ; Wdzieczak-Bakala, J. ; Desravines, D. ; Dubois, J. ; Tueni, M. ; Yassine, A. ; Brion, J.D. ; Alami, M. Synthesis, biological evaluation, and structure–activity relationships of tri- and tetrasubstituted olefins related to isocombretastatin A-4 as new tubulin inhibitors. Org. Biomol. Chem. 2013, 11, 430-442. DOI : 10.1039/C2OB26253C

Front cover of issue 3

Abstract

The synthesis and structure–activity relationships associated with a series of 1,1-diarylethylene tubulin polymerization inhibitors 3 and 4 are described. The key step for their preparation involves a palladium-catalyzed coupling of N-arylsulfonylhydrazones with aryl halides, thus providing flexible and convergent access to tri- and tetrasubstituted 1,1-diarylolefins 3 and 4 related to isocombretastatin A-4 (isoCA-4). These compounds have been evaluated for tubulin polymerization inhibitory activity as well as for cytotoxic activity. The most potent compounds are 1,1-diaryl-2-methoxyethylenes 4b, 4d and 4e having a trisubstituted double bond. They exhibited good antiproliferative activity against various human cancer cell lines (GI50 = 8–80 nM). Compounds 4b and 4e strongly inhibited tubulin polymerization with IC50 values of 2 and 3 μM, respectively, and induced cell cycle arrest in the G2/M phase in the K562 cell line. Docking studies in the colchicine binding site of tubulin allowed identification of residues most likely to interact with these inhibitors and explain their potent anti-tubulin activity.


26. Khan, J. ; Tikad, A. ; Fay, M. ; Hamze, A. ; Fagart, J. ; Chabbert-Buffet, N. ; Meduri, G. ; Amazit, L. ; Brion, J-D. ; Alami, M. ; Lombes, M. ; Loosfelt, H. ; Rafestin-Oblin, M-E. A new strategy for selective targeting of progesterone receptor with passive antagonists. Mol. Endocrinol. (Baltimore, Md.) 2013, 27, 909-24. DOI : 10.1210/me.2012-1328

Abstract

Currently available progesterone receptor (PR) antagonists, such as mifepristone (RU486), lack specificity and display partial agonist properties, leading to potential drawbacks in their clinical use. Recent X-ray crystallographic studies have identified key contacts involved in the binding of agonists and antagonists with PR opening the way for a new rational strategy for inactivating PR. We report here the synthesis and characterization of a novel class of PR antagonists designed from such studies. The lead molecule, the homosteroid APR19, displays in vivo endometrial antiprogesterone activity. APR19 inhibits progesterone-induced PR recruitment and transactivation from synthetic and endogenous gene promoters. Importantly, it exhibits high PR selectivity with respect to other steroid hormone receptors, and is devoid of any partial agonist activity on PR target gene transcription. Two-hybrid and immunostaining experiments reveal that APR19-bound PR is unable to interact with either transcriptional coactivators (SRC1, SCR2) or corepressors (NCoR, SMRT), in contrast to RU486-PR complexes. APR19 also inhibits agonist-induced phosphorylation of serine 294 regulating PR transcriptional activity and turnover kinetics. In-silico docking studies based on the crystal structure of the PR ligand-binding domain show that, in contrast to progesterone, APR19 does not establish stabilizing hydrogen bonds with the ligand binding cavity, resulting in an unstable ligand-receptor complex. Altogether, these properties highly distinguish APR19 from RU486 and likely its derivatives, suggesting that it belongs to a new class of pure antiprogestins which inactivate PR by a passive mechanism. These specific PR antagonists open new perspectives for long term hormonal therapy.


25. Rasolofonjatovo, E. ; Provot, O. ; Hamze, A. ; Rodrigo, J. ; Bignon, J. ; Wdzieczak-Bakala, J. ; Lenoir, C. ; Desravines, D. ; Dubois, J. ; Brion, J.-D. ; Alami, M., Design, synthesis and anticancer properties of 5-arylbenzoxepins as conformationally restricted isocombretastatin A-4 analogs. Eur. J. Med. Chem. 2013, 62, 28-39.. DOI:10.1016/j.ejmech.2012.12.042

Abstract

A series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogs according to a convergent strategy using the coupling of N-tosylhydrazones with aryl iodides under palladium catalysis. The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range. In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations. Docking studies demonstrated that benzoxepin 6b adopt an orientation similar to that of isoCA-4 at the colchicine binding site on β-tubulin.


24. Rasolofonjatovo, E. ; Provot, O. ; Hamze, A. ; Rodrigo, J. ; Bignon, J. ; Wdzieczak-Bakala, J. ; Desravines, D. ; Dubois, J. ; Brion, J.-D. ; Alami, M., Conformationnally restricted naphthalene derivatives type isocombretastatin A-4 and isoerianin analogues : Synthesis, cytotoxicity and antitubulin activity. Eur. J. Med. Chem. 2012, 52, 22-32. DOI:10.1016/j.ejmech.2012.03.001

Abstract

A novel series of dihydronaphtalene, tetrahydronaphtalene and naphtalene derivatives as restricted analogues of isoCA-4 were designed, synthesized and evaluated for their anticancer properties. High cell growth inhibition against four tumour cell lines was observed at a nanomolar level with dihydronaphtalenes 1d, e and 1h, tetrahydronaphtalene 2c and naphtalene 3c. Structure–activity relationships are also considered. These compounds exhibited a significant inhibitory activity toward tubulin polymerization (IC50 = 2–3 μM), comparable to that of isoCA-4. The effect of the lead compounds 1e and 2c on the cancer cells tested was associated with cell cycle arrest in the G2/M phase. Docking studies reveal that these compounds showed a binding mode similar to those observed with their non-constraint isoCA-4 and isoerianin congeners.


23. Hamze, A. ; Rasolofonjatovo, E. ; Provot, O. ; Mousset, C. ; Veau, D. ; Rodrigo, J. ; Bignon, J. ; J-M Liu. ; Wdzieczak-Bakala, J. ; Thoret, S. ; Dubois, J. ; Brion, J.-D. ; Alami, M. B-Ring-Modified isoCombretastatin A-4 Analogues Endowed with Interesting Anticancer Activities. ChemMedChem 2011, 6, 2179-2191. DOI : 10.1002/cmdc.201100325

Abstract

A novel class of isocombretastatin A-4 (isoCA-4) analogues with modifications at the 3′-position of the B-ring by replacement with C-linked substituents was studied. Exploration of the structure–activity relationships of theses analogues led to the identification of several compounds that exhibit excellent antiproliferative activities in the nanomolar concentration range against H1299, MDA-MB231, HCT116, and K562 cancer cell lines ; they also inhibit tubulin polymerization with potency similar to that of isoCA-4. 1,1-Diarylethylenes 8 and 17, respectively with (E)-propen-3-ol and propyn-3-ol substituents at the 3′-position of the B-ring, proved to be the most active in this series. Both compounds led to the arrest of various cancer cell lines at the G2/M phase of the cell cycle and strongly induced apoptosis. Docking of compounds 8 and 17 in the colchicine binding site indicated that their C3′ substituents guide the positioning of the B-ring in a manner different from that observed for isoCA-4.


22. Messaoudi, S. ; Hamze, A. ; Provot, O. ; Tréguier, B. ; Rodrigo De Losada, J. ; Bignon, J. ; Liu, J.-M. ; Wdzieczak-Bakala, J. ; Thoret, S. ; Dubois, J. ; Brion, J.-D. ; Alami, M. Discovery of Isoerianin Analogues as Promising Anticancer Agents. ChemMedChem 2011, 6, 488-497. DOI : 10.1002/cmdc.201000456

isoerianin

This article was classified among the most frequently cited ones among those published in 2010 or 2011 (according to the ChemMedChem Journal)

Abstract

The cytotoxic activity of a series of 23 new isoerianin derivatives with modifications on both the A and B rings was studied. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. The most cytotoxic compound, isoerianin (3), strongly inhibits tubulin polymerization in the micromolar range. Moreover, isoerianin leads to G2/M phase cell-cycle arrest in H1299 and K562 cancer cells, and strongly induces apoptosis. Isoerianin also disrupts the vessel-like structures formed by human umbilical vein endothelial cells (HUVECs) in vitro, suggesting that this compound may act as a vascular disrupting agent. It clearly appears that in this compound series, the 1,1-ethane bridge encountered in isoerianin derivatives can replace the 1,2-ethane bridge of natural erianin with no loss of activity. This reinforces the bioisosteric replacement approach in the combretastatin series previously reported by our research group.


21. Rasolofonjatovo, E. ; Provot, O. ; Hamze, A. ; Brion, J-D. ; Alami, A. Regioselective Hydrostannation of Diarylalkynes Directed by a Labile ortho Bromine Atom : An Easy Access to Stereodefined Triarylolefins, Hybrids of Combretastatin A-4 andisoCombretastatin A-4. Eur. J. Med Chem 2010, 45, 3617-3626. DOI : 10.1016/j.ejmech.2010.05.007

triarylolefines

Abstract

A series of triarylolefins bearing the combretastatin A-4 and the isocombretastatin A-4 cores were synthesized and evaluated. The cooperative ortho-effect of a labile bromine atom in the regioselective hydrostannation of unsymmetrical diarylalkynes leading to stereodefined triarylolefins is presented.


20. Caldarelli, S. A. ; Boisbrun, M. ; Alarcon, K. ; Hamze, A. ; Ouattara, M. ; Salom-Roig, X. ; Maynadier, M. ; Wein, S. ; Peyrottes, S. ; Pellet, A. ; Calas, M. ; Vial, H. Exploration of potential prodrug approach of the bis-thiazolium salts T3 and T4 for orally delivered antimalarials. Bioorg. Med. Chem. Lett. 2010, 20, 3953-3956. doi:10.1016/j.bmcl.2010.05.001

prodrugs malaria

Abstract

We report here the synthesis and biological evaluation of a series of 37 compounds as precursors of potent antimalarial bis-thiazolium salts (T3 and T4). These prodrugs were either thioester, thiocarbonate or thiocarbamate type and were synthesized in one step by reaction of an alkaline solution of the parent drug with the appropriate activated acyl group. Structural variations affecting physicochemical properties were made in order to improve oral activity. Twenty-five of them exhibited potent antimalarial activity with IC50 lower than 7 nM against Plasmodium falciparum in vitro. Notably, 3 and 22 showed IC50 = 2.2 and 1.8 nM, respectively. After oral administration 22 was the most potent compound clearing the parasitemia in Plasmodium vinckei infected mice with a dose of 1.3 mg/kg.


19. Oblin, M. E. ; Alami, M. ; Brion, J.-D. ; Tikad, A. ; Hamze, A. ; Fay, M. ; Loosfelt, H. ; Lombes, M. ; Fagart, J. ; Khan, J. A. ; Chabert-Buffet, N. ; Turque, N. Progesterone receptor antagonists and use thereof. 2010, Brevet-Européen INSERM-CNRS-UPS ; EP N°10305484.7.


18. Messaoudi, S. ; Treguier, B. ; Hamze, A. ; Provot, O. ; Peyrat, J-F. ; De Losada, J-R. ; Liu, J-M. ; Bignon, J. ; Wdzieczak-Bakala J. ; Thoret, S. ; Dubois, J. ; Brion, J-D. ; Alami. M. Isocombretastatins A versus Combretastatins A : The Forgotten isoCA-4 Isomer as a Highly Promising Cytotoxic and Antitubulin Agent. J. Med. Chem., 2009, 52 (14), pp 4538–4542. DOI : 10.1021/jm900321u

isoCA4

Abstract

Herein is reported a convergent synthesis of isocombretastatins A, a novel class of potent antitubulin agents. These compounds having a 1,1-diarylethylene scaffold constitute the simplest isomers of natural Z-combretastatins A that are easy to synthesize without need to control the Z-olefin geometry. The discovery of isoCA-4 with biological activities comparable to that of CA-4 represents a major progress in this field.


17. Hamze, A. ; Giraud, A. ; Messaoudi, S. ; Provot, O. ; Peyrat, J-F. ; Bignon, J. ; Liu, J-M. ; Wdzieczak-Bakala, J. ; Thoret, S. ; Dubois, J. ; Brion, J-D. ; Alami, M. Synthesis, Biological Evaluation of 1,1-Diarylethylenes as a Novel Class of Antimitotic Agents. ChemMedChem, 2009, 4, 1912-1924. DOI : 10.1002/cmdc.200900290

isoFCA4

Abstract

The cytotoxic activities of 23 new isocombretastatin A derivatives with modifications on the B-ring were investigated. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. Compounds isoFCA-4 (2 e), isoCA-4 (2 k) and isoNH2CA-4 (2 s) were the most cytotoxic, and strongly inhibited tubulin polymerization with IC50 values of 4, 2 and 1.5 μm, respectively. These derivatives were found to be 10-fold more active than phenstatin and colchicine with respect to growth inhibition but displayed similar activities as tubulin polymerization inhibitors. In addition, cell cycle arrest in the G2/M phase and subsequent apoptosis was observed in three cancer cell lines when treated with these compounds. The disruptive effect of 2 e, 2 k and 2 s on the vessel-like structures formed by human umbilical vein endothelial cells (HUVEC) suggest that these compounds may act as vascular disrupting agents. Both compounds 2 k and 2 s have the potential for further prodrug modification and development as vascular disrupting agents for treatment of solid tumors.


16. Giraud, A. ; Provot, O. ; Hamze, A. ; Brion, J-D. ; Alami M. One-pot hydrosilylation–protodesilylation of functionalized diarylalkynes : a highly selective access to Z-stilbenes. Application to the synthesis of combretastatin A-4. Tetrahedron Lett. 2008, 49, 1107-1110. doi:10.1016/j.tetlet.2007.12.057

Abstract

An efficient stereoselective synthesis of Z-stilbenes has been developed from diarylalkynes via a new hydrosilylation–protodesilylation process. The scope and limitation of this method is presented to stereoselectively prepare a wide range of (Z)-stilbenes in a one-pot way is presented. A concise application to the preparation of combretastatin A-4 (CA-4), a vascular targeting agent inhibitor of tubulin polymerisation is described.


15. Mousset, C. ; Giraud, A. ; Provot, O. ; Hamze, A. ; Bignon, J. ; Liu, J.-M. ; Thoret, S. ; Dubois, J. ; Brion, J.-D. ; Alami, M. Synthesis and anti-tumor activity of benzils related to Combretastatin A-4. Bioorg. Med. Chem. Lett. 2008, 18, 3266-3271. doi:10.1016/j.bmcl.2008.04.053

Abstract

A series of benzil derivatives related to combretastatin A-4 (CA-4) have been synthesized by oxidation of diarylalkynes promoted by PdI2 in DMSO. Using this new protocol, 14 benzils were prepared in good to excellent yields and their biological activity has been delineated. Several benzils exhibited excellent antiproliferative activity : for example, 4j and 4k bearing the greatest resemblance to CA-4 and AVE-8062, respectively, were found to inhibit cell growth at the nanomolar level (20–50 nM) on four human tumor cell lines. Flow cytometric analysis indicates that these compounds act as antimitotics and arrest the cell cycle in G2/M phase. A cell-based assay indicated that compounds 4j and 4k displayed a similar inhibition of tubulin assembly with an IC50 value similar to CA-4. These results clearly demonstrated that the Z-double bond of CA-4 can be replaced by a 1,2-diketone unit without significant loss of cytotoxicity and inhibition of tubulin assembly potency.


14. Alami, M. ; Brion, J-D. ; Messaoudi, S. ; Hamze, A. ; Provot, O. ; Peyrat, J-F. ; Bignon, J. ; Bakala-Wdzieczak, J. ; Liu, J-M. ; Lallemand, J-Y. DHCA-4 et analogues : une nouvelles classe de composés cytotoxiques, inhibiteurs de la polymérisation de la tubuline et à propriétés anti-vasculaires. 2008. Brevet-CNRS-UPS N° FR 08/53694.


13. Alami, M. ; Brion, J.-D. ; Provot, O. ; Peyrat, J.-F. ; Messaoudi, S. ; Hamze, A. ; Giraud, A. ; Bignon, J. ; Bakala-Wdzieczak, J. ; Liu, J.-M. CA-4 et analogues : puissants cytotoxiques, inhibiteurs de la polymérisation de la tubuline. Brevet-CNRS-UPS N° 0754280 ; déposé le 04 avril 2007. Étendu à l’international sous le N° PCT N° EP2008/054118, PCT WO2008/122620 A1.


12. Hamze, A. ; Rubi, E. ; Arnal, P. ; Boisbrun, M. ; Carcel, C. ; Salom-Roig, X. ; Vial, H. ; Wein, S. ; Calas M. Antimalarial Activity of Mono and Bis-Thiazolium Interfering with Plasmodium falciparum Phospholipid Metabolism. J. Med. Chem. 2005, 48, 3639-3643.

Abstract

Three new series comprising 24 novel cationic choline analogues and consisting of mono- or bis (N or C-5-duplicated) thiazolium salts have been synthesized. Bis-thiazolium salts showed potent antimalarial activity (much superior to monothiazoliums). Among them, bis-thiazolium salts 12 and 13 exhibited IC50 values of 2.25 nM and 0.65 nM, respectively, against P. falciparum in vitro. These compounds also demonstrated good in vivo activity (ED50 ≤ 0.22 mg/kg), and low toxicity in mice infected by Plasmodium vinckei.


11. Salom-Roig, X. ; Hamze, A. ; Calas, M. ; Vial, H. J. Dual Molecules As New Antimalarials. Comb. Chem. High T. Scr., 2005, 8, 49-62(14).

Abstract

A new antimalarial pharmacological approach based on inhibition of the plasmodial phospholipid
metabolism has been developed. The drugs mimic choline structure and inhibit de novo phosphatidylcholine
biosynthesis. Three generations of compounds were rationally designed. Bisquaternary ammonium salts
showed powerful antimalarial activity, with IC50 in the nanomolar range. To remedy their low per os
absorption, bioisosteric analogues (bis-amidines) were designed and exhibited similar powerful activities.
Finally, the third generation compounds are bis-thiazolium salts and their non-ionic precursors : prodrugs,
which in vivo can lead to thiazolium drugs after enzymatic transformation.
The compounds are equally effective against multiresistant Plasmodium falciparum malaria. These molecules
exert a very rapid cytotoxic effect against malarial parasites in the very low nanomolar range and are active in
vivo against P. vinckei-infected mice, with ED50 lower than 0.2 mg/kg. They are able to cure highly infected
mice and, retain full activity after a single injection. They also retain full activity against P. falciparum and P.
cynomolgi in primate models with no recrudescence and at lower doses.
Compounds are accumulated in P.falciparum-infected erythrocyte, which ensures their potency and specificity.
Recently, we discovered that compounds also interact with malarial pigment enhancing the antimalarial effect.
It is quite likely that they are dual molecules, exerting their antimalarial activity via two simultaneous toxic
effects on the intracellular intraerythrocytic parasites. The current leader compounds are accessible in few steps
from commercial products. These crystalline molecules present a remarkable biological activity and low
toxicity which is promising for the development of a new antimalarial drug.

10. Touati-Jallabe, Y. ; Chiche, L. ; Hamze, A. ; Aumelas, A. ; Lisowski, V. ; Berthomieu, D. ; Martinez, J. ; Hernandez, J. F. Cyclic Peptides with a Diversely Substituted Guanidine Bridge : Solid-Phase Synthesis and Structural Analysis. Chem. Eur. J. 2011, 17, 2566-2570. DOI : 10.1002/chem.201003299

peptide cyclique

9. Touati-Jallabe, Y. ; Hamze, A. ; Berge, G. ; Verna, C. ; Lajoix, A.D. ; Fulerand, P. ; Martinez, J. ; Hernandez, J.F. Solid-phase synthesis of dipeptidic and pseudo-dipeptidic potential NOS inhibitors through a side-chain anchoring approach. Adv. Exp. Med. Biol. 2009, 611 : 133-134. DOI : 10.1007/978-0-387-73657-0_59https://springerlink3.metapress.com...


8. Hernandez, J. F. ; Touati-Jallabe, Y. ; Hamze, A. ; Berge, G. ; Vema, C. ; Martinez, J. Solid-phase synthesis of dipeptidomimefic substrate-based NOS inhibitors through a side-chain anchoring approach. Biopolymers. 2007, 88, 569-569.


7. Hamze, A. ; Gandreuil, C. ; Andureu, F. ; Fulcrand, P. ; Martinez, J. ; Hernandez, J-F. Solid phase synthesis of mono- or disubstituted arginine containing peptides from an isothiocitrulline precursor. Tetrahedron Lett. 2005, 46, 7349-7353. doi:10.1016/j.tetlet.2005.08.120


6. Hamze, A. ; Martinez, J. ; Hernandez, J.-F. Method for solid-phase peptide synthesis, in particular for peptides containing an arginine residue. Fr. Demande (2005), 122 pp. FR 286480 A1 20050708. Application : FR 2004-46 20040106. Demande internationale PCT/FR 05/00007 déposée le 4 janvier 2005. WO 2005/068488.


5. Hamze, A. ; Martinez, J. ; Hernandez, J.-F. Solid-phase Synthesis of Arginine-Containing Peptides and Fluorogenic Substrates Using a Side-Chain Anchoring Approach.J. Org. Chem. 2004, 69, 8394-8402.


4. Hamze, A. ; Fulcrand, P. ; Martinez, J. ; Hernandez, J. F., SOLID PHASE SYNTHESIS OF CYCLIC PEPTIDES WITH A GUANIDINE BRIDGE. J. Pept. Sci. 2004, 10, 130.


3. Hamze, A. ; Verna, C. ; Martinez, J. ; Hernandez, J. F., SOLID PHASE SYNTHESIS OF ARGININE-CONTAINING PEPTIDES AND THEIR INHIBITORS THROUGH A SIDE-CHAIN ANCHORING APPROACH. J. Pept. Sci. 2004, 10, 148.


2. Hamze, A. ; Hernandez, J.-F. ; Fulcrand, P. ; Martinez, J. Synthesis of Various 3-Substituted 1,2,4-oxadiazole-containing Fmoc-beta-3- and beta-aminoacids from Fmoc-Protected Aspartic Acid. J. Org. Chem. 2003, 68, 7316-7321.


1. Hamze, A. ; Hernandez, J-F. ; Martinez, J. Synthesis of R and S Enantiomers of Fmoc-protected 1,2,4-oxadiazole-containing beta-3-aminoacids from Fmoc-R-beta-Asp(OtBu)-OH. Tetrahedron Lett. 2003, 44, 6079-6082. doi:10.1016/S0040-4039(03)01471-0

H-M of Alkynes


62. Hamze, A. ; Veau, D. ; Provot, O. ; Brion, J.-D ; Alami, M. Palladium-Catalyzed Markovnikov Terminal Arylalkynes Hydrostannation : Application to the Synthesis of 1,1-Diarylethylenes. J. Org. Chem. 2009, 74, 1337–1340. DOI : 10.1021/jo802460z

HSn terminal alkyne

Abstract

The palladium-catalyzed hydrostannation of terminal arylalkynes was achieved. The regioselectivity of the H−Sn bond addition across the triple bond was found to be controlled by an ortho substituent on the aromatic ring, whatever its electronic nature, to give exclusively α-branched vinylstannanes 2 in accordance with Markovnikov’s rule. Subsequent Stille cross-coupling reaction of 2 with a variety of aryl halides readily provided, in moderate to good yields, a family of functionalized 1,1-diarylethylenes 1.


61. Hamze, A. ; Le Menez, P. ; Provot, O. ; Estelle Morvan, Brion, J-D. ; Alami, A. Regioselective Hydrostannation of Hindered Arylalkynes under Ortho-Directing Effects. Tetrahedron 2010, 66, 8698-8706. DOI 10.1016/j.tet.2010.09.010

HSn otho orthoprim

Abstract

Palladium-catalyzed hydrostannation reactions of ortho-disubstituted arylalkynes were achieved with total stereo- and regio-selectivity in THF at room temperature. The regioselectivity was found to be under the control of the ortho-substituents (ortho-directing effects, ODE) and pure α-vinylstannanes are produced in good yields and as single isomers regardless of the substituents’ nature. These hydrostannation α-products are precursors of choice for the preparation of stereo-defined triarylolefins.


60. Rasolofonjatovo, E. ; Provot, O. ; Hamze, A. ; Bignon, J. ; Thoret, S. ; Brion, JD. ; Alami, M. Regioselective hydrostannation of diarylalkynes directed by a labile ortho bromine atom : An easy access to stereodefined triarylolefins, hybrids of combretastatin A-4 and isocombretastatin A-4. EUR. J. MED. CHEM.  2010, 45 , 3617-3626.

10.1016/j.ejmech.2010.05.007

Abstract

A series of triarylolefins bearing the combretastatin A-4 and the isocombretastatin A-4 cores were synthesized and evaluated. The cooperative ortho-effect of a labile bromine atom in the regioselective hydrostannation of unsymmetrical diarylalkynes leading to stereodefined triarylolefins is presented.


59. Hamze, A. ; Provot, O. ; Brion, J.-D ; Alami, M. Platinum chloride/Xphos-catalyzed regioselective hydrosilylation of functionalized terminal arylalkynes. Tetrahedron Lett. 2008, 49, 2429-2431. doi:10.1016/j.tetlet.2008.02.060

Hsi tetlett

Abstract

Totally regioselective hydrosilylation of functionalized terminal arylalkynes was achieved using PtCl2 associated with the air-stable and bulky Xphos ligand with various silanes. Regardless of the electronic nature of the substituents on the aromatic ring, a single β-(E)-vinylsilane was obtained in excellent yields.


58. Hamze, A. ; Provot, O. ; Brion, J.-D ; Alami, M. Platinum chloride/Xphos-catalyzed regioselective hydrosilylation of functionalized terminal arylalkynes. J. Organomet. Chem. 2008, 693, 2789-2779. doi:10.1016/j.jorganchem.2008.05.028

HSi alcynes JOrgonmetChem

Abstract

Hydrosilylation of functionalized terminal arylalkynes with a variety of silanes catalyzed by PtCl2 or PtO2 in the presence of the air-stable and bulky Xphos ligand was investigated. Regardless of the electronic nature (electron withdrawing or donating group) and the position (o, m, p) of the substituents on the aromatic ring, a single β-(E)-styrylsilanes was obtained in good to excellent yields. The regioselectivity of the H-Si bond addition was found to be governed by steric effects induced by the bulky Xphos ligand. A dramatic regioselectivity was also observed when functionalized terminal aliphatic alkynes were employed as a substrate and in these cases regioisomeric β-(E)-vinylsilanes were generated with excellent selectivity.


57. Hamze, A. ; Provot, O. ; Alami, M. ; Brion, J-D. Regiocontrol of the Palladium-Catalyzed Tin Hydride Addition to Z-Enynols : Remarkable Z-Directing Effects. J. Org. Chem. 2007, 72, 3868-3874.

Highlighted in Synfacts. 2007, 13, 839-839. And
http://www.organic-chemistry.org/abstracts/lit1/683.shtm

Z enynes JOC

Abstract

Palladium-catalyzed hydrostannation of substituted Z- and E-enynols is discussed and compared. The regioselectivity of the H−Sn bond addition was found to be controlled by the geometry of the double bond (Z- or syn-directing effect) rather than the nature of its substituents. Exclusively α-vinyl stannanes were obtained from Z-enynols having various substituents on the double bond regardless of their electronic, steric, or chelating natures.


56 Hamze, A. ; Provot, O. ; Brion, J.-D ; Alami, M. Regiochemical Aspects of the Platinum Oxide Catalyzed Hydrosilylation of Alkynes. Synthesis, 2007, 13, 2025-2036.

(Special Topic : Platinum in organic synthesis) "invited paper").
>https://www.thieme-connect.com/ejournals/abstract/10.1055/s-2007-983742]

Abstract

The platinum-catalyzed hydrosilylation of unsymmetrical substituted arylalkynes with various hydrosilanes was investigated and the reaction selectivity of various para-substituted substrates was compared with that of their corresponding ortho-substituted derivatives. We showed that heterogeneous platinum oxide is a very efficient catalyst for such hydrosilylations and that H-Si bond addition proceeds in a stereoselective cis-fashion. The regioselectivity was found to be under the control of the ortho-substituent rather than due to the nature of the platinum catalyst. Aryl­alkynes with an ortho-substituent provided predominantly to exclusively α-selectivity, regardless of the electronic nature of the substituent. The precise contributions of steric, electronic, and coordinative factors controlling the regioselectivity of the H-Si bond addition are discussed.


55. Hamze, A. ; Provot, O. ; Alami, M. ; Brion, J-D. Platinum oxide catalyzed silylation of aryl halides with triethylsilane : an efficient synthetic route to functionalized aryltriethylsilanes. Org. Lett. 2006, 8, 931-934.
Highlighted in Synfacts. 2006, 5, 0495-0495.

Abstract

The first platinum-catalyzed selective silylation of aryl halides including aryl iodides and bromides having an electron-withdrawing group is described. The reaction takes place rapidly in NMP with triethylsilane as a silicon source and sodium acetate to provide functionalized aryltriethylsilanes in moderate to good yields. Heteroaromatic halides also were found to be readily silylated with triethylsilane. The procedure is chemoselective and tolerates a wide variety of functional groups.


54. Hamze, A. ; Provot, O. ; Alami, M. ; Brion, J-D. ; Platinum oxide catalyzed hydrosilylation of unsymmetrical internal aryl alkynes under ortho-substituent regiocontrol. Org. Lett. 2005, 7, 5625-5628.

Highlighted in Synfacts. 2006, 2, 0127-0127.

Abstract

PtO2- and H2PtCl6-catalyzed hydrosilylation of internal aryl alkynes having a para or an ortho substituent with triethylsilane are discussed and compared. The regioselectivity of the H−Si bond addition was found to be controlled by the ortho substituent rather than the nature of the platinum catalyst. Arylalkynes with an ortho substituent, regardless of its electronic nature, directed the silyl substituent mainly to the α-position. PtO2 proved to be a versatile and powerful catalyst compared to H2PtCl6 since it prevents the alkyne reduction.

Functionalizat° of Alkynes

53. Lin, H.-P. ; Ibrahim, N. ; Provot, O. ; Alami, M. ; Hamze, A. PtO2/PTSA system catalyzed regioselective hydration of internal arylalkynes bearing electron withdrawing groups. RSC Adv. 2018, 8, 11536-11542.
>http://dx.doi.org/10.1039/C8RA00564H

Abstract

A highly efficient PtO2/PTSA catalyst system for the hydration of a wide array of alkynes was developed. This method proved to be compatible with a large range of functional groups and the ketone products were obtained in high yields. The scope of this methodology was also extended to the synthesis of 3-aryl-isochromenones, -indoles and -benzofurans.


52. Yuan, L.-Z. ; Guangkoun, Z. ; Hamze, A. ; Alami, M. ; Provot, O., Chlorotrimethylsilane and Sodium Iodide : A Useful Combination for the Regioselective Deoxygenation of Arylalkyl-α-Diketones. Adv. Synth. Catal. 2017, 359, 2682.
>http://onlinelibrary.wiley.com/doi/10.1002/adsc.201700276/full]

Abstract

An efficient regioselective deoxygenation of arylalkyl‐1,2‐diketones by the couple trimethylsilylchloride/sodium iodide has been reported. In all cases, the deoxygenation takes place on the carbonyl group (Cα=O) proximal to the aromatic ring in methylene chloride at room temperature in good yields, furnishing a series of variously functionalized alkylbenzylketones. A large range of functional groups were well tolerated on the ortho‐, meta‐ and para‐positions by this mild process regardless of their electronic effects, demonstrating the general character of the present methodology. The trimethylsilylchloride/sodium iodide reducing process was also successfully applied to reduce α‐ketoacid and α‐ketoester substrates.


51. Yuan, L.-Z. ; Hamze, A. ; Alami, M. ; Provot, O., Synthesis of Substituted Benzils from Diarylalkyne Oxidation. Synthesis 2017, 49, 504.
>https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0036-1588608]

Abstract

In this review, the oxidation of diarylalkynes leading to functionalized benzils [di(het)aryl 1,2-diketones] is summarized. Some synthetic one-pot transformations of internal arylalkynes leading to the construction of heterocycles are presented.


50. Yuan, L.-Z. ; Renko, D. ; Khelifi, I. ; Provot, O. ; Brion, J.-D. ; Hamze, A. ; Alami, M., Selective Metal-Free Deoxygenation of Unsymmetrical 1,2-Dicarbonyl Compounds by Chlorotrimethylsilane and Sodium Iodide. Org. Lett. 2016, 18, 3238. DOI : 10.1021/acs.orglett.6b01491

Abstract

For the first time, the combination of chlorotrimethylsilane with NaI is used as a selective reducting system toward 1,2-diketones. This combination is successfully evaluated with several unsymmetrically benzil derivatives, which are reduced in good yields and with a total α-regioselectivity at room temperature. Identification of benzoin intermediates is achieved, and a mechanistic radical process is proposed.


49. Zhao, G. ; Yuan, L.-Z. ; Roudier, M. ; Peyrat, J.-F. ; Hamze, A. ; Brion, J.-D. ; Provot, O. ; Alami, M., A Convenient Metal-Free Synthesis of (E)-3-Styrylisocoumarins through Annulation of (E)-1,4-Diarylenynes. Synthesis 2016, 48, 3382.
>https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0035-1562501]

Abstract

A metal-free procedure for the cyclization of (E)-1,4-di­arylenynes is described. The reaction is promoted by a catalytic amount of p-toluenesulfonic acid and takes place in ethanol at 160 °C under microwave irradiation to afford stereoselectively (E)-3-styrylisocoumarins in good to excellent yields.


48. Coupling reactions between sp Carbon Centers. M. Alami, A. Hamze and S. Messaoudi, in Comprehensive Organic Synthesis II (Second Edition), ed. P. Knochel, Elsevier, Amsterdam, 2014, pp. 528. (Book chapter on invitation)
[>http:http://www.sciencedirect.com/science/article/pii/B9780080977423003153]


47. Jacubert, M. ; Hamze, A. ; Provot, O. ; Brion, J.-D ; Peyrat, J-F. ; Alami, M. p-Toluenesulfonic acid-mediated cyclization of o-(1-alkynyl)anisoles or thioanisoles : synthesis of 2-arylsubstituted benzofurans and benzothiophenes. Tetrahedron Lett. 2009, 50, 3588-3592. doi:10.1016/j.tetlet.2009.03.087

Highlighted in 50th Anniversary of Tetrahedron Lett.

APTS tet lett

Abstract

A variety of 2-arylbenzo[b]furans are readily prepared in good to excellent yields from the cyclization of o-(1-alkynyl)anisole derivatives under mild reaction conditions using an alcoholic media, p-toluenesulfonic acid under microwave irradiation. Starting from the corresponding o-(1-alkynyl)thioanisole derivatives, this friendly and environmentally free-metal procedure has been successfully extended to the synthesis of benzo[b]thiophenes. Relative to the electronic nature of the substituents, the selectivity of the cyclization reaction from differently o,o′-substituted diarylalkynes is also discussed.


46. Tréguier, B. ; Rasolofonjatovo, E. ; Hamze, A. ; Provot, O. ; Wdzieczak-Bakala, J. ; Dubois, J. ; Brion, J.-D. ; Alami, M. Synthesis of 2-(1-Phenylvinyl)benzofurans and 2-(1-Phenylvinyl)indoles as Antimitotic Agents by a Tandem Palladium-Assisted Coupling-Cyclization Reaction between 1-Phenylvinyl Iodides and ortho-Substituted Arylalkynes. Eur. J. Org. Chem. 2011, 4868-4876. DOI : 10.1002/ejoc.201100540

vinylbenzofuranes

Abstract

A series of functionalized 2-(1-phenylvinyl)benzofurans 2 and 2-(1-phenylvinyl)indoles 3 were prepared from 1-phenylvinyl iodides and silylated alkynes in a one-pot reaction. After a desilylation step, the Sonogashira coupling reaction between the resulting terminal alkynes and 1-phenylvinyliodide derivatives 6 gave enyne intermediates, which underwent a 5-endo-dig cyclization to afford 2-(1-phenylvinyl) heterocycles 2 and 3 in good yields. This method provides a rapid and efficient approach to build up benzoheterocycle-based isocombretastatin A-4 analogues of biological interest. From this series of compounds, the indoles 3o and 3r inhibited tubulin assembly at a micromolar level comparable to that of isoCA-4.


45. Le Menez, P. ; Hamze, A. ; Provot, O. ; Brion, J-D. ; Alami, A. Tributyltin Hydride in NMP-Promoted Reduction of Acid Chlorides to Aldehydes under Transition-Metal-Free Conditions. SYNLETT. 2010, 7, 1101-1103. DOI : 10.1055/s-0029-1219796

HSn RCOCl

Abstract

Tributyltin hydride in N-methyl-2-pyrrolidinone (NMP) was used for the partial reduction of various functionalized acid chlorides at room temperature. This transition-metal-free procedure allows the synthesis of a range of (hetero)aromatic- and aliphatic aldehydes in good to excellent yields.


44. Mousset, C. ; Provot, O. ; Hamze, A. ; Bignon, J. ; Brion, J-D. ; Alami, M. DMSO-PdI2 as a powerful oxidizing couple of alkynes into benzils : One-pot synthesis of nitrogen-containing 5- or 6-membred heterocycles. Tetrahedron, 2008, 64, 4287-4294. doi:10.1016/j.tet.2008.02.081

diketones

Abstract

PdI2 in DMSO promoted the oxidation of functionalized diarylalkynes into benzil derivatives in excellent yields. This new oxidation reaction was achieved with short reaction times and low loading of palladium catalyst. This efficient catalytic process has been applied successfully to the one-pot construction of a series of nitrogen-containing heterocycles of biological interest according to a tandem oxidation–nitrogen nucleophiles condensation–cyclization.


43. Le Bras, G. ; Hamze, A. ; Messaoudi, S. ; Provot, O. ; Le Calvez, P-B. ; Brion, J-D. ; Alami, M. Synthesis of isocoumarin via PTSA-catalyzed annulation of diarylalkynes. Synthesis, 2008, 1607–1611.

Highlighted in organic chemistry portal http://www.organic-chemistry.org/abstracts/lit2/118.shtm
DOI : 10.1055/s-2008-1072575

APTS Synthesis

Abstract

p-Toluenesulfonic acid (PTSA) in ethanol was used as a mild acid catalyst for the annulation of various functionalized diarylalkynes under microwave irradiation. This metal-free process allowed the synthesis of a range of 3-aryl-substituted isocoumarins in good yields.


42. Jacubert, M. ; Provot, O. ; Peyrat, J-F. ; Hamze, A. ; Brion, J-D. ; Alami, A. p-Toluenesulfonic acid-promoted selective functionalization of unsymmetrical arylalkynes : a regioselective access to various arylketones and heterocycles. Tetrahedron 2010, 66, 3775-3787. doi:10.1016/j.tet.2010.03.055

APTS tetrahedron

Abstract

Regioselective hydration of a wide range of internal alkynes has been afforded in high to good yields by using PTSA in EtOH. The scope of the reaction of alkynes has been delineated. Arylaliphatic alkynes and diarylalkynes were regioselectively hydrated in good to excellent yields and short reaction times when the reaction was achieved under microwave irradiation. Moreover, diarylalkynes, arylenynes as well as diaryldiynes bearing a methoxy- or a thiomethyl substituent on the ortho position underwent a regioselective 5-endo-dig-cyclization to give a variety of 2-aryl- and 2-styrylbenzofuran or benzothiphene derivatives. We believe that, this new environmentally metal-free procedure combined to microwave irradiation would be in importance in the search of green laboratory-scale synthesis.


41. Jacubert, M. ; Tikad, A. ; Hamze, A. ; Provot, O. ; Brion, J-D. ; Alami, A. MPHT Promoted Bromocyclization of Ortho Substituted Arylalkynes : Application to the Synthesis of 2-Substituted-3-Bromo-Benzofurans and -Benzo[b]thiophenes. Eur. J. Org. Chem. 2010, 23, 4492-4500. DOI : 10.1002/ejoc.201000529

MPHTenynes

Abstract

A convenient and general approach to the synthesis of 2-substituted 3-bromobenzofurans and -benzothiophenes was developed. The procedure is based on the cyclization of ortho-substituted arylalkynes in the presence of N-methylpyrrolidin-2-one hydrotribromide (MPHT) as a soft and easy-to-handle electrophilic brominating reagent. Under mild reaction conditions, MPHT promoted the bromocyclization of various enynes and diynes as well as arylalkynes to give 2-substituted 3-bromobenzofurans and -benzothiophenes in high to excellent yields. Subsequent functionalization by palladium-catalyzed coupling reactions at the C–Br bond afforded general access to 2,3-disubstituted benzofurans and benzothiophenes of biological interest.


40. Tikad, A. ; Hamze, A. ; Provot, O. ; Brion, J-D. ; Alami, A. Suzuki Coupling Reactions of (E)- and (Z)-Chloroenynes with Boronic Acids : Versatile Access to Functionalized 1,3-Enynes. Eur. J. Org. Chem. 2010, 4. 725-731. DOI : 10.1002/ejoc.200901137

boronic enyne

Abstract

A stereoselective, palladium-catalyzed, cross-coupling reaction between chloroenynes 4 and boronic acids was successfully developed. This procedure is general and provides desired functionalized enynes 1 in high yields. The scope and limitations of this new reaction are described.


39. Russo, O. ; Messaoudi, S. ; Hamze, A. ; Olivi, N. ; Peyrat, J-F. ; Brion, J-D ; Sicsic, S. ; Berque-Bestel, I. ; Alami, M ; Three-component one-pot process to propargylic amines and related amide and sulfonamide compounds : application to the construction of 2-(aminomethyl)benzofurans and indoles. Tetrahedron, 2007, 63, 10671-10683. doi:10.1016/j.tet.2007.07.096 |

one_pot_tetrah.gif

Abstract

An efficient palladium–copper-catalyzed three-component assembling of propargyl halides, aryl or heteroaryl halides, and secondary amines is described. A wide variety of tertiary propargylic amines were synthesized in good to excellent yields from easily accessible starting materials. This three-component assembling was also effective when using potassium phthalimide or di-tert-butyliminodicarbonate instead of secondary amines. Consequently, it provides a quick entry to N-protected propargylic amines suitable intermediates for the synthesis of primary and secondary propargylic amines. In a similar way, related compounds including propargylic amide, carbamate and sulfonamide derivatives were efficiently obtained. This catalytic domino three-component process has been applied successfully to the construction of functionalized 2-(aminomethyl)benzo[b]furan or indole derivatives of biological interest.

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