Raymond Houssin

Synthesis and activity of a new methoxytetrahydropyran derivative as dual cyclooxygenase-2/5-lipoxygenase inhibitor.

Dual COX-2/5-LO inhibitors are described as potential new therapeutic agents for inflammatory diseases. A surprisingly potent effect of a 5-LO pharmacophoric group on the COX-2 inhibition is presented as well as pharmacological in vitro and in vivo results.

Synthesis, Cytotoxicity, DNA Interaction, and Topoisomerase II Inhibition Properties of Novel Indeno[2,1-c]quinolin-7-one and Indeno[1,2-c]isoquinolin-5,11-dione Derivatives

Indeno[2,1- c]quinolin-7-ones and 6 H-indeno[1,2- c]isoquinolin-5,11-diones, bearing two cationic aminoalkyl side chains, were synthesized and evaluated for DNA interaction, topoisomerases inhibition, and cytotoxicity against human cancer cell lines. They displayed strong interaction with DNA and one indeno[1,2- c]isoquinolin-5,11-dione bearing side chains at N-6 and C-8 positions ( 6a) was a potent human topoisomerase II inhibitor with high cytotoxicity toward HL60 cells. An increased topoisomerase II inhibition is found with (a) a cationic aminoalkyl side chain at the C-8 rather than at the C-9 position, (b) a dimethylaminoethoxy side chain at the C-8 position introduced on the N-6 monosubstituted derivative, going with suppression of topoisomerase I poisoning, and (c) a dimethylaminoethyl rather than a dimethylaminopropyl side chain at the N-6 position. The cytotoxicity was only partially reduced when using the topoisomerase II-mutated mitoxantrone-resistant HL60/MX2 cell line, suggesting that additional targets are involved in their mechanism of action. These indeno[1,2- c]isoquinolin-5,11-dione derivatives represent new DNA-topoisomerase II interfering anticancer molecules.

Synthesis of Two New Thiazole-containing Oligopeptides as Potential DNA Minor Groove Binding Analogs of Netropsin

On the basis of previous studies on synthetic models related to the antibiotic agents Netropsin and Distamycin-A, the design and synthesis of two potential DNA minor groove ligands are described. Methia-Nt and Isothia-Nt were prepared by liquid-phase peptidic synthesis from the key compounds ethyl 2-amino-5-methylthiazole-4-carboxylate (1) and ethyl 2-aminothiazole-5-carboxylate (8) respectively

Depsipeptide analogs of the antitumor drug distamycin containing thiazole amino acids residues

Abstract Three compounds structurally related to the natural antiviral antitumor drugs netropsin and distamycin have been synthetized. They have been designed starting from 2-((aminomethyl)-thiazole-4 carboxylic acid, gly (Thz), a key element in the structure of highly cytotoxic natural peptides. In the structure of the three new compounds, this unit replaces N-methyl pyrrole carboxylic acid which seems to play a crucial role in DNA base sequence recognition by the parent natural agents.

Copper(II)- and iron(II)-complexes of methyl 2-(2-aminoethyl)-aminomethyl-pyridine-6-carboxyl-histidinate (AMPHIS), a peptide mimicking the metal-chelating moiety of bleomycin. An ESR investigation

Methyl 2-(2-aminoethyl)-aminomethyl-pyridine-6-carboxyl-histidinate (AMPHIS), a synthetic analogue of the chelating part of bleomycin (BLM), has been studied for its metal binding properties. Electron spin resonance parameters of AMPHIS-Cu(II) and BLM-Cu(II) have been found to be closely similar likewise spectra of oxygen radicals spin-adducts induced by AMPHIS-Fe(II)-O2 and BLM-Fe(II)-O2 systems. Thus, AMPHIS could constitute a very useful tool for the study of BLM mode of action.

2,6-Diphenylthiazolo[3,2-b][1,2,4]triazoles as telomeric G-quadruplex stabilizers.

The design and synthesis of 2,6-diphenylthiazolo[3,2-b][1,2,4]triazoles characterized by a large aromatic building block bearing cationic side chains are reported. These molecules are evaluated as telomeric G-quadruplex stabilizers and for their selectivity towards duplex DNA by competition experiments. Two compounds (14a, 19) were found active with high selectivity for telomeric G-quadruplex over duplex DNA.

Synthetic model of a bleomycin metal complex

A simple analogue of the metal-complexing pseudopeptide bleomycin has been synthesised and the e.s.r. spectral parameters of its CuII-complex were found to correspond to the characteristics of the CuII-bleomycin system.

Novel potent substance P and neurokinin A receptor antagonists. Conception, synthesis and biological evaluation of indolizine derivatives.

Exploration of SAR around dual NK(1)/NK(2) antagonist Cbz-Gly-Leu-Trp-OBzl(CF(3))(2) and its derivatives disclosed the essential requirements for more potent dual NK(1)/NK(2) binding. We report here the synthesis and the biological properties of a novel series of indolizine including pharmacophoric elements.

Synthesis of an azabicycloalkane amino acid scaffold as potential rigid dipeptide mimetic

Abstract Short syntheses are presented of the pseudo-dipeptide (3 S ,6 S )-6-[(benzyloxy)carbonyl]amino-5-oxo-1,2,3,5,6,7-hexahydro-3-indolizinecarboxylic acid ( 1a ) and of its (3 S ,6 R ) diastereoisomer ( 1b ). The key step involves adding vinylogous β-enaminoester derived from pyroglutamic acid on an acrylate derivative. The 6,5-fused bicyclic lactam obtained may be viewed as a conformationally restricted Ala-Pro mimetic.

Acces aux dinitro-2,4 diarylamines par substitution nucleophile SNAr-limites de la reaction et application a la synthese de cyanocarbazoles

Abstract 3-Cyanocarbazoles, key-intermediates in the total synthesis of pyrido [4,3- b ] carbazoles, have been obtained starting from easily available materials and involving the cyclization of diarylamines. The first step of the preparation consists in a S N Ar reaction between a para substituted aniline and a chloro- (or bromo)-dinitrobenzene. This nucleophilic substitution has been found to be hindered by the steric effect of a methyl group, explained in terms of inhibition of resonance and confirmed by X-ray determination.