Category: heterocycles

Synthesis of [1,2,4]Triazolo[4,3- a]piperazin-6-ones: An Approach to the Triazole-Fused Ketopiperazine Scaffold

Org Lett. 2018 Jun 1;20(11):3250-3254. doi: 10.1021/acs.orglett.8b01112. Epub 2018 May 15.

Ben Haj Salah K, Legrand B, Bibian M, Wenger E, Fehrentz JA, Denoyelle S.

Abstract

A stereoconservative synthesis to access the triazole-fused ketopiperazine (TKP) scaffold is presented. This underexplored platform offers a wide range of structural modulations with several points of diversity and chiral centers. A series of [1,2,4]triazolo[4,3- a]piperazin-6-ones was synthesized from optically pure dipeptides. The methodology was then successfully applied to access the pyrrolo[1,2- a]triazolo[3,4- c]piperazin-6-one tricycle. Importantly, the crystal structures of representative TKPs confirmed that the configuration of the chiral centers was controlled during the synthetic route and facilitated description of the orientation of the substituents depending on their nature and position on the TKP scaffold.

Continuous flow ring-closing metathesis, an environmentally-friendly route to 2,5-dihydro-1H-pyrrole-3-carboxylates

Green Chemistry, Pages: Ahead of Print

M. Drop, X. Bantreil, K. Grychowska, G.U. Mahoro, E. Colacino, M. Pawlowski, J. Martinez, G. Subra, P. Zajdel, F. Lamaty

Astract

2,5-Dihydro-1H-pyrrole-3-carboxylates are important building blocks for the synthesis of high value pyrroles and pyrroloquinoline derivs. with interesting biol. activities. The use of continuous flow allowed us to perform a key synthetic step, namely ruthenium-catalyzed ring-closing metathesis, with a residence time of 1 min at 120 °C. Di-Me carbonate, a green solvent, was demonstrated for the first time to be an excellent solvent for this reaction in continuous flow. The continuous flow conditions proved to be general and the scale-up of this reaction was not only possible, but also highly efficient. Conversion of 10 g of diene was realized in 37 min under continuous flow, yielding the desired heterocycle in 91% yield.

Application of the ring-closing metathesis to the formation of 2-aryl-1H-pyrrole-3-carboxylates as building blocks for biologically active compounds

Tetrahedron, 2016, Volume: 72, Issue: 47, Pages: 7462-7469,  DOI: 10.1016/j.tet.2016.09.059

K. Grychowska, B. Kubica, M. Drop, E. Colacino, X. Bantreil, M. Pawlowski, J. Martinez, G. Subra, P. Zajdel, F. Lamaty 

Abstract

Ring-closing metathesis (RCM) is a powerful tool for the prepn. of cyclic org. compds. Yet, one of the major limitations of this method is the difficulty to prep. large quantities of target mols. Herein we describe a comprehensive study regarding the gram-scale synthesis of 2-aryl-1H-pyrrole-3-carboxylates based on the ring-closing metathesis of the corresponding β-amino esters as a key step. This study includes evaluation of solvent and catalyst as well as reaction kinetics on the RCM. After an aromatization step, this methodol. allowed for an efficient generation of variously substituted and unprecedented 2-aryl-1H-pyrrole-3-carboxylates in good yields and cost-effectiveness. The resulting mols. might serve as key building blocks for the generation of CNS-oriented compd. libraries.

Imidazopyridine-fused [1,3]-diazepinones part 2: Structure-activity relationships and antiproliferative activity against melanoma cells

European Journal of Medicinal Chemistry, 2016, Volume: 125, Pages: 1225-1234, DOI: 10.1016/j.ejmech.2016.11.023

V. Bellet, L. Lichon, D. P. Arama, A. Gallud,  V. Lisowski, L. T. Maillard, M. Garcia, J. Martinez, N. Masurier

Diapositive 1

Abstract

We recently described a pyrido-imidazodiazepinone deriv. which could be a promising hit compd. for the development of new drugs acting against melanoma cells. In this study, a series of 28 novel pyrido-imidazodiazepinones were synthesized and screened for their in vitro cytotoxic activities against the melanoma MDA-MB-435 cell line. Among the derivs., seven of them showed 50% growth inhibitory activity at 1 μM concn., and high selectivity against the melanoma cell line MDA-MB-435.

New trisubstituted 1,2,4-triazoles as ghrelin receptor antagonists

Bioorganic & Medicinal Chemistry Letters, 2015, Volume: 25, Issue: 1, Pages: 20-24, DOI: 10.1016/j.bmcl.2014.11.031

A. Blayo, M. Maingot, B. Aicher, C. M’Kadmi, P. Schmidt, G. Muller, M. Teifel, E. Gunther, D. Gagne, S. Denoyelle, J. Martinez, J.-A. Fehrentz

Abstract

Ghrelin receptor ligands based on a trisubstituted 1,2,4-triazole scaffold were recently synthesized and evaluated for their in vitro affinity for the GHS-R1a receptor and their biol. activity.  In this study, replacement of the α-aminoisobutyryl (Aib) moiety (a common feature present in numerous growth hormone secretagogues described in the literature) by arom. and heteroarom. groups was explored.  We found potent antagonists incorporating the picolinic moiety in place of the Aib moiety.  In an attempt to increase affinity and activity of our lead compd. 2, we explored the modulation of the pyridine ring.  Herein we report the design and the structure-activity relationships study of these new ghrelin receptor ligands.

Pyrido-imidazodiazepinones as a new class of reversible inhibitors of human kallikrein 7

European Journal of Medicinal Chemistry, 2015, Volume: 93, Pages: 202-213, DOI: 10.1016/j.ejmech.2015.02.008

D. P. Arama, F. Soualmia, V. Lisowski, J.-F. Longevial, E. Bosc, L. T. Maillard, J. Martinez, N. Masurier, C. El Amri

Abstract

The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrein family.  KLK7 is involved in skin homeostasis and inflammation.  Excess of KLK7 activity is also assocd. with tumor metastasis processes, esp. in ovarian carcinomas, prostatic and pancreatic cancers.  Development of Kallikrein 7 inhibitors is thus of great interest in oncol. but also for treating skin diseases.  Most of the developed synthetic inhibitors present several drawbacks such as poor selectivity and unsuitable physico-chem. properties for in vivo use.  Recently, the authors described a practical sequence for the synthesis of imidazopyridine-fused [1,3]-diazepines.  Here, the authors report the identification of pyrido-imidazodiazepinone core as a new potential scaffold to develop selective and competitive inhibitors of kallikrein-related peptidase 7.  Structure-activity relationships (SAR), inhibition mechanisms and selectivity as well as cytotoxicity against selected cancer cell lines were investigated.

Cross-Claisen condensation of N-Fmoc-amino acids – a short route to heterocyclic γ-amino acids

European Journal of Organic Chemistry, 2015, Volume: 2015, Issue: 10, Pages: 2262-2270, DOI: 10.1002/ejoc.201500012

L. Mathieu, C. Bonnel, N. Masurier, L. T. Maillard, J. Martinez, V. Lisowski

Abstract

4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) are a new class of constrained heterocyclic γ-amino acids built around a thiazole ring; these compds. are valuable as design mimics of the secondary structures of proteins such as helixes, β-sheets, turns, and β-hairpins.  We report herein a short and versatile chem. route to orthogonally protected ATCs.  The synthesis is centered on cross-Claisen condensations between N-Fmoc-amino acids and sterically hindered 1,1-dimethylallyl acetate.  The optimized conditions are compatible with aliph., arom., acidic, and basic amino acids.  The resulting N-Fmoc-β-keto ester intermediates were engaged in a two-step process to give ATCs in 45-90 % yields.  The synthetic protocol provides a highly flexible method for the introduction of a wide variety of lateral chains either on the γ-carbon atom or on the thiazole core of the γ-amino acids.

Solid-supported synthesis and 5-HT7/5-HT1A receptor affinity of arylpiperazinylbutyl derivatives of 4,5-dihydro-1,2,4-triazine-6-(1H)-one

Chemical Biology & Drug Design, 2015, Volume: 86, Issue: 4, Pages: 697-703,  DOI: 10.1111/cbdd.12539

K. Grychowska, N. Masurier, P. Verdie, G. Satala, A. J. Bojarski, J. Martinez,  M. Pawlowski, G. Subra, P. Zajdel

Abstract

A series of arylpiperazinylbutyl derivs. I [R1 = H, 2-OMe, 2-SMe, 2-F, 4-Cl, 2,3-diCl; R2 = Ph, 2-ClC6H4, cyclohexyl] of 4,5-dihydro-1,2,4-triazine-6(1H)-ones was designed and synthesized according to the new solid-supported methodol.  In this approach, triazinone scaffold was constructed from the fmoc-protected glycine.  The library representatives showed different levels of affinity for 5-HT7 and 5-HT1A receptors, among which compds. I [R1 = 2-SMe, 2-F; R2 = Ph and R1 = 2-OMe, 2-SMe, 2,3-diCl; R2 = cyclohexyl] were classified as dual 5-HT7/5-HT1A receptors ligands.  The structure-affinity relationship anal. revealed that receptor affinity and selectivity of the tested compds. depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of phenylpiperazine moiety.

Synthesis of Thieno[3,2-e][1,4]diazepin-2-ones: Application of an Uncatalysed Pictet-Spengler Reaction

European Journal of Organic Chemistry, 2015, Volume: 2015, Issue: 32, Pages: 7146-7153, DOI: 10.1002/ejoc.201500943

S. Denoyelle, G. Tambutet, N. Masurier, L. T. Maillard, J. Martinez, V. Lisowski

Abstract

A series of 5-substituted thieno[3,2-e][1,4]diazepin-2-ones was synthesized in four steps from Me 3-aminothiophene-2-carboxylate.  After the coupling of 3-aminothiophene with α-amino acids, the key final step that involves an uncatalyzed Pictet-Spengler reaction allowed the cyclization of the seven-membered diazepinone ring.  The reaction was first optimized and then exemplified in three different series (phenylalanine, alanine and proline) that led to 24 target diazepinones, which includes 19 optically pure diastereomers.

Imidazopyridine-fused [1,3]-diazepinones: Synthesis and antiproliferative activity

European Journal of Medicinal Chemistry, 2014, Volume: 75, Pages: 382-390,  DOI: 10.1016/j.ejmech.2014.01.044

A. Gallud, O. Vaillant, L.T. Maillard, D. Arama, J. Dubois, M. Maynadier, V. Lisowski, M. Garcia, J. Martinez, N. Masurier

Abstract

A series of 15 pyrido-imidazo-1,3-diazepin-5-ones and pyrido-1,3-diazepine-2,5-diones were synthesized and their anticancer activities were evaluated.  Among tested compds. on a cell lines panel, compd. I presents the best growth inhibition activity on 21 cell lines with a cytotoxic effect on MDA-MB-435 melanoma cells.  This compd. led to deep cell morphol. changes and revealed to be an inhibitor of the Hepatocyte progenitor kinase-like kinase (HGK), which is known to be implicated in the migration, adhesion and invasion of various tumor cells.