Heterocycles are common structural units in marketed drugs and in medicinal chemistry due to the central role they play in modern drug design. Indeed, heterocycles are useful scaffolds that can be decorated with various substituents in order to modulate lipophilicity, polarity, and hydrogen bonding capacity of molecules. These structural modulations may lead to improved pharmacological, pharmacokinetic, toxicological, and physicochemical properties of drug candidates. Heterocycles are also routinely used as bioisosteres for a variety of functional groups in drug candidates. Therefore, heterocycles represent privileged structures in the drug discovery process.
In order to find new potential lead compounds for therapeutic applications, we develop methodologies to access and structurally modulate heterocycle scaffolds such as [1,2,4]triazoles, diazepines, thiazoles and triazole-ketopiperazines.
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Vegetable Oil-based Hybrid Submicron Particles Loaded with JMV5038: A Promising Formulation against Melanoma
Abstract
The aim of this work was to carry out a preformulation study on JMV5038 as a new potent cytotoxic agent, and to develop its formulation within vegetable oil-based hybrid submicron particles (HNP) in order to obtain a versatile dosage form against melanoma. JMV5038 was first characterized through physico-chemical tests and it exhibited high melting point and logP value, an important pH-sensitivity that led to the formation of well-identified degradation products at low pH, as well as a substantial solubility value in silylated castor oil (ICO). Then, JMV5038-loaded HNP were formulated through a thermostabilized emulsion process based on the sol-gel cross-linking of ICO. They showed high loading efficiency and their in vitro release kinetic assessed in a biorelevant PBS/octanol biphasic system showed a constant sustained release over one month. The cytotoxic activity and cytocompatibility of HNP were evaluated on A375 melanoma cells and NIH 3T3 cells, respectively. JMV5038-loaded HNP exhibited a slightly enhanced cytotoxic activity of JMV5038 on melanoma cells while demonstrating their safety on NIH 3T3 cells. In conclusion, JMV5038-loaded HNP proved to be an efficient and safe drug subcutaneous delivery system that will be interesting to evaluate through preclinical studies.
Identification of Quinazolinone Analogs Targeting CDK5 Kinase Activity and Glioblastoma Cell Proliferation
Front Chem. 2020; 8: 691. https://doi.org/10.3389/fchem.2020.00691
Marion Peyressatre, Dominique Patomo Arama, Arthur Laure, Juan A. González-Vera, Morgan Pellerano, Nicolas Masurier, Vincent Lisowski, May C. Morris
Abstract
CDK5/p25 kinase plays a major role in neuronal functions, and is hyperactivated in several human cancers including glioblastoma and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s. CDK5 therefore constitutes an attractive pharmacological target. Since the successful discovery and development of Roscovitine, several ATP-competitive inhibitors of CDK5 and peptide inhibitors of CDK5/p25 interface have been developed. However, these compounds suffer limitations associated with their mechanism of action and nature, thereby calling for alternative targeting strategies. To date, few allosteric inhibitors have been developed for successful targeting of protein kinases. Indeed, although this latter class of inhibitors are believed to be more selective than compounds targeting the active site, they have proven extremely difficult to identify in high throughput screens. By implementing a fluorescent biosensor that discriminates against ATP-pocket binding compounds to screen for allosteric inhibitors that target conformational activation of CDK5, we have identified a novel family of quinazolinones. Characterization of these hits and several of their derivatives revealed their inhibitory potential toward CDK5 kinase activity in vitro and to inhibit glioblastoma cell proliferation. The quinazolinone derivatives described in this study are the first small molecules reported to target CDK5 at a site other than the ATP pocket, thereby constituting attractive leads for glioblastoma therapeutics and providing therapeutic perspectives for neurodegenerative diseases. These compounds offer alternatives to conventional ATP-competitive inhibitors or peptides targeting CDK5/p25 interface with the potential of bypassing their limitations.
Imidazopyridine-fused [1,3]diazepinones: modulations of positions 2 to 4 and their impacts on the anti-melanoma activity
J Enzyme Inhib Med Chem. 2020; 35(1): 935–949. https://doi.org/10.1080/14756366.2020.1748024
Paul Le Baccon-Sollier, Yohan Malki, Morgane Maye, Lamiaa M. A. Ali, Laure Lichon, Pierre Cuq, Laure-Anaïs Vincent, and Nicolas Masurier
Abstract
A series of 19 novel pyrido-imidazodiazepinones, with modulations of positions 2, 3 and 4 of the diazepine ring were synthesised and screened for their in vitro cytotoxic activities against two melanoma cell lines (A375 and MDA-MB-435) and for their potential toxicity against NIH-3T3 non-cancerous cells. Selected compounds were also evaluated on the NCI-60 cell line panel. The SAR study revealed that the molecular volume and the cLogP of compounds modified at position 2 were significantly correlated with the activity of these compounds on melanoma cell lines. Moreover, introduction of a heterocyclic group at position 2 or an azido-alkyl chain at position 4 led to compounds displaying a significantly different activity profile on the NCI-60 cell line panel, compared to phenyl-substituted compounds at position 2 of the diazepinone. This study provides us crucial information for the development of new derivatives active against melanoma.
Structure and dynamics of G protein-coupled receptor-bound ghrelin reveal the critical role of the octanoyl chain
Proc Natl Acad Sci U S A. 2019 Aug 27;116(35):17525-17530. doi: 10.1073/pnas.1905105116. Epub 2019 Aug 15
Ferré G, Louet M, Saurel O, Delort B, Czaplicki G, M’Kadmi C, Damian M, Renault P, Cantel S, Gavara L, Demange P, Marie J, Fehrentz JA, Floquet N, Milon A, Banères JL.
Abstract
Ghrelin plays a central role in controlling major biological processes. As for other G protein-coupled receptor (GPCR) peptide agonists, the structure and dynamics of ghrelin bound to its receptor remain obscure. Using a combination of solution-state NMR and molecular modeling, we demonstrate that binding to the growth hormone secretagogue receptor is accompanied by a conformational change in ghrelin that structures its central region, involving the formation of a well-defined hydrophobic core. By comparing its acylated and nonacylated forms, we conclude that the ghrelin octanoyl chain is essential to form the hydrophobic core and promote access of ghrelin to the receptor ligand-binding pocket. The combination of coarse-grained molecular dynamics studies and NMR should prove useful in improving our mechanistic understanding of the complex conformational space explored by a natural peptide agonist when binding to its GPCR. Such information should also facilitate the design of new ghrelin receptor-selective drugs.
Synthesis of Peptide–Adenine Conjugates as a New Tool for Monitoring Protease Activity
Eur. J. Org. Chem. January 2019: 176-183. doi:10.1002/ejoc.201801490.
Masurier, N. , Soualmia, F. , Sanchez, P. , Lefort, V. , Roué, M. , Maillard, L. T., Subra, G. , Percot, A. and El Amri, C.
Abstract
We took advantage of the powerful adenine SERS (Surface Enhanced Raman Spectroscopy) probe to design peptide–adenine conjugates as candidates for use as serine protease substrates. Whereas the direct introduction of the peptide sequence on the adenine exocyclic N6 amine gave an imidazopurinone derivative, the introduction of an aminoethyl linker between the adenine group and the peptide chain led to the expected candidate probes. These potential substrates were then evaluated for monitoring the hydrolytic activity of trypsin, used as a model protease, by HPLC and by SERS. We demonstrated that the Boc–VPR–adenine conjugate is a substrate of trypsin and constitutes a good starting point to design optimized substrates to monitor protease activity by SERS.
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
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.
