Category: 2015

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.

Ghrelin receptor conformational dynamics regulate the transition from a preassembled to an active receptor:Gq complex

Proceedings of the National Academy of Sciences of the United States of America, 2015, Volume: 112, Issue: 5, Pages: 1601-1606, DOI: 10.1073/pnas.1414618112

M. Damian, S. Mary, M. Maingot, C. M’Kadmi, D. Gagne, J.-P. Leyris,  S. Denoyelle, G. Gaibelet, L. Gavara, M. Costa, D. Perahia, E. Trinquet,  B. Mouillac, S. Galandrin, C. Gales, J.-A. Fehrentz, N. Floquet, J. Martinez,  J. Marie, J.-L. Baneres

Abstract

How G protein-coupled receptor conformational dynamics control G protein coupling to trigger signaling is a key but still open question.  We addressed this question with a model system composed of the purified ghrelin receptor GHS-R1a assembled into lipid disks.  Combining receptor labeling through genetic incorporation of unnatural amino acids, lanthanide resonance energy transfer, and normal mode analyses, we directly demonstrate the occurrence of two distinct receptor:Gq assemblies with different geometries whose relative populations parallel the activation state of the receptor.  The first of these assemblies is a preassembled complex with the receptor in its basal conformation.  This complex is specific of Gq and is not obsd. with Gi.  The second one is an active assembly in which the receptor in its active conformation triggers G protein activation.  The active complex is present even in the absence of agonist, in a direct relationship with the high constitutive activity of the ghrelin receptor.  These data provide direct evidence of a mechanism for ghrelin receptor-mediated Gq signaling in which transition of the receptor from an inactive to an active conformation is accompanied by a rearrangement of a preassembled receptor:G protein complex, ultimately leading to G protein activation and signaling.

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.

A new way to silicone-based peptide polymers

Angewandte Chemie, 2015, Volume: 54, Issue: 12, Pages: 3778-3782,  DOI: 10.1002/anie.201411065

S. Jebors, J. Ciccione, S. Al-Halifa, B. Nottelet, C. Enjalbal, C. M’Kadmi,  M. Amblard, A. Mehdi, J. Martinez, G. Subra

Abstract

We describe a new class of silicone-contg. peptide polymers obtained by a straightforward polymn. in water using tailored chlorodimethylsilyl peptide blocks as monomeric units.  This general strategy is applicable to any type of peptide sequences, yielding linear or branched polymer chains composed of well-defined peptide sequences.

In vitro and in vivo application of radiolabeled gastrin-releasing peptide receptor ligands in breast cance

Journal of Nuclear Medicine, 2015, Volume: 56, Issue: 5, Pages: 752-757, DOI: 10.2967/jnumed.114.153023

S. U. Dalm, J. W. M. Martens, A. M. Sieuwerts, C. H. M. van Deurzen, S. J. Koelewijn, E. de Blois, T. Maina, B. A. Nock, L. Brunel, J.-A. Fehrentz, J. Martinez, M. de Jong, M. Melis

Abstract

Breast cancer (BC) consists of multiple subtypes defined by various mol. characteristics, for instance, estrogen receptor (ER) expression.  Methods for visualizing BC include mammog., MR imaging, ultrasound, and nuclear medicine-based methods such as 99mTc-sestamibi and 18F-FDG PET, unfortunately all lacking specificity.  Peptide receptor scintigraphy and peptide receptor radionuclide therapy are successfully applied for imaging and therapy of somatostatin receptor-expressing neuroendocrine tumors using somatostatin receptor radioligands.  On the basis of a similar rationale, radioligands targeting the gastrin-releasing peptide receptor (GRP-R) might offer a specific method for imaging and therapy of BC.  The aim of this study was to explore the application of GRP-R radioligands for imaging and therapy of BC by introducing valid preclin. in vitro and in vivo models.  Methods: GRP-R expression of 50 clin. BC specimens and the correlation with ER expression was studied by in vitro autoradiog. with the GRP-R agonist 111In-AMBA.  GRP-R expression was also analyzed in 9 BC cell lines applying 111In-AMBA internalization assays and quant. reverse transcriptase polymerase chain reaction.  In vitro cytotoxicity of 111Lu-AMBA was detd. on the GRP-R-expressing BC cell line T47D.  SPECT/CT imaging and biodistribution were studied in mice with s.c. and orthotopic ER-pos. T47D and MCF7 xenografts after injection of the GRP-R antagonist 111In-JMV4168.  Results: Most of the human BC specimens (96%) and BC cell lines (6/9) were found to express GRP-R.  GRP-R tumor expression was pos. (P = 0.026, Χ2(4) = 12,911) correlated with ER expression in the human BC specimens.  Treatment of T47D cells with 10-7 M/50 MBq of 111Lu-AMBA resulted in 80% redn. of cells in vitro.  Furthermore, s.c. and orthotopic tumors from both BC cell lines were successfully visualized in vivo by SPECT/CT using 111In-JMV4168; T47D tumors exhibited a higher uptake than MCF7 xenografts.  Conclusion: Targeting GRP-R-expressing BC tumors using GRP-R radioligands is promising for nuclear imaging and therapy, esp. in ER-pos. BC patients.

Straightforward strategy to substitute amide bonds by 1,2,3-triazoles in peptaibols analogs using Aibψ[Tz]-Xaa dipeptides

Biopolymers, 2015, Volume: 104, Issue: 5, Pages: 611-621, DOI: 10.1002/bip.22641

K. Ben Haj Salah, B. Legrand, S. Das, J. Martinez, N. Inguimbert

Abstract

Structured peptides have gained more attention over time because of their biol. properties, biocompatibility and ability to act as modulators of protein/protein interactions, antibiotics, analgesics, immunosuppressants, and imaging agents to cite a few relevant applications.  However, their poor bioavalability due in part to the susceptibility of the peptide bond to proteolytic cleavages has often impaired their development and considerably limited their therapeutic use.  To circumvent these problems, many efforts have been undertaken to discover stable amide bond mimics resistant to proteolytic degrdn.  Among them the 1,2,3-triazole (Tz) moiety has emerged as a highly stable analog of the trans-peptide bond as a means of generating bioactive peptides.  Here we report a convenient approach to readily substitute amide bonds by triazole rings in Aib-contg. peptides using Aibψ[Tz]-Xaa dipeptide-like units.  We have defined their application in solid phase synthesis and generated short model peptide sequences to study the impact of triazole incorporation on their conformations in soln. by CD and NMR spectroscopies.  © 2015 Wiley Periodicals, Inc.  Biopolymers (Pept Sci) 104: 611-621, 2015.

Turning Peptide Sequences into Ribbon Foldamers by a Straightforward Multicyclization Reaction

Angewandte Chemie, International Edition, 2015, Volume: 54, Issue: 47, Pages: 13966-13970, DOI: 10.1002/anie.201506955

V. Martin, B. Legrand, L. L. Vezenkov, M. Berthet, G. Subra, M. Calmes, J-L. Bantignies, J. Martinez, M. Amblard

Abstract

The conformational control of mol. scaffolds allows the display of functional groups in defined spatial arrangement.  This is of considerable interest for developing fundamental and applied systems in both the fields of biol. and material sciences.  Peptides afford a large diversity of functional groups, and peptide synthetic routes are very attractive and accessible.  However, most short peptides do not possess well-defined secondary structures.  Herein, we developed a simple strategy for converting peptide sequences into structured γ-lactam-contg. oligomers while keeping the amino acids side chain diversity.  We showed the propensity of these mols. to adopt ribbon-like secondary structures.  The periodic distribution of the functional groups on both sides of the ribbon plane is encoded by the initial peptide sequence.

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.