Synthesis and biological studies of new piperidino-1,2,3-triazole hybrids with 3-aryl isoxazole side chains

Appala Venkata Ramana Murthy; Vennu Narendar; Nangunoori Sampath Kumar; Pasula Aparna; Anagani Kanaka Durga Bhavani; Hélène Solhi; Rémy Le Guevel; Julie Roul; Fabien Gautier; Philippe Juin; Chada Raji Reddy; Paul Mosset; Nicolas Levoin; René Grée

doi:10.1016/j.bmcl.2021.128390

Synthesis and biological studies of new piperidino-1,2,3-triazole hybrids with 3-aryl isoxazole side chains

Bioorg Med Chem Lett. 2021 Nov 15:52:128390. doi: 10.1016/j.bmcl.2021.128390. Epub 2021 Sep 30.

Authors

Affiliations

¹ Chemveda Life Sciences India Pvt. Ltd., #B-11/1, IDA Uppal, Hyderabad-500039, Telangana, India; Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad-500 085, Telangana, India.
² Chemveda Life Sciences India Pvt. Ltd., #B-11/1, IDA Uppal, Hyderabad-500039, Telangana, India.
³ Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad-500 085, Telangana, India.
⁴ Osmania University, Department of Chemistry, Hyderabad 500007, Telangana, India.
⁵ Univ Rennes, Plateform ImPACcell, BIOSIT, F-35000 Rennes, France.
⁶ UMR 892 INSERM/6299 CNRS/Université de Nantes, Team 8 "Cell Survival and Tumor Escape in Breast Cancer", Institut de Recherche Thérapeutique de l'Université de Nantes, 8 Quai Moncousu, BP 70721, 44007 Nantes Cedex 1, France; Institut de Cancérologie de l'Ouest, Centre de Lutte contre le Cancer René Gauducheau, Boulevard Jacques Monod, 44805 Saint Herblain-Nantes Cedex, France.
⁷ UMR 892 INSERM/6299 CNRS/Université de Nantes, Team 8 "Cell Survival and Tumor Escape in Breast Cancer", Institut de Recherche Thérapeutique de l'Université de Nantes, 8 Quai Moncousu, BP 70721, 44007 Nantes Cedex 1, France.
⁸ Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
⁹ Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes), UMR 6226, F-35000 Rennes, France.
¹⁰ Bioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint Grégoire, France.

PMID: 34601029
DOI: 10.1016/j.bmcl.2021.128390

Abstract

A small library of new piperidine-triazole hybrids with 3-aryl isoxazole side chains has been designed and synthesized. Their cytotoxicity against a panel of seven cancer cell lines has been established. For the most promising compound, an IC₅₀ value of 3.8 μM on PUMA/Bcl-xL interaction in live cancer cells was established through BRET analysis. A rationale was proposed for these results through complete molecular modelling studies.

Keywords: BRET (Bioluminescence Resonance Energy Transfer); Bcl-xL (B-cell lymphoma-extra large); Cancer; Molecular modelling; PUMA (p53 upregulated modulator of apoptosis); Protein-protein interactions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Isoxazoles / chemistry
Isoxazoles / pharmacology*
Models, Molecular
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Structure-Activity Relationship
Triazoles / chemical synthesis
Triazoles / chemistry
Triazoles / pharmacology*

Substances

Antineoplastic Agents
Isoxazoles
Piperidines
Triazoles
piperidine