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.
Appala Venkata Ramana Murthy  1 ,  Vennu Narendar  2 ,  Nangunoori Sampath Kumar  2 ,  Pasula Aparna  3 ,  Anagani Kanaka Durga Bhavani  4 ,  Hélène Solhi  5 ,  Rémy Le Guevel  5 ,  Julie Roul  6 ,  Fabien Gautier  6 ,  Philippe Juin  7 ,  Chada Raji Reddy  8 ,  Paul Mosset  9 ,  Nicolas Levoin  10 ,  René Grée  9
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.