2. Academic Validation
  3. Design and synthesis of new bioisosteres of spirooxindoles (MI-63/219) as anti-breast cancer agents

Design and synthesis of new bioisosteres of spirooxindoles (MI-63/219) as anti-breast cancer agents

  • Bioorg Med Chem. 2015 Feb 15;23(4):839-48. doi: 10.1016/j.bmc.2014.12.037.
Atul Kumar 1,  Garima Gupta 2,  Ajay Kumar Bishnoi 3,  Ruchi Saxena 4,  Karan Singh Saini 4,  Rituraj Konwar 4,  Sandeep Kumar 5,  Anila Dwivedi 6
Affiliations

Affiliations

  • 1 Academy of Scientific & Innovative Research (AcSIR), New Delhi, India; Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India. Electronic address: dratulsax@gmail.com.
  • 2 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India.
  • 3 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India; Academy of Scientific & Innovative Research (AcSIR), New Delhi, India.
  • 4 Endocrinology Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India.
  • 5 Department of Surgery, CSM Medical University, Lucknow, India.
  • 6 Academy of Scientific & Innovative Research (AcSIR), New Delhi, India; Endocrinology Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India.
PMID: 25618595 DOI: 10.1016/j.bmc.2014.12.037
Abstract

We report herein the design and synthesis of bioisosteres of spirooxindole (MI-63/219), a small-molecule inhibitors of the MDM2-p53 interaction as anti-breast Cancer agents. Compound 5b has been exhibiting significant anti-proliferative activity in nude mice bearing MCF-7 xenograft tumor. The compound 5b was found to act via modulation of MDM2 and p53 expression in breast Cancer cells expressing wild type p53. Compound 5b stimulated p53 activation, caused modulation of downstream effectors p21, pRb, and cyclin D1 which regulate cell cycle. Thus, compound triggered G1-S phase cell cycle arrest, which was evident by flow cytometric analysis of treated breast Cancer cells. Thus, compound 5b restores the p53 function, which triggers molecular events consistent with cell cycle arrest at G1/S phase.

Keywords

Anticancer agents; Bioisosteres; Breast cancer; MDM2–p53; Spirooxindoles.

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