title: Design and synthesis of new bioisosteres of spirooxindoles (MI-63/219) as anti-breast cancer agents.
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.
authors.affiliation: 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.
authors.forename: Atul
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India.
authors.forename: Garima
authors.initials: G
authors.lastname: Gupta
authors.affiliation: 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.
authors.forename: Ajay Kumar
authors.initials: AK
authors.lastname: Bishnoi
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Saxena
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India.
authors.forename: Karan Singh
authors.initials: KS
authors.lastname: Saini
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Konwar
authors.affiliation: Department of Surgery, CSM Medical University, Lucknow, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.affiliation: 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.
authors.forename: Anila
authors.initials: A
authors.lastname: Dwivedi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D008819:Mice, Nude; D000078183:Oxindoles; D060066:Protein Interaction Maps / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C022960:2-oxindole; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Anticancer agents; Bioisosteres; Breast cancer; MDM2–p53; Spirooxindoles