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

被引：65

作者：

Kumar, Atul ^{[1
,4
]}

Gupta, Garima ^{[1
]}

Bishnoi, Ajay Kumar ^{[1
,4
]}

Saxena, Ruchi ^{[2
]}

Saini, Karan Singh ^{[2
]}

Konwar, Rituraj ^{[2
]}

Kumar, Sandeep ^{[3
]}

Dwivedi, Anila ^{[2
,4
]}

机构：

[1] CSIR CDRI, Med & Proc Chem Div, Lucknow 226031, Uttar Pradesh, India

[2] CSIR CDRI, Div Endocrinol, Lucknow 226031, Uttar Pradesh, India

[3] CSM Med Univ, Dept Surg, Lucknow, Uttar Pradesh, India

[4] Acad Sci & Innovat Res AcSIR, New Delhi, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 04期

关键词：

Spirooxindoles; MDM2-p53; Bioisosteres; Breast cancer; Anticancer agents; MDM2; INHIBITOR; MULTIDRUG-RESISTANCE; P53; PATHWAY; AMG; 232; DISCOVERY; PROTEIN; CELLS; AMPLIFICATION; EXPRESSION; POTENT;

D O I：

10.1016/j.bmc.2014.12.037

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (c) 2015 Elsevier Ltd. All rights reserved.

引用

页码：839 / 848

页数：10

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