Synthesis and Optimization of New 3,6-Disubstitutedindole Derivatives and Their Evaluation as Anticancer Agents Targeting the MDM2/MDMx Complex

被引：3

作者：

Rezk, Mohamed Salah ^{[1
,2
]}

Abdel-Halim, Mohammad ^{[1
]}

Keeton, Adam ^{[3
]}

Franklin, Derek ^{[4
,5
,6
]}

Bauer, Matthias ^{[7
]}

Boeckler, Farnk Michael ^{[7
]}

Engel, Matthias

Hartmann, Rolf Wolfgang ^{[2
]}

Zhang, Yanping ^{[4
,5
,6
]}

Piazza, Gary Anthony ^{[3
]}

Abadi, Ashraf Hassan ^{[1
]}

机构：

[1] German Univ Cairo, Fac Pharm & Biotechnol, Dept Pharmaceut Chem, Cairo 11835, Egypt

[2] Univ Saarland, Dept Pharmaceut & Med Chem, D-66123 Saarbrucken, Germany

[3] Univ S Alabama, Mitchell Canc Inst, Dept Oncol Sci & Pharmacol, Drug Discovery Res Ctr, Mobile, AL 36604 USA

[4] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC 27514 USA

[5] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA

[6] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA

[7] Univ Tubingen, Dept Pharmaceut & Med Chem, Inst Pharmaceut Sci, D-72076 Tubingen, Germany

来源：

CHEMICAL & PHARMACEUTICAL BULLETIN | 2016年 / 64卷 / 01期

关键词：

indole derivative; p53; murine double minute 4 (MDM4); murine double minute 2 (MDM2); STRUCTURE-BASED DESIGN; P53; PATHWAY; CANCER-THERAPY; IN-VIVO; MDM2; ACTIVATION; INHIBITORS; GROWTH; POTENT; DOMAIN;

D O I：

10.1248/cpb.c15-00608

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Twelve derivatives of the general formula 3-substituted-6-chloroindoles were synthesized and tested for their growth inhibitory effects versus p53(+/+) colorectal cancer HCT116 and its p53 knockout isogenic cells; colorectal cancer cell p53(-/-) SW480; the lung cancer cell line p53(-/-) H1299; mouse embryonic fibroblasts (MEF) p53(+/+) and its p53 knockout isogenic cells. The compounds were also evaluated for their ability to induce p53 nuclear translocation and binding to murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Of these, compound 5a was the most active in inhibiting the growth of cells, with selectivity towards the p53(+/+) cell lines, and it showed stronger binding to MDM4 rather than MDM2. The activity profile of compound 5a is strongly similar to that of Nutlin-3.

引用

页码：34 / 41

页数：8

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