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

Mohamed Salah Rezk; Mohammad Abdel-Halim; Adam Keeton; Derek Franklin; Matthias Bauer; Frank Michael Boeckler; Matthias Engel; Rolf Wolfgang Hartmann; Yanping Zhang; Gary Anthony Piazza; Ashraf Hassan Abadi

doi:10.1248/cpb.c15-00608

Regular Articles

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

Mohamed Salah Rezk, Mohammad Abdel-Halim, Adam Keeton, Derek Franklin, Matthias Bauer, Frank Michael Boeckler, Matthias Engel, Rolf Wolfgang Hartmann, Yanping Zhang, Gary Anthony Piazza, Ashraf Hassan Abadi

Author information

Mohamed Salah Rezk
Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo
Department of Pharmaceutical and Medicinal Chemistry, Saarland University
Mohammad Abdel-Halim
Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo
Adam Keeton
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama
Derek Franklin
Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Department of Pharmacology, University of North Carolina at Chapel Hill
Matthias Bauer
Department of Pharmaceutical & Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard-Karls-University Tuebingen
Frank Michael Boeckler
Department of Pharmaceutical & Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard-Karls-University Tuebingen
Matthias Engel
Department of Pharmaceutical and Medicinal Chemistry, Saarland University
Rolf Wolfgang Hartmann
Department of Pharmaceutical and Medicinal Chemistry, Saarland University
Yanping Zhang
Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Department of Pharmacology, University of North Carolina at Chapel Hill
Gary Anthony Piazza
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama
Ashraf Hassan Abadi Corresponding author
Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo

Keywords: indole derivative, p53, murine double minute 4 (MDM4), murine double minute 2 (MDM2)

JOURNAL FREE ACCESS FULL-TEXT HTML

2016 Volume 64 Issue 1 Pages 34-41

DOI https://doi.org/10.1248/cpb.c15-00608

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Abstract

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.

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