Synthesis, anticancer activities and molecular modeling studies of novel indole retinoid derivatives

• Published in: European journal of medicinal chemistry Vol. 58; pp. 346 - 354
• Main Authors: Gurkan-Alp, A. Selen, Mumcuoglu, Mine, Andac, Cenk A., Dayanc, Emre, Cetin-Atalay, Rengul, Buyukbingol, Erdem
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.12.2012; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Proliferation - drug effects; Chemistry, Medicinal; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Indole; Life Sciences & Biomedicine; MDA-MB-231; Medical sciences; Miscellaneous; Models, Molecular; Molecular dynamics; Molecular Dynamics Simulation; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Retinoid; Retinoids - chemical synthesis; Retinoids - chemistry; Retinoids - pharmacology; Science & Technology; Structure-Activity Relationship; T47D; Temperature; Tumor Cells, Cultured; PBS; SRB; Indole; CPT; Retinoid; Molecular dynamics; T47D; ER; RXR; DMEM; TCA; FCS; MD; MDA-MB-231; APOPTOSIS; SUBTYPES; CHEMOPREVENTION; ANTITUMOR-ACTIVITY; SIMULATION; SOLVENT; ACID RECEPTORS; BREAST-CANCER; INHIBITOR; EXPRESSION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.10.013

In this study, novel (E)-3-(5-substituted-1H-indol-3-yl)-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-2-en-1-one (5(a–e)) derivatives were synthesized and their anticancer effects were determined in vitro. Novel indole retinoid compounds except 5e have anti-proliferative capacity in liver, breast and colon cancer cell lines. This anti-proliferative effect was further analyzed in breast cancer cell line panel by using the most potent compound 5a. It was determined that 5a can inhibit proliferation at very low IC50 concentrations in all of the breast cancer cell lines. Here, we present some evidence on apoptotic termination of cancer cell proliferation which may be primarily driven by the inhibition of RXRα and, to a lesser extent, RXRγ. [Display omitted] Compound 5a was found to possess the best anticancer activity with IC50 < 0.01 μM in Huh7 cell line. ► Five novel indole retinoid derivatives were synthesized. ► Compounds were evaluated for their anticancer activities. ► Compound 5a was subjected to docking and molecular dynamics studies on RXRα and RXRγ.