Efficient synthesis of new antiproliferative steroidal hybrids using the molecular hybridization approach

• Published in: European journal of medicinal chemistry 2016-07, Vol.117, p.241-255
• Main Authors: Yu, Bin, Qi, Ping-Ping, Shi, Xiao-Jing, Huang, Ruilei, Guo, Hao, Zheng, Yi-Chao, Yu, De-Quan, Liu, Hong-Min
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Apoptosis; Catalytic Domain; Cell cycle arrest; Cell Line, Tumor; Docking simulations; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Isatin - chemistry; Isatin - pharmacology; LSD1 inactivation; Molecular Docking Simulation; Molecular hybridization; Steroids; Steroids - chemical synthesis; Steroids - pharmacology; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.04.024

A series of steroidal hybrids with different terminal bioactive scaffolds were synthesized using the molecular hybridization approach and further evaluated for their antiproliferative activity against several cancer cell lines of different origins using the MTT assay. The preliminary results indicated that compounds 12a–h with the terminal isatin motif were remarkably sensitive to SH-SY5Y cells, thereby exerting potent growth inhibition in vitro. This selectivity is possibly attributed to LSD1 inactivation (IC50 = 3.18 μM). Besides, we also found that the chloro atom at the 7-position on the isatin core was beneficial for the activity through the SARs studies. Among this series, compound 12g showed the best inhibitory activity (IC50 = 4.06 μM) against SH-SY5Y cells, which was comparable to that of 5-FU. Compound 12g arrested cell cycle at G2/M phase, induced apoptosis accompanied with decrease of mitochondrial membrane potential, and inhibited LSD1 potently (IC50 = 3.18 μM). Docking studies showed that compound 12g formed interactions with surrounding amino acid residues and the steroid nucleus occupied the tubular hydrophobic cavity of the active site. Compounds 13–18 represented weak to moderate activity against the tested cancer cell lines. The steroidal dimer 20 and the structurally simplified non-steroidal dimer 21 were found to be devoid of the inhibitory activity. Steroidal hybrids were synthesized and evaluated for their antiproliferative activity. Compound 12g potently inhibited growth of SH-SY5Y cells possibly through the inactivation of LSD1, arrested cell cycle at G2/M phase, induced apoptosis and decreased MMP. Docking simulations were performed to rationalize the potency toward LSD1. [Display omitted] •Steroidal hybrids 12a–x were synthesized and showed varied cytotoxicity against the tested cancer cell lines.•Compounds with terminal isatin scaffold were sensitive to SH-SY5Y cells possibly through LSD1 inactivation.•Compound 12g potently inhibited growth of SH-SY5Y cells (IC50 = 4.06 μM).•Compound 12g arrested cell cycle at G2/M phase, induced apoptosis and decreased MMP.•Docking simulations were performed to show the binding models of compound 12g in the active site of LSD1.