3,5-Bis(benzylidene)-1-[4-2-(morpholin-4-yl)ethoxyphenylcarbonyl]-4-piperidone Hydrochloride: a Lead Tumor-specific Cytotoxin Which Induces Apoptosis and Autophagy

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2010 Jan 13

PMID 20064715

Citations 5

Authors

Umashankar Das

Hiroshi Sakagami

Qing Chu

Qintao Wang

Masami Kawase

Ponniah Selvakumar

Rajendra K Sharma

Jonathan R Dimmock

Affiliations

Soon will be listed here.

Abstract

A number of N-4-(2-aminoethoxy)phenylcarbonyl derivatives of various 3,5-bis(benzylidene)-4-piperidones 2-5 demonstrated noteworthy cytotoxic potencies towards human HL-60 leukemic cells as well as human HSC-2 and HSC-4 squamous cell carcinomas. In general, toxicity towards HGF, HPC, and HPLF normal cells was substantially lower. The highest selective toxicity was noted when the terminal base is morpholine. Lead optimization was based on finding compounds which had (i) high cytotoxic potencies, (ii) a greater toxicity to neoplasms than normal cells, and (iii) drug-likeness based on the rule of five. From the biodata generated, 5a evolved as a promising lead compound for further development. The mode of action of 5a included the induction of apoptosis in HL-60 cells in which internucleosomal DNA fragmentation and activation of caspase-3 was noted. In addition, 5a caused autophagy in HSC-2 cells.

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