Thioaryl naphthylmethanone oxime ether analogs as novel anticancer agents

  • J Med Chem. 2014 Oct 9;57(19):8010-25. doi: 10.1021/jm500873e.
Bandana Chakravarti  1 ,  Tahseen Akhtar ,  Byanju Rai ,  Manisha Yadav ,  Jawed Akhtar Siddiqui ,  Shailendra Kumar Dhar Dwivedi ,  Ravi Thakur ,  Anup Kumar Singh ,  Abhishek Kumar Singh ,  Harish Kumar ,  Kainat Khan ,  Subhashis Pal ,  Srikanta Kumar Rath ,  Jawahar Lal ,  Rituraj Konwar ,  Arun Kumar Trivedi ,  Dipak Datta ,  Durga Prasad Mishra ,  Madan Madhav Godbole ,  Sabyasachi Sanyal ,  Naibedya Chattopadhyay ,  Atul Kumar
Affiliations
  • 1. Medicinal and Process Chemistry Division; ‡Endocrinology Division, §Biochemistry Division, ∥Toxicology Division, and ⊥Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute , Lucknow 226031, India.
PMID: 25198997 DOI: 10.1021/jm500873e
Abstract

Employing a rational design of thioaryl naphthylmethanone oxime ether analogs containing functional properties of various Anticancer drugs, a series of compounds were identified that displayed potent cytotoxicity toward various Cancer cells, out of which 4-(methylthio)phenyl)(naphthalen-1-yl)methanone O-2-(diethylamino)ethyl oxime (MND) exhibited the best safety profile. MND induced Apoptosis, inhibited migration and invasion, strongly inhibited Cancer stem cell population on a par with salinomycin, and demonstrated orally potent tumor regression in mouse MCF-7 xenografts. Mechanistic studies revealed that MND strongly abrogated EGF-induced proliferation, migration, and tyrosine kinase (TK) signaling in Breast Cancer cells. However, MND failed to directly inhibit EGFR or other related receptor TKs in a cell-free system. Systematic investigation of a putative target upstream of EGFR revealed that the biological effects of MND could be abrogated by pertussis toxin. Together, MND represents a new nonquinazoline potential drug candidate having promising antiproliferative activity with good safety index.