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

Affiliation

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.

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