Thioaryl Naphthylmethanone Oxime Ether Analogs as Novel Anticancer Agents

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• 作者：Bandana Chakravarti ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 9, 2014
• 年：2014
• 卷：57
• 期：19
• 页码：8010-8025
• 全文大小：1049K
• ISSN：1520-4804

文摘

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.