title: Thioaryl naphthylmethanone oxime ether analogs as novel anticancer agents.
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.
authors.affiliation: Medicinal and Process Chemistry Division; ‡Endocrinology Division, §Biochemistry Division, ∥Toxicology Division, and ⊥Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Bandana
authors.initials: B
authors.lastname: Chakravarti
authors.forename: Tahseen
authors.initials: T
authors.lastname: Akhtar
authors.forename: Byanju
authors.initials: B
authors.lastname: Rai
authors.forename: Manisha
authors.initials: M
authors.lastname: Yadav
authors.forename: Jawed
authors.initials: J
authors.lastname: Akhtar Siddiqui
authors.forename: Shailendra Kumar
authors.initials: SK
authors.lastname: Dhar Dwivedi
authors.forename: Ravi
authors.initials: R
authors.lastname: Thakur
authors.forename: Anup Kumar
authors.initials: AK
authors.lastname: Singh
authors.forename: Abhishek Kumar
authors.initials: AK
authors.lastname: Singh
authors.forename: Harish
authors.initials: H
authors.lastname: Kumar
authors.forename: Kainat
authors.initials: K
authors.lastname: Khan
authors.forename: Subhashis
authors.initials: S
authors.lastname: Pal
authors.forename: Srikanta Kumar
authors.initials: SK
authors.lastname: Rath
authors.forename: Jawahar
authors.initials: J
authors.lastname: Lal
authors.forename: Rituraj
authors.initials: R
authors.lastname: Konwar
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Trivedi
authors.forename: Dipak
authors.initials: D
authors.lastname: Datta
authors.forename: Durga Prasad
authors.initials: DP
authors.lastname: Mishra
authors.forename: Madan Madhav
authors.initials: MM
authors.lastname: Godbole
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
authors.forename: Atul
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010091:Oximes / Q000138:chemical synthesis* / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: C000593789:4-(methylthio)phenyl)(naphthalen-1-yl)methanone O-2-(diethylamino)ethyl oxime; D000970:Antineoplastic Agents; D001559:Benzhydryl Compounds; D010091:Oximes; D066246:ErbB Receptors