title: Second generation benzofuranone ring substituted noscapine analogs: synthesis and biological evaluation.
abstract: Microtubules, composed of α/β tubulin heterodimers, represent a validated target for cancer chemotherapy. Thus, tubulin- and microtubule-binding antimitotic drugs such as taxanes and vincas are widely employed for the chemotherapeutic management of various malignancies. Although quite successful in the clinic, these drugs are associated with severe toxicity and drug resistance problems. Noscapinoids represent an emerging class of microtubule-modulating anticancer agents based upon the parent molecule noscapine, a naturally occurring non-toxic cough-suppressant opium alkaloid. Here we report in silico molecular modeling, chemical synthesis and biological evaluation of novel analogs derived by modification at position-7 of the benzofuranone ring system of noscapine. The synthesized analogs were evaluated for their tubulin polymerization activity and their biological activity was examined by their antiproliferative potential using representative cancer cell lines from varying tissue-origin [A549 (lung), CEM (lymphoma), MIA PaCa-2 (pancreatic), MCF-7 (breast) and PC-3 (prostate)]. Cell-cycle studies were performed to explore their ability to halt the cell-cycle and induce subsequent apoptosis. The varying biological activity of these analogs that differ in the nature and bulk of substituent at position-7 was rationalized utilizing predictive in silico molecular modeling.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, United States.
authors.forename: Ram Chandra
authors.initials: RC
authors.lastname: Mishra
authors.forename: Prasanthi
authors.initials: P
authors.lastname: Karna
authors.forename: Sushma Reddy
authors.initials: SR
authors.lastname: Gundala
authors.forename: Vaishali
authors.initials: V
authors.lastname: Pannu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Stanton
authors.forename: Kamlesh Kumar
authors.initials: KK
authors.lastname: Gupta
authors.forename: M Hope
authors.initials: MH
authors.lastname: Robinson
authors.forename: Manu
authors.initials: M
authors.lastname: Lopus
authors.forename: Leslie
authors.initials: L
authors.lastname: Wilson
authors.forename: Maged
authors.initials: M
authors.lastname: Henary
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D009665:Noscapine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D014404:Tubulin; D050257:Tubulin Modulators; D009665:Noscapine