title: Synthesis and biological evaluation of 4-aza-2,3-dihydropyridophenanthrolines as tubulin polymerization inhibitors.
abstract: A series of novel 4-aza-2,3-dihydropyridophenanthrolines 12(a-t) were synthesized by a one-step three component condensation of 1,10-phenanthroline amine, tetronic acid and various aromatic aldehydes. These were evaluated for their antiproliferative activity against three human cancer cell lines (MIAPACA, MCF-7 and HeLa) using SRB assay. Majority of the tested compounds exhibited significant anticancer activity on these cell lines and interestingly compounds 12h and 12i were more potent than etoposide and podophyllotoxin against all three tested cancer cell lines with GI50 values in the range of 0.01-0.5 μM. Furthermore, these compounds showed significant inhibition of tubulin polymerization which is comparable to that of podophyllotoxin and disrupted microtubule network by accumulating tubulin in the soluble fraction. The flow cytometry analysis confirmed that the synthesized compounds led to cell cycle arrest at the G2/M phase. Moreover, the structure activity relationship studies in this series are also discussed.
authors: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: ahmedkamal@iict.res.in.
authors: Ahmed
authors: A
authors: Kamal
authors: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India; IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
authors: T
authors: T
authors: Srinivasa Reddy
authors: Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors: Sowjanya
authors: S
authors: Polepalli
authors: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
authors: Suresh
authors: S
authors: Paidakula
authors: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
authors: Vunnam
authors: V
authors: Srinivasulu
authors: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
authors: V
authors: V
authors: Ganga Reddy
authors: Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors: Nishant
authors: N
authors: Jain
authors: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors: Nagula
authors: N
authors: Shankaraiah
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D010618:Phenanthrolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058105:Polymerization / Q000187:drug effects; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000595740:13-(2-fluoro-5-methoxyphenyl)-10,13-dihydrofuro(3,4-b)pyrido(3,2-f)(1,7)phenanthrolin-12(9H)-one; C000595741:13-(3,4-difluorophenyl)-10,13-dihydrofuro(3,4-b)pyrido(3,2-f)(1,7)phenanthrolin-12-(9H)-one; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D010618:Phenanthrolines; D014404:Tubulin; D050257:Tubulin Modulators
keywords: 1,10-Phenanthroline; 4-Azapodophyllotoxin; Cytotoxicity; Multicomponent reaction; Tubulin polymerization