title: Synthesis and biological evaluation of imidazopyridine-oxindole conjugates as microtubule-targeting agents.
abstract: A library of imidazopyridine-oxindole conjugates was synthesised and investigated for anticancer activity against various human cancer cell lines. Some of the tested compounds, such as 10 a, 10 e, 10 f, and 10 k, exhibited promising antiproliferative activity with GI50 values ranging from 0.17 to 9.31 μM. Flow cytometric analysis showed that MCF-7 cells treated by these compounds arrested in the G2 /M phase of the cell cycle in a concentration-dependent manner. More particularly, compound 10 f displayed a remarkable inhibitory effect on tubulin polymerisation. All the compounds depolarised mitochondrial membrane potential and caused apoptosis. These results are further supported by the decreased phosphorylation of Akt at Ser473. Studies on embryonic development revealed that the lead compounds 10 f and 10 k caused delay in the development of zebra fish embryos. Docking of compound 10 f with tubulin protein suggested that the imidazo[1,2-a]pyridine moiety occupies the colchicine binding site of tubulin.
authors.affiliation: Medicinal Chemistry & Pharmacology Division, Indian Institute of Chemical Technology, Hyderabad 500007 (India). ahmedkamal@iict.res.in.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.forename: Vangala Santhosh
authors.initials: VS
authors.lastname: Reddy
authors.forename: Santosh
authors.initials: S
authors.lastname: Karnewar
authors.forename: Sumit S
authors.initials: SS
authors.lastname: Chourasiya
authors.forename: Anver Basha
authors.initials: AB
authors.lastname: Shaik
authors.forename: G Bharath
authors.initials: GB
authors.lastname: Kumar
authors.forename: Chandan
authors.initials: C
authors.lastname: Kishor
authors.forename: M Kashi
authors.initials: MK
authors.lastname: Reddy
authors.forename: M P
authors.initials: MP
authors.lastname: Narasimha Rao
authors.forename: Ananthamurthy
authors.initials: A
authors.lastname: Nagabhushana
authors.forename: Kallaganti V S
authors.initials: KV
authors.lastname: Ramakrishna
authors.forename: Anthony
authors.initials: A
authors.lastname: Addlagatta
authors.forename: Srigiridhar
authors.initials: S
authors.lastname: Kotamraju
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D047108:Embryonic Development / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D061986:MCF-7 Cells; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism*; D000078183:Oxindoles; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D015027:Zebrafish / Q000254:growth & development
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D011725:Pyridines; D014404:Tubulin; D050257:Tubulin Modulators; C022960:2-oxindole; C023666:pyridine
keywords: apoptosis; cytotoxicity; imidazopyridine-oxindoles; molecular docking; tubulin polymerisation