title: Synthesis and structure-activity relationships of pyridinyl-1H-1,2,3-triazolyldihydroisoxazoles as potent inhibitors of tubulin polymerization.
abstract: Three series of compounds; pyridinyl-1H-1,2,3-triazoles, pyridinyl-1H-1,2,3-triazolylisoxazoles and pyridinyl-1H-1,2,3-triazolyldihydroisoxazoles with TMP moiety were designed, synthesized and screened for their anti-cancer and anti-tubulin properties. By sequentially designing three series of compounds comprising of dihydroisoxazole in the linker, a small substituent like chlorine on one side (R(1)) and aromatic group (R) on the pyridine ring, we have optimized the anti-cancer as well as anti-tubulin activity. Pyridinyl-1H-1,2,3-triazolyldihydroisoxazoles 28b and 28c were found to be potent anti-cancer agents against all the cell lines tested with a concomitant accumulation of cells in the G2/M phase of the cell cycle. Molecular modeling suggests that the trimethoxyphenyl ring in 28b and 28c occupies the cholchicine binding domain of β-tubulin, whereas, the dihydroisoxazole extends towards the interface of α,β-tubulin.
authors.affiliation: Natural Product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: P
authors.initials: P
authors.lastname: Suman
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: T Ramalinga
authors.initials: TR
authors.lastname: Murthy
authors.affiliation: Natural Product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: K
authors.initials: K
authors.lastname: Rajkumar
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: D
authors.initials: D
authors.lastname: Srikanth
authors.affiliation: Natural Product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Ch
authors.initials: Ch
authors.lastname: Dayakar
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Chandan
authors.initials: C
authors.lastname: Kishor
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. Electronic address: anthony@iict.res.in.
authors.forename: Anthony
authors.initials: A
authors.lastname: Addlagatta
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. Electronic address: kalivendi@iict.res.in.
authors.forename: Shasi V
authors.initials: SV
authors.lastname: Kalivendi
authors.affiliation: Natural Product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. Electronic address: chinaraju@iict.res.in.
authors.forename: B China
authors.initials: BC
authors.lastname: Raju
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D058105:Polymerization / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007555:Isoxazoles; D011725:Pyridines; D014404:Tubulin; C000601849:pyridinyl-1H-1,2,3-triazolyldihydroisoxazole
keywords: 2-Chloronicotinaldehyes; Anti-cancer activity; Anti-tubulin activity; Molecular modeling; Pyridinyl-1H-1,2,3-triazoles; Triazolyldihydroisoxazoles; Triazolylisoxazoles