title: Development of a novel class of tubulin inhibitors with promising anticancer activities.
abstract: We have developed a novel class (2-amino-4-phenyl-4H-chromene-3-carboxylate) of inhibitors of tubulin assembly by modifying HA14-1, which is a Bcl-2 inhibitor discovered by our group. Three of these compounds, mHA1, mHA6, and mHA11, showed in vitro cytotoxicities against tumor cells that were more potent and more stable than the backbone compound HA14-1, with nM IC50 values. In contrast, the cytotoxic effects of these compounds on normal cells were minimal. Computational docking, colchicine-tubulin competitive binding, and tubulin polymerization studies demonstrated that these compounds bind at the colchicine-binding site on tubulin and inhibit the formation of microtubules. Treatment of HL-60/Bcl-2 leukemia and CRL5908 lung cancer cells with these mHA compounds led to pronounced microtubule density decreases, G2/M cell cycle arrest, and apoptosis, as determined by immunofluorescence microscopy, flow cytometry, and DNA fragmentation analysis. Combined, these data identify a novel class of compounds that inhibit tubulin assembly and limit cancer cell phenotypes.
  
  
  CONCLUSIONS
  This study supports the continued development of novel anti-tubulin assembly inhibitors as potential anticancer agents.
authors.affiliation: Department of Pharmacology, SUNY Upstate Cancer Research Institute, State University of New York, 750 East Adams Street, Syracuse, NY 13210, USA. anji@upstate.edu
authors.forename: Jingle
authors.initials: J
authors.lastname: Xi
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhu
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Feng
authors.forename: Na
authors.initials: N
authors.lastname: Huang
authors.forename: Guifen
authors.initials: G
authors.lastname: Luo
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Mao
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Han
authors.forename: Wang
authors.initials: W
authors.lastname: Tian
authors.forename: Guirong
authors.initials: G
authors.lastname: Wang
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Han
authors.forename: Rongcheng
authors.initials: R
authors.lastname: Luo
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Huang
authors.forename: Jing
authors.initials: J
authors.lastname: An
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000187:drug effects; D045744:Cell Line, Tumor; D003078:Colchicine / Q000378:metabolism / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D055808:Drug Discovery; D016195:G2 Phase / Q000187:drug effects* / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D009570:Nitriles; D014404:Tubulin; D050257:Tubulin Modulators; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D003078:Colchicine