title: Synthesis and biological evaluation of novel pyrano[3,2-c]carbazole derivatives as anti-tumor agents inducing apoptosis via tubulin polymerization inhibition.
abstract: A series of novel pyrano[3,2-c]carbazole derivatives have been synthesized by a simple one-pot, three component reaction of aromatic aldehydes, malononitrile-ethyl cyanoacetate and 4-hydroxycarbazoles catalyzed by triethylamine. The antiproliferative activity of the derivatives on various cancer cell lines such as MDA-MB-231, K562, A549 and HeLa was investigated. Among 9a-p, congeners 9a, 9c, 9g and 9i showed profound antiproliferative activity with IC50 values ranging from 0.43 to 8.05 μM and induced apoptosis significantly by inhibiting tubulin polymerization. Cell-based biological assays demonstrated that treatment of cell lines with compounds 9a, 9c, 9g and 9i results in G2/M phase arrest of the cell cycle. Moreover the derivatives significantly disrupted the microtubule network, produced an elevation of cyclinB1 protein levels and induced apoptosis by increasing the caspase-3 levels. In particular, 9i strongly inhibited tubulin assembly compared to the positive control CA-4. Molecular docking studies demonstrated that all the lead compounds selectively occupy the colchicine binding site of the tubulin polymer.
authors.affiliation: Department of Chemistry, JNTUH College of Engineering, Kukatpally, Hyderabad (T.S), 500 085, India. padduiict@gmail.com.
authors.forename: Pannala
authors.initials: P
authors.lastname: Padmaja
authors.forename: Garikapati
authors.initials: G
authors.lastname: Koteswara Rao
authors.forename: Adisherla
authors.initials: A
authors.lastname: Indrasena
authors.forename: Basireddy V
authors.initials: BV
authors.lastname: Subba Reddy
authors.forename: Nibedita
authors.initials: N
authors.lastname: Patel
authors.forename: Anver Basha
authors.initials: AB
authors.lastname: Shaik
authors.forename: Narayana
authors.initials: N
authors.lastname: Reddy
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Dubey
authors.forename: Manika Pal
authors.initials: MP
authors.lastname: Bhadra
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D014404:Tubulin; D050257:Tubulin Modulators; C041514:carbazole; D053148:Caspase 3