title: Thiazolidinone Constraint Combretastatin Analogs as Novel Antitubulin Agents: Design, Synthesis, Biological Evaluation and Docking Studies.
abstract: BACKGROUND
  Microtubules act as a useful and strategic molecular target for various anticancer drugs that binds to its distinct sites in tubulin subunits and inhibits its polymerization and ultimately leads to cell death. Moreover, numerous reports highlight the cytotoxic effects of constraint Combretastatin analogs and thiazolidinone derivatives.
  
  
  OBJECTIVE
  Therefore, the present study investigates the potential of thiazolidinone constraint combretastatin analogs as tubulin inhibitors.
  
  
  METHODS
  By incorporating silica supported fluroboric acid, a series of thiazolidinone constraint combretastatin analogs were synthesized in a microwave reactor under solvent free conditions. To optimize the reaction conditions, the detailed investigation was done for the catalytic influence of HBF4-SiO2. All the synthesized analogs were assessed for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. Top hits were further examined for their tubulin polymerization inhibition and their effect on microtubule assembly. The significant cytotoxicity and tubulin polymerization inhibition of the most potent structure was further rationalized by molecular modelling studies.
  
  
  RESULTS
  The results stated that CS-2, CS-3 and CS-20 possessed significant cytotoxic potential with the IC50 values ranging from 1.21 to 5.50 μM against THP-1, COLO-205, HCT-116 human cancer cell lines. Established structure activity relationship revealed that the nature of Ring A substantially influences the cytotoxic potential of the compounds. Placement of methoxy substituents on the phenyl ring (Ring A) was found to be the most preferred structural feature. Compound CS-2 was found to considerably inhibit the tubulin polymerization (IC50 value 2.12 μM) and caused disruption of microtubule assembly as demonstrated by immunoflourescence technique. In molecular modelling studies, CS-2 exhibited various hydrophobic as well as hydrogen bonding interactions at colchicine binding site and was found to be stabilized in this cavity.
  
  
  CONCLUSIONS
  This work provides an efficient methodology for the synthesis of antitubulin thiazolodinonecombretastatin hybrids.
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005,India.
authors.forename: Sahil
authors.initials: S
authors.lastname: Sharma
authors.forename: Manish Kumar
authors.initials: MK
authors.lastname: Gupta
authors.forename: Ajit Kumar
authors.initials: AK
authors.lastname: Saxena
authors.forename: Preet Mohinder Singh
authors.initials: PM
authors.lastname: Bedi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001632:Bibenzyls / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry* / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D045162:Thiazolidinediones; D014404:Tubulin; D050257:Tubulin Modulators; C040105:combretastatin