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Synthetic and biological studies of tubulin targeting c2-substituted 7-deazahypoxanthines derived from marine alkaloid rigidins.

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      Abstract

      C2-aryl- and C2-alkyl-7-deazahypoxanthines as analogues of marine alkaloid rigidins were prepared utilizing novel synthetic methods developed for the construction of the pyrrolo[2,3-d]pyrimidine ring system. The new compounds exhibited sub-micromolar to nanomolar antiproliferative potencies against a panel of cell lines including in vitro models for drug-resistant tumors, such as glioblastoma, melanoma and non-small-cell lung cancer. A selected representative C2-methyl-7-deazahypoxanthine was found to inhibit microtubule dynamics in cancer cells, lending evidence for tubulin targeting as a mode of action for these compounds in cancer cells. The results of the docking studies utilizing the colchicine site on β-tubulin were consistent with the observed structure-activity relationship data, including an important finding that derivatization at C2 with linear alkyl groups leads to the retention of activity, thus permitting the attachment of a biotin-containing linker for the subsequent proteomics assays. Because many microtubule-targeting compounds are successfully used to fight cancer in the clinic, the reported antitubulin rigidin analogues have significant potential as new anticancer agents.

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      Affiliations
      [1 ] Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666 (USA).
      Journal
      ChemMedChem
      ChemMedChem
      1860-7187
      1860-7179
      Jul 2014
      : 9
      : 7
      24644272
      10.1002/cmdc.201300532
      4945961
      NIHMS799910
      © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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