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.