1616967-52-2Relevant academic research and scientific papers
Synthetic and biological studies of tubulin targeting C2-substituted 7-deazahypoxanthines derived from marine alkaloid rigidins
Scott, Robert,Karki, Menuka,Reisenauer, Mary R.,Rodrigues, Roberta,Dasari, Ramesh,Smith, W. Ross,Pelly, Stephen C.,Van Otterlo, Willem A. L.,Shuster, Charles B.,Rogelj, Snezna,Magedov, Igor V.,Frolova, Liliya V.,Kornienko, Alexander
, p. 1428 - 1435 (2014/07/21)
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. Rigid(in) development! Novel analogues of marine alkaloid rigidins were prepared utilizing new synthetic methods developed for the construction of the pyrrolo[2,3-d]pyrimidine ring system. The compounds exhibited sub-micromolar to nanomolar antiproliferative potencies against drug-resistant cells, such as glioblastoma, melanoma and non-small-cell lung cancer.
