Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins: Exploration of the N3 and N9 Positions and Interaction with Multi-Drug Resistance Proteins
Date
2019-02-05
Authors
Dasari, Ramesh
Blauz, Andrzej
Medellin, Derek C.
Kassim, Roaa M.
Viera, Carlos
Santarosa, Maximo
Turner, Danielle
van der Westhuyzen, Alet E.
van Otterlo, Willem
Olivas, Taryn
Journal Title
Journal ISSN
Volume Title
Publisher
John Wiley and Sons Ltd.
Abstract
Our laboratories have been investigating synthetic analogues of marine alkaloid rigidins that possess promising anticancer activities. These analogues, based on the 7-deazahypoxanthine skeleton, are available in one- or two-step synthetic sequences and exert cytotoxicity by disrupting microtubule dynamics in cancer cells. In the present work we extended the available structure-activity relationship (SAR) data to N3- and N9-substituted derivatives. Although N3 substitution results in loss of activity, the N9-substituted compounds retain nanomolar antiproliferative activities and the anti-tubulin mode of action of the original unsubstituted compounds. Furthermore, our results also demonstrate that multidrug-resistance (MDR) proteins do not confer resistance to both N9-unsubstituted and -substituted compounds. It was found that sublines overexpressing ABCG2, ABCC1, and ABCB1 proteins are as responsive to the rigidin analogues as their parental cell lines. Thus, the study reported herein provides further impetus to investigate the rigidin-inspired 7-deazahypoxanthines as promising anticancer agents.
Description
Keywords
alkaloids, antitumor agents, drug discovery, pyrrolo[2,3-d]pyrimidines, 7-deazapurines, Chemistry and Biochemistry
Citation
Dasari, R., Blauz, A., Medellin, D. C., Kassim, R. M., Viera, C., Santarosa, M., Turner, D., van der Westhuyzen, A. E., van Otterlo, W. A. L., Olivas, T., Yildiz, T., Betancourt, T., Shuster, C. B., Rogelj, S., Rychlik, B., Hudnall, T., Frolova, L. V., Kornienko, A. (2019). Microtubule-targeting 7-deazahypoxanthines derived from marine alkaloid rigidins: Exploration of the N3 and N9 positions and interaction with multidrug-resistance proteins. ChemMedChem, 14(3), pp. 322–333.