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Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins: Exploration of the N3 and N9 Positions and Interaction with Multidrug-Resistance Proteins |
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| Authors: | Dr. Ramesh Dasari Andrzej Błauż Derek C. Medellin Roaa M. Kassim Carlos Viera Maximo Santarosa Alet E. van der Westhuyzen Prof. Willem A. L. van Otterlo Taryn Olivas Dr. Tugba Yildiz Prof. Tania Betancourt Prof. Charles B. Shuster Prof. Snezna Rogelj Dr. Błażej Rychlik Prof. Todd Hudnall Prof. Liliya V. Frolova Prof. Alexander Kornienko |
| Affiliation: | 1. Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666 USA These authors contributed equally to this work.;2. Cytometry Lab, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, ul. Pomorska 141/143, 90-236 Łódź, Poland These authors contributed equally to this work.;3. Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666 USA;4. Department of Biology, New Mexico State University, Las Cruces, NM, 88003 USA;5. Departments of Chemistry and Biology, New Mexico Tech, Socorro, NM, 87801 USA;6. Department of Chemistry and Polymer Science, University of Stellenbosch, 7602 Stellenbosch, South Africa;7. Materials Science and Engineering Program, Texas State University, San Marcos, TX, 78666 USA;8. Cytometry Lab, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, ul. Pomorska 141/143, 90-236 Łódź, Poland |
| 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. |
| Keywords: | 7-deazapurines alkaloids antitumor agents drug discovery pyrrolo[2,3-d]pyrimidines |