| Autor: |
van der Westhuyzen AE; Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch 7600, South Africa., Ashraf N; Department of Biology, New Mexico State University, Las Cruces ,New Mexico 88003, United States., Conradie D; Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch 7600, South Africa.; Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa., Loots L; Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch 7600, South Africa., Kaschula CH; Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch 7600, South Africa., Pelly SC; Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch 7600, South Africa.; Department of Chemistry, Emory University, 1515 Dickey Drive ,Atlanta ,Georgia 30322, United States., Frolova LV; Department of Chemistry and Biochemistry, Purdue University, 2101 East Coliseum Blvd. ,Fort Wayne ,Indiana 46805, United States., Landfair T; Department of Biology, New Mexico State University, Las Cruces ,New Mexico 88003, United States., Shuster CB; Department of Biology, New Mexico State University, Las Cruces ,New Mexico 88003, United States., Betancourt T; Department of Chemistry and Biochemistry, Texas State University, San Marcos ,Texas 78666, United States., Kornienko A; Department of Chemistry and Biochemistry, Texas State University, San Marcos ,Texas 78666, United States., van Otterlo WAL; Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch 7600, South Africa. |
| Abstrakt: |
To improve their aqueous solubility characteristics, water-solubilizing groups were added to some antiproliferative, rigidin-inspired 7-deazahypoxanthine frameworks after molecular modeling seemed to indicate that structural modifications on the C7 and/or C8 phenyl groups would be beneficial. To this end, two sets of 7-deazahypoxanthines were synthesized by way of a multicomponent reaction approach. It was subsequently determined that their antiproliferative activity against HeLa cells was retained for those derivatives with a glycol ether at the 4'-position of the C8 aryl ring system, while also significantly improving their solubility behavior. The best of these compounds were the equipotent 6-[4-(2-ethoxyethoxy)benzoyl]-2-(pent-4-yn-1-yl)-5-phenyl-1,7-dihydro-4 H -pyrrolo[2,3- d ]pyrimidin-4-one 33 and 6-[4-(2-ethoxyethoxy)benzoyl]-5-(3-fluorophenyl)-2-(pent-4-yn-1-yl)-1,7-dihydro-4 H -pyrrolo[2,3- d ]pyrimidin-4-one 59 . Similarly to the parent 1 , the new derivatives were also potent inhibitors of tubulin assembly. In treated HeLa cells, live cell confocal microscopy demonstrated their impact on microtubulin dynamics and spindle morphology, which is the upstream trigger of mitotic delay and cell death. |
