Details

Autor(en) / Beteiligte

• van der Westhuyzen, Aletta E.
• Ashraf, Naghmana
• Conradie, Daleen
• Loots, Leigh
• Kaschula, Catherine H.
• Pelly, Stephen C.
• Frolova, Liliya V.
• Landfair, Taylor
• Shuster, Charles B.
• Betancourt, Tania
• Kornienko, Alexander
• van Otterlo, Willem A. L.

Titel

Improved Rigidin-Inspired Antiproliferative Agents with Modifications on the 7‑Deazahypoxanthine C7/C8 Ring Systems

Ist Teil von

• Journal of medicinal chemistry, 2024-06, Vol.67 (12), p.9950-9975

Ort / Verlag

American Chemical Society

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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-4H-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-4H-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.