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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Jun 12

PMID 38865195

Authors

Aletta E van der Westhuyzen

Naghmana Ashraf

Daleen Conradie

Leigh Loots

Catherine H Kaschula

Stephen C Pelly

Liliya V Frolova

Taylor Landfair

Charles B Shuster

Tania Betancourt

Alexander Kornienko

Willem A L van Otterlo

Affiliations

Soon will be listed here.

Abstract

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-pyrrolo[2,3-]pyrimidin-4-one and 6-[4-(2-ethoxyethoxy)benzoyl]-5-(3-fluorophenyl)-2-(pent-4-yn-1-yl)-1,7-dihydro-4-pyrrolo[2,3-]pyrimidin-4-one . Similarly to the parent , 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.

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