Future medicinal chemistry · 2025
Multi-target design of fused cyclic pyrimidine-2-thione candidates as DNA intercalators and topoisomerase I/II inhibitors.
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Khalil Mahmoud S, Al-Karmalawy Ahmed A, Abo Elmaaty Ayman, Elsayed Galal A, Hassan A M A
Аннотация
AIM: We aimed to design and synthesize novel pyrimidine-2-thione derivatives (1-13) as Topoisomerase I/II (Topo I/II) inhibitors with DNA intercalation potential for cancer treatment.
MATERIALS & METHODS: Inhibitory concentration 50 (IC50) against mammary gland breast cancer, hepatocellular carcinoma, and colorectal carcinoma was determined for all compounds. The frontier candidates (2, 6, 9, 10, and 11) were evaluated for their DNA-binding ability, Topo I, and Topo II inhibiting potential. Moreover, cell cycle and apoptosis analysis were carried out.
RESULTS: Compound 2 displayed the best DNA-binding affinity with an IC50 value of 37.24 µM in comparison to doxorubicin (Dox). Both compounds 2 and 9 showed superior nanomolar Topo I inhibitory potential, compared to Dox. Similarly, compounds 2 and 9 achieved better Topo II inhibition, exceeding that of Dox. It was revealed that compound 9 halted the cell cycle at both the P1 and G2 phases. In addition, compound 9 was able to boost the apoptosis at both the early and late apoptotic phases.
CONCLUSION: Consequently, the compounds afforded can be regarded as prominent lead anticancer compounds for further optimization and investigation.
MATERIALS & METHODS: Inhibitory concentration 50 (IC50) against mammary gland breast cancer, hepatocellular carcinoma, and colorectal carcinoma was determined for all compounds. The frontier candidates (2, 6, 9, 10, and 11) were evaluated for their DNA-binding ability, Topo I, and Topo II inhibiting potential. Moreover, cell cycle and apoptosis analysis were carried out.
RESULTS: Compound 2 displayed the best DNA-binding affinity with an IC50 value of 37.24 µM in comparison to doxorubicin (Dox). Both compounds 2 and 9 showed superior nanomolar Topo I inhibitory potential, compared to Dox. Similarly, compounds 2 and 9 achieved better Topo II inhibition, exceeding that of Dox. It was revealed that compound 9 halted the cell cycle at both the P1 and G2 phases. In addition, compound 9 was able to boost the apoptosis at both the early and late apoptotic phases.
CONCLUSION: Consequently, the compounds afforded can be regarded as prominent lead anticancer compounds for further optimization and investigation.
Предметные рубрики MeSH
HumansTopoisomerase I InhibitorsTopoisomerase II InhibitorsPyrimidinesAntineoplastic AgentsDrug DesignDNA Topoisomerases, Type IApoptosisDNA Topoisomerases, Type IIStructure-Activity RelationshipDrug Screening Assays, AntitumorIntercalating AgentsThionesDNAMolecular StructureCell Line, TumorCell ProliferationCell Cycle