Cycloguanil

Cycloguanil (Chlorguanide triazine) is a dihydrofolate reductase (DHFR) inhibitor with an IC₅₀ of 10.8 μM against human DHFR. Cycloguanil blocks the folate metabolic pathway, thereby affecting nucleotide synthesis and interfering with DNA replication. Cycloguanil inhibits DHFR in Plasmodium and is thus used in malaria research. Cycloguanil also potently inhibits DHFR in human cancer cells and blocks the transcriptional activity of STAT3, thereby exhibiting anticancer activity^[1][2]. In Vitro:Cycloguanil exhibits anticancer activity against the NCI-60 panel of human tumor cell lines, and shows selective activity toward the MDA-MB-468 and MCF-7 breast cancer cell lines^[2].
Cycloguanil (72 h) induces growth arrest in MDA-MB-468, MDA-MB-231 and MCF-7 breast cancer cells, with cell viability maintained at approximately 50% of that in the vehicle control group at high concentrations, and this effect cannot be reversed by folinic acid treatment^[2].
Cycloguanil (0.001-10 μM; 24 h) binds to DHFR in intact MDA-MB-468 breast cancer cells, resulting in a dose-dependent accumulation of DHFR protein after 24 hours of treatment^[2].
Cycloguanil (10 μM; 24 h) disrupts folate metabolism and nucleotide homeostasis in MDA-MB-231 breast cancer cells, and supplementation with Folinic acid (HY-17556) reverses the metabolite changes induced by it, a result consistent with DHFR inhibition^[2].
Cycloguanil (0.02-20 μM; 6 h) potently inhibits the transcriptional activity of STAT3 in U3A fibrosarcoma cells at concentrations as low as 0.02 μM, which is consistent with the downstream effects of DHFR inhibition^[2].