Design, synthesis and anticancer evaluation of imamine-1,3,5-triazine derivatives

Abstract

To find novel and effective anti-cancer agents, sixteen novel imamine-1,3,5-triazine derivatives were firstly designed and synthesized using a molecular hybridization strategy and nucleophilic substitution reaction. The structures of imamine-1,3,5-triazine derivatives were characterized by ¹H NMR, ¹³C NMR, IR, HR-MS and single crystal X-ray diffraction. These compounds were tested using the methyl thiazolyl tetrazolium (MTT) assay for their antiproliferative properties against MDA-MB-231 (breast cancer cells), HeLa (cervical cancer cells) and A498 (kidney cancer cells) cells with imatinib as the positive control which is the parent compound of imamine. The data revealed that some of the imamine-1,3,5-triazine derivatives possessed better anticancer activity than imatinib. The imamine-1,3,5-triazine derivatives were selective against triple-negative MDA-MB-231 breast cancer cells. Compound 4f (N²-allyl-6-chloro-N²-methyl-N⁴-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl)-1,3,5-triazine-2,4-diamine) and 4k (6-chloro-N²-cyclohexyl-N²-methyl-N⁴-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl)-1,3,5-triazine-2,4-diamine) demonstrated potent anti-proliferative activity against MDA-MB-231 cells with IC₅₀ of 6.25 μM and 8.18 μM respectively surpassing that of imatinib (IC₅₀ = 35.50 μM). Further studies have shown that compound 4f not only inhibits the migration, invasion, adhesion, and proliferation of MDA-MB-231 cells, but also has a strong inhibitory effect on the proliferation of MDA-MB-231 tumor xenografts in vivo. In addition, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties suggest that these compounds may have the properties of drug candidates. Thus, compound 4f may be a promising drug candidate for the treatment of cancer.