Studies on the synthesis and anticancer activity of novel 2,4-diaminopyrimidine derivatives

Cancer is one of the leading causes of human deaths globally, and breast cancer is the most common type of cancer, especially among women, with a high mortality rate. Therefore, studies on potential new targets have become important due to the therapeutic resistance developed against therapies currently used in breast cancer treatment. One of these new therapeutic targets is the TACC3 protein, a member of the intracellular TACC protein family that interacts with the centrosome and microtubules. Overexpression of the TACC3 protein has been associated with various types of cancer including breast cancer making TACC3 as a remarkable biological target for cancer treatment. The 2,4-Diaminopyrimidine ring system is a frequently used motif in anticancer drug discovery. Based on this potential, a compound with the chemical structure of 3-(4-methoxyphenyl)-N-(2-morpholinopyrimidin-4-yl) isoxazol-5-amine, namely BO-264, was discovered as a new TACC3 inhibitor chemotype by our research group. BO-264 showed potent cytotoxicity against the high TACC3 expressing human JIMT-1 (breast) cancer cell line with IC50 values in the range of 188-258 nM. However, the in vitro and in vivo pharmacokinetic studies demonstrated that BO-264 had a limited oral bioavailability of 11,8%, and is a metabolically unstable compound due to its short half-life (t1/2= 5,86 min) and high hepatic clearance (CLint= 236,44 µL/min/mg protein) in human liver microsomes. In this thesis, seventy new derivatives were synthesized in order to improve the biological efficiency of BO-264, and to optimize the in vitro ADME and bioavailability profile. Among these derivatives, Compound 28 which has fluorine substituent in the third position of the 4-methoxyphenyl ring was the most active compound in the series with its IC50 value of 13 nM against the JIMT-1 cell line. Moreover, Compound 89, which has a relatively good activity (IC50= 206 nM) in the same cell line, showed over 60% oral bioavailability in in vivo pharmacokinetic studies with in two different formulations. To conclude, Compound 89 has the potential for further clinical development in anticancer drug development studies.