全球,结直肠癌(CRC)是第三常见的癌症类型,也是癌症相关死亡的第二常见原因。胸苷酸合成酶(TS)是DNA生物合成的关键组成部分,并已成为癌症治疗的重要靶标。在目前的工作中,我们设计并合成了28种新的基于二芳基的吡啶并[2,3-d]嘧啶/烷基取代的吡啶并[2,3-d]嘧啶衍生物,并评估了它们对HCT116,MCF-7,HepG2和PC-3细胞系的抗癌活性。此外,我们已经对化合物1n和2j进行了TS抑制活性和计算机模拟研究。所合成的化合物均表现出良好的抗癌活性,但其中,化合物1n和2j表现出优异的抗癌活性,IC50值为1.98±0.69、2.18±0.93、4.04±1.06和4.18±1.87µM;1.48±0.86、3.18±0.79、3.44±1.51和5.18±1.85µM,分别用对照雷替曲塞对HCT116,MCF-7,HepG2和PC-3细胞系(IC501.07±1.08,1.98±0.72,1.34±1.0和3.09±0.96µM,分别)和hTS抑制活性,IC50值为20.47±1.09和13.48±0.96nM,对照雷替曲塞(IC50为14.95±1.01nM)。Further,通过分子对接揭示了抑制的机制,显示1n和2j与TS催化位点的结合模式,对接评分为-10.6和-9.5kcal/mol,分别,参考雷替曲塞(-9.4kcal/mol)。此外,物理化学的评估,生物化学,结构,和毒理学特征也在这些化合物的可接受范围内。基于化合物的抗癌活性,还进行了SAR以进行引线优化。
Worldwide, colorectal cancer (CRC) is the third most common type of cancer and the second most common cause of cancer-related deaths. Thymidylate synthase (TS) is a crucial component of DNA biosynthesis and has drawn interest as an essential target for cancer treatment. In the current work, we have designed and synthesized twenty-eight new diaryl-based pyrido[2,3-d]pyrimidine/alkyl-substituted pyrido[2,3-d]pyrimidine derivatives and evaluated their anticancer activity against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines cell lines. Additionally, we have carried out TS inhibitory activity and in silico studies for compounds 1n and 2j. All the synthesized compounds exhibited good anticancer activity, but among them, compounds 1n and 2j showed excellent anticancer activity, having IC50 values of 1.98 ± 0.69, 2.18 ± 0.93, 4.04 ± 1.06, and 4.18 ± 1.87 µM; and 1.48 ± 0.86, 3.18 ± 0.79, 3.44 ± 1.51, and 5.18 ± 1.85 µM, against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines respectively with control raltitrexed (IC50 1.07 ± 1.08, 1.98 ± 0.72, 1.34 ± 1.0, and 3.09 ± 0.96 µM, respectively) and hTS inhibitory activity with IC50 values of 20.47 ± 1.09 and 13.48 ± 0.96 nM with control raltitrexed (IC50 14.95 ± 1.01 nM). Further, the mechanism of inhibition was revealed by molecular docking, which showed the binding pattern of 1n and 2j to the catalytic site of TS with docking scores of -10.6 and - 9.5 kcal/mol, respectively, with reference raltitrexed (-9.4 kcal/mol). Additionally, the assessment of physicochemical, biochemical, structural, and toxicological characteristics were also in the acceptable range for these compounds. Based on the anticancer activity of compounds, SAR was also performed for lead optimization.