PDF(Pubmed)
Abstract：
Structural-based drug design and solvent-free synthesis were combined to obtain three novel series of 5-arylethylidene-aminopyrimidine-2,4-diones (4, 5a-c, 6a,b), 5-arylethylidene-amino-2-thiopyrimidine-4-ones (7,8), and 6-arylpteridines (9,10) as dual BRD4 and PLK1 inhibitors. MTT assays of synthesized compounds against breast (MDA-MB-231), colorectal (HT-29), and renal (U-937) cancer cells showed excellent-to-good cytotoxic activity, compared to Methotrexate; MDA-MB-231 were the most sensitive cancer cells. The most active compounds were tested against normal Vero cells. Compounds 4 and 7 significantly inhibited BRD4 and PLK1, with IC50 values of 0.029, 0.042 µM, and 0.094, 0.02 µM, respectively, which are nearly comparable to volasertib (IC50 = 0.017 and 0.025 µM). Compound 7 triggered apoptosis and halted cell growth at the G2/M phase, similarly to volasertib. It also upregulated the BAX and caspase-3 markers while downregulating the Bcl-2 gene. Finally, active compounds fitted the volasertib binding site at BRD4 and PLK1 and showed ideal drug-like properties and pharmacokinetics, making them promising anticancer candidates.
摘要：
基于结构的药物设计和无溶剂合成相结合，获得了三个新系列的5-芳基亚乙基-氨基嘧啶-2,4-二酮（4，5a-c，a.)5-芳基亚乙基-氨基-2-硫代嘧啶-4-酮（7,8），和6-芳基蝶啶（9,10）作为BRD4和PLK1双重抑制剂。合成化合物抗乳腺的MTT测定法（MDA-MB-231），结直肠（HT-29），肾（U-937）癌细胞表现出极好的细胞毒活性，与甲氨蝶呤相比，MDA-MB-231是最敏感的癌细胞。针对正常Vero细胞测试最具活性的化合物。化合物4和7显著抑制BRD4和PLK1,IC50值分别为0.029,0.042µM,和0.094，0.02µM，分别,几乎与volasertib相当(IC50=0.017和0.025µM)。化合物7在G2/M期触发细胞凋亡并停止细胞生长，类似于volasertib。它还上调BAX和caspase-3标记，同时下调Bcl-2基因。最后,活性化合物在BRD4和PLK1处符合volasertib结合位点，并显示出理想的药物样特性和药代动力学，使他们成为有前途的抗癌候选人。
