Abstract

A series of thieno[2,3-d]pyrimidine-based hydroxamic acid hybrids was designed and synthesised as multitarget anti-cancer agents, through incorporating the pharmacophore of EGFR, VEGFR2 into the inhibitory functionality of HDAC6. Three compounds (12c, 15b and 20b) were promising hits, whereas (12c) exhibited potent VEGFR2 inhibition (IC₅₀=185 nM), potent EGFR inhibition (IC₅₀=1.14 µM), and mild HDAC6 inhibition (23% inhibition). Moreover, compound (15c) was the most potent dual inhibitor among all the synthesised compounds, as it exhibited potent EGFR and VEGFR2 inhibition (IC₅₀=19 nM) and (IC₅₀=5.58 µM), respectively. While compounds (20d) and (7c) displayed nanomolar selective kinase inhibition with EGFR IC₅₀= 68 nM and VEGFR2 IC₅₀= 191 nM, respectively. All of the synthesised compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumour cell lines. Additionally, molecular docking studies and ADMET studies were carried out to gain further insight into their binding mode and predict the pharmacokinetic properties of all the synthesised inhibitors.

摘要

通过将EGFR、VEGFR2的药效团结合到HDAC6的抑制功能中，设计并合成了一系列基于噻吩并[2,3 - d ]嘧啶的异羟肟酸杂化物作为多靶点抗癌剂。三种化合物（12c、15b 和 20b）很有前景，而（12c）表现出有效的 VEGFR2 抑制（IC ₅₀ =185 nM）、有效的 EGFR 抑制（IC ₅₀ =1.14 µM）和轻度 HDAC6 抑制（23% 抑制）。此外，化合物(15c)是所有合成化合物中最有效的双重抑制剂，因为它表现出有效的 EGFR 和 VEGFR2 抑制 (IC ₅₀ =19 nM) 和 (IC ₅₀=5.58 µM)，分别。而化合物(20d)和(7c) 分别显示出纳摩尔级选择性激酶抑制，EGFR I​​C ₅₀ = 68 nM 和 VEGFR2 IC ₅₀ = 191 nM。所有合成的化合物都在体外筛选了它们对 60 个人类 NCI 肿瘤细胞系的细胞毒性作用。此外，还进行了分子对接研究和 ADMET 研究，以进一步了解它们的结合模式并预测所有合成抑制剂的药代动力学特性。