Design, synthesis and antitumor activity evaluation of novel IMPDH II and HDAC1 dual inhibitor†

IF 3.6 4区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

RSC medicinal chemistry Pub Date : 2025-05-21 DOI:10.1039/D5MD00007F

Fang-Bo Deng, Hong-Wei Jia, De-Xiang Hu, Zhen-Li Li, Xiao-Meng Xiu, Xue-Qi Zhao, Yang Liu, Hua-Li Yang and Maosheng Cheng

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Abstract

The development of multi-target inhibitors has garnered considerable attention in the field of cancer therapy. We have designed and synthesized a total of 80 derivatives, categorized into A, B, and C series. Among these compounds, C12 (hIMPDH II, IC₅₀ = 84.69 ± 0.83 nM; HDAC1, IC₅₀ = 81.75 ± 0.82 nM) and C18 (hIMPDH II, IC₅₀ = 820.50 ± 1.41 nM; HDAC1, IC₅₀ = 131.90 ± 1.02 nM) exhibited promising inhibitory activity against hIMPDH II and HDAC1. Compared to the IMPDH-positive compound MPA (IC₅₀ = 403.23 ± 2.92 nM) and the HDAC-positive compound SAHA (IC₅₀ = 1165.72 ± 1.22 nM), compound C12 (IC₅₀ value of 305.31 ± 0.67 nM) demonstrated superior anti-proliferative activity against K-562 cells in vitro. Compound C12 exhibited good liver microsomal stability with a moderate half-life (T_1/2). Furthermore, compound C12 exhibited acceptable in vivo pharmacokinetics of properties. In conclusion, compound C12 represents a potential new dual inhibitor targeting both hIMPDH II and HDAC1.

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新型IMPDH II和HDAC1双抑制剂的设计、合成及抗肿瘤活性评价。

多靶点抑制剂的开发在癌症治疗领域引起了相当大的关注。我们共设计合成了80种衍生物，分为a、B、C系列。其中，C12 (hIMPDH II) IC50 = 84.69±0.83 nM；HDAC1, IC50 = 81.75±0.82 nM)和C18 (hIMPDH II, IC50 = 820.50±1.41 nM；HDAC1 （IC50 = 131.90±1.02 nM）对hIMPDH II和HDAC1具有良好的抑制活性。与impdh阳性化合物MPA （IC50 = 403.23±2.92 nM）和hdac阳性化合物SAHA （IC50 = 1165.72±1.22 nM）相比，化合物C12 （IC50值为305.31±0.67 nM）对K-562细胞具有更强的体外抗增殖活性。化合物C12表现出良好的肝微粒体稳定性，半衰期中等（t1 /2）。此外，化合物C12表现出可接受的体内药代动力学性质。综上所述，化合物C12是一种潜在的针对hIMPDH II和HDAC1的新型双重抑制剂。

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来源期刊

RSC medicinal chemistry Multiple-

CiteScore

5.80

自引率

2.40%

发文量

129