PDF(Pubmed)
Abstract：
Aldehyde dehydrogenases (ALDHs) are a family of enzymes that aid in detoxification and are overexpressed in several different malignancies. There is a correlation between increased expression of ALDH and a poor prognosis, stemness, and resistance to several drugs. Several ALDH inhibitors have been generated due to the crucial role that ALDH plays in cancer stem cells. All of these inhibitors, however, are either ineffective, very toxic, or have yet to be subjected to rigorous testing on their effectiveness. Although various drug-like compounds targeting ALDH have been reported in the literature, none have made it to routine use in the oncology clinic. As a result, new potent, non-toxic, bioavailable, and therapeutically effective ALDH inhibitors are still needed. In this study, we designed and synthesized potent multi-ALDH isoform inhibitors based on the isatin and indazole pharmacophore. Molecular docking studies and enzymatic tests revealed that among all of the synthesized analogs, compound 3 is the most potent inhibitor of ALDH1A1, ALDH3A1, and ALDH1A3, exhibiting 51.32%, 51.87%, and 36.65% inhibition, respectively. The ALDEFLUOR assay further revealed that compound 3 acts as an ALDH broad spectrum inhibitor at 500 nM. Compound 3 was also the most cytotoxic to cancer cells, with an IC50 in the range of 2.1 to 3.8 µM for ovarian, colon, and pancreatic cancer cells, compared to normal and embryonic kidney cells (IC50 7.1 to 8.7 µM). Mechanistically, compound 3 increased ROS activity due to potent multi-ALDH isoform inhibition, which increased apoptosis. Taken together, this study identified a potent multi-isoform ALDH inhibitor that could be further developed as a cancer therapeutic.
摘要：
醛脱氢酶(ALDHs)是有助于解毒的酶家族,并且在几种不同的恶性肿瘤中过表达。ALDH的表达增加与不良预后之间存在相关性，stemness,和对几种药物的抗药性。由于ALDH在癌症干细胞中发挥的关键作用,已经产生了几种ALDH抑制剂。所有这些抑制剂，然而,要么无效，剧毒,或尚未对其有效性进行严格测试。尽管文献中已经报道了靶向ALDH的各种药物样化合物,没有人在肿瘤诊所常规使用。因此,新的强效，无毒,生物可利用，仍然需要治疗有效的ALDH抑制剂。在这项研究中,我们设计并合成了有效的多ALDH同工型抑制剂，其基础是拉丁红和吲哚唑药效团。分子对接研究和酶学测试表明，在所有合成的类似物中，化合物3是ALDH1A1，ALDH3A1和ALDH1A3的最有效抑制剂，表现为51.32％，51.87%,和36.65%的抑制，分别。ALDEFLUOR测定进一步揭示了化合物3在500nM下作为ALDH广谱抑制剂起作用。化合物3对癌细胞的细胞毒性最大，对于卵巢，IC50在2.1至3.8µM的范围内，结肠,和胰腺癌细胞，与正常和胚胎肾细胞相比（IC507.1至8.7µM）。机械上,由于有效的多ALDH亚型抑制，化合物3增加了ROS活性，增加了细胞凋亡。一起来看,这项研究确定了一种有效的多同工型ALDH抑制剂,该抑制剂可以进一步开发为癌症治疗剂.
