Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States; Melanoma and Skin Cancer Center, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States.
Melanoma and Skin Cancer Center, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States; College of Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, United States.
Eur J Med Chem. 2020 Feb 1;187:111962. doi: 10.1016/j.ejmech.2019.111962. Epub 2019 Dec 12.
The aldehyde dehydrogenases (ALDHs) are a family of detoxifying enzymes that are overexpressed in various cancers. Increased expression of ALDH is associated with poor prognosis, stemness, and drug resistance. Because of the critical role of ALDH in cancer stem cells, several ALDH inhibitors have been developed. Nonetheless, all these inhibitors either lack efficacy or are too toxic or have not been tested extensively. Thus, the continued development of ALDH inhibitors is warranted. In this study, we designed and synthesized potent multi-ALDH isoform inhibitors based on the isatin backbone. The early molecular docking studies and enzymatic tests revealed that 3(a-l) and 4(a-l) are the potent ALDH1A1, ALDHA2, and ALDH3A1 inhibitors. ALDH inhibitory ICs of 3(a-l) and 4(a-l) were 230 nM to >10,000 nM for ALDH1A1, 939 nM to >10,000 nM for ALDH2 and 193 nM to >10,000 nM for ALDH3A1. The most potent compounds 3(h-l) had ICs for killing melanoma cells ranged from 2.1 to 5.7 μM, while for colon cancer cells, it ranged from 2.5 to 5.8 μM and for multiple myeloma cells ranging from 0.3 to 4.7 μM. Toxicity studies of 3(h-l) revealed that 3h to be the least toxic multi-ALDH isoform inhibitor. Mechanistically, 3(h-l) caused increased ROS activity, lipid peroxidation, and toxic aldehyde accumulation, secondary to potent multi-ALDH isoform inhibition leading to increased apoptosis and G2/M cell cycle arrest. Together, the study details the design, synthesis, and evaluation of potent, multi-isoform ALDH inhibitors to treat cancers.
醛脱氢酶（ALDHs）是一组解毒酶，在各种癌症中过度表达。ALDH 的表达增加与预后不良、干性和耐药性有关。由于 ALDH 在癌症干细胞中的关键作用，已经开发了几种 ALDH 抑制剂。然而，所有这些抑制剂要么疗效不足，要么毒性太大，要么尚未经过广泛测试。因此，有必要继续开发 ALDH 抑制剂。在这项研究中，我们基于色胺骨架设计并合成了有效的多 ALDH 同工型抑制剂。早期的分子对接研究和酶测试表明，3(a-l)和 4(a-l)是有效的 ALDH1A1、ALDHA2 和 ALDH3A1 抑制剂。3(a-l)和 4(a-l)对 ALDH1A1 的抑制 IC 为 230 nM 至>10,000 nM，对 ALDH2 的抑制 IC 为 939 nM 至>10,000 nM，对 ALDH3A1 的抑制 IC 为 193 nM 至>10,000 nM。最有效的化合物 3(h-l)对黑素瘤细胞的杀伤 IC 范围为 2.1 至 5.7 μM，对结肠癌细胞的杀伤 IC 范围为 2.5 至 5.8 μM，对多发性骨髓瘤细胞的杀伤 IC 范围为 0.3 至 4.7 μM。3(h-l)的毒性研究表明，3h 是毒性最小的多 ALDH 同工型抑制剂。从机制上讲，3(h-l)导致活性氧（ROS）活性、脂质过氧化和毒性醛积累增加，这是由于强效的多 ALDH 同工型抑制导致细胞凋亡和 G2/M 细胞周期停滞增加所致。总之，该研究详细介绍了设计、合成和评估有效的多同工型 ALDH 抑制剂治疗癌症的方法。
