Department of Chemistry, Pusan National University, Busan, 46241, Republic of Korea.
AmcoBio Inc, Seoul, 08758, Republic of Korea.
Sci Rep. 2020 Nov 16;10(1):19889. doi: 10.1038/s41598-020-77056-4.
Cancer is one of the main causes of mortality in the world. Many cancer cells produce ATP through high-level lactic acid fermentation catalyzed by lactate dehydrogenase (LDH), which converts pyruvic acid to lactic acid. LDH plays a dominant role in the Warburg effect, wherein aerobic glycolysis is favored over oxidative phosphorylation. Due to the high lactic acid production level in cancer cells, LDH-targeting could be a potential cancer treatment strategy. A few approaches, such as drug treatment, reportedly inhibited LDH activity. In this study, we describe new 1,3-benzodioxole derivatives that might be potential small molecule candidates for LDHA inhibition. The synthesis was carried out by trans-esterification between aryl ester and alcohol groups from piperonyl alcohol. Compounds 2 and 10 exhibited a selective LDHA IC value of 13.63 µM and 47.2 µM, respectively. Whereas only compound 10 showed significant cytotoxicity in several lines of cancer cells, especially in human pancreatic cancer PANC-1 cells. These synthesized compounds possess 2 aromatic rings and -CF moiety, which expectedly contributes to LDHA inhibition. The presented products have the potential to become a promising LDHA inhibitor drug candidate.
癌症是世界上主要的死亡原因之一。许多癌细胞通过乳酸脱氢酶（LDH）催化的高水平乳酸发酵产生 ATP，将丙酮酸转化为乳酸。LDH 在瓦博格效应中起主导作用，其中有氧糖酵解优先于氧化磷酸化。由于癌细胞中乳酸的产生水平较高，因此靶向 LDH 可能是一种潜在的癌症治疗策略。一些方法，如药物治疗，据报道可以抑制 LDH 活性。在这项研究中，我们描述了一些新的 1,3-苯并二恶唑衍生物，它们可能是潜在的小分子 LDHA 抑制剂候选物。合成是通过芳基酯和胡椒醇的醇基之间的酯交换反应进行的。化合物 2 和 10 分别表现出对 LDHA 的选择性 IC 值为 13.63µM 和 47.2µM。而只有化合物 10 对几种癌细胞系表现出显著的细胞毒性，特别是对人胰腺癌细胞 PANC-1 细胞。这些合成的化合物具有 2 个芳香环和-CF 部分，预计这有助于 LDHA 的抑制。所呈现的产物有可能成为有前途的 LDHA 抑制剂药物候选物。
