2. Academic Validation
  3. Synthesis of 1-Hydroxy(and 1-Alkoxy, 1-Acyloxy)-1H-indoles and evaluations of their suppressive activities against tumor growth through inhibiting lactate dehydrogenase A

Synthesis of 1-Hydroxy(and 1-Alkoxy, 1-Acyloxy)-1H-indoles and evaluations of their suppressive activities against tumor growth through inhibiting lactate dehydrogenase A

  • Eur J Med Chem. 2025 Feb 5:283:117104. doi: 10.1016/j.ejmech.2024.117104.
Se-Yun Cheon 1,  Ye Eun Kim 2,  Eun-Sun Yang 1,  Yoo Jin Lim 2,  Chang-Hwan Bae 3,  Jung-Sook Jin 1,  Wonyoung Park 4,  Bo-Sung Kim 4,  Chorong Kim 2,  Hyunsung Cho 2,  Seungtae Kim 4,  Sang Hyup Lee 5,  Ki-Tae Ha 6
Affiliations

Affiliations

  • 1 Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea.
  • 2 College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul, 01369, Republic of Korea.
  • 3 Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do, 58245, Republic of Korea.
  • 4 Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea; Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea.
  • 5 College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul, 01369, Republic of Korea. Electronic address: sanghyup@duksung.ac.kr.
  • 6 Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea; Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. Electronic address: hagis@pusan.ac.kr.
PMID: 39642694 DOI: 10.1016/j.ejmech.2024.117104
Abstract

Inhibition of Lactate Dehydrogenase (LDH) has emerged as a promising Cancer therapy strategy due to its essential role in the metabolic transformation of Cancer cells. In this study, 53 derivatives of 1-hydroxy(and 1-alkoxy, 1-acyloxy)indoles were designed, synthesized, and biologically evaluated. Several multi-substituted 1-hydroxy(and 1-alkoxy, 1-acyloxy)indole compounds exhibited inhibitory activity against the LDH-A isoform (LDHA). We confirmed that the C(3)-substituent provided additional significant hydrogen bonding and hydrophobic interactions, which enhanced the LDHA inhibitory activity with high selectivity. Our results revealed that methyl 4-bromo-3-[(n-hexyloxy)methyl]-1-hydroxy-1H-indole-2-carboxylate (1g), selectively inhibited LDHA (IC50 = 25 ± 1.12 nM) without affecting the LDH-B isoform (LDHB). The compound exhibited potent cytotoxic activity in several Cancer cell lines, including DLD-1 colorectal Cancer cells (GI50 = 27 ± 1.2 μM). Compound 1g significantly inhibited Cancer cell growth by activating apoptotic pathways in a xenograft Cancer model, without causing weight loss or liver and kidney damage. Therefore, compound 1g may serve as a highly specific and promising candidate for the development of LDHA inhibitors for Cancer therapy.

Keywords

1-Hydroxyindole; Anticancer; Apoptosis; DLD-1; Lactate dehydrogenase (LDH).

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