Design, Synthesis and Biological Evaluation of Novel MDH Inhibitors Targeting Tumor Microenvironment
In: Pharmaceuticals; Volume 16; Issue 5; Pages: 683, 2023
academicJournal
Zugriff:
MDH1 and MDH2 enzymes play an important role in the survival of lung cancer. In this study, a novel series of dual MDH1/2 inhibitors for lung cancer was rationally designed and synthesized, and their SAR was carefully investigated. Among the tested compounds, compound 50 containing a piperidine ring displayed an improved growth inhibition of A549 and H460 lung cancer cell lines compared with LW1497. Compound 50 reduced the total ATP content in A549 cells in a dose-dependent manner; it also significantly suppressed the accumulation of hypoxia-inducible factor 1-alpha (HIF-1α) and the expression of HIF-1α target genes such as GLUT1 and pyruvate dehydrogenase kinase 1 (PDK1) in a dose-dependent manner. Furthermore, compound 50 inhibited HIF-1α-regulated CD73 expression under hypoxia in A549 lung cancer cells. Collectively, these results indicate that compound 50 may pave the way for the development of next-generation dual MDH1/2 inhibitors to target lung cancer.
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Design, Synthesis and Biological Evaluation of Novel MDH Inhibitors Targeting Tumor Microenvironment
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Autor/in / Beteiligte Person: | Godesi, Sreenivasulu ; Han, Jeong-Ran ; Kim, Jang-Keun ; Kwak, Dong-Ik ; Lee, Joohan ; Nada, Hossam ; Kim, Minkyoung ; Yang, Hyun-A ; Im, Joo-Young ; Hyun Seung Ban ; Chang Hoon Lee ; Choi, Yongseok ; Won, Misun ; Lee, Kyeong |
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Zeitschrift: | Pharmaceuticals; Volume 16; Issue 5; Pages: 683, 2023 |
Veröffentlichung: | Multidisciplinary Digital Publishing Institute, 2023 |
Medientyp: | academicJournal |
DOI: | 10.3390/ph16050683 |
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