Development of Anthraquinone Analogues as Phosphoglycerate Mutase 1 Inhibitors
| Autor: | Deyong Ye, Lulu Jiang, Ke Huang, Lu Zhou, Huiti Li |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Lung Neoplasms
Stereochemistry Pharmaceutical Science Anthraquinones Antineoplastic Agents Alizarin Anthraquinone cancer treatment Analytical Chemistry lcsh:QD241-441 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Non-competitive inhibition lcsh:Organic chemistry Biosynthesis Phosphoglycerate Mutase 1 Drug Discovery Tumor Cells Cultured Humans co-crystal structure Physical and Theoretical Chemistry Enzyme Inhibitors IC50 030304 developmental biology Cell Proliferation Phosphoglycerate Mutase 0303 health sciences Sulfonamides phosphoglycerate mutase 1 Molecular Structure Communication Organic Chemistry In vitro anthraquinone inhibitors chemistry Chemistry (miscellaneous) 030220 oncology & carcinogenesis Molecular Medicine Crystallization |
| Zdroj: | Molecules Molecules, Vol 24, Iss 5, p 845 (2019) |
| ISSN: | 1420-3049 |
| Popis: | Phosphoglycerate mutase 1 (PGAM1) coordinates glycolysis and biosynthesis to promote cancer cell proliferation, and is believed to be a promising target for cancer therapy. Herein, based on the anthraquinone scaffold, we synthesized 31 anthraquinone derivatives and investigated the structure−activity relationship (SAR). The 3-substitient of sulfonamide on the anthraquinone scaffold was essential for maintaining potency and the modifications of the hydroxyl of alizarin would cause a sharp decrease in potency. In the meantime, we determined the co-crystal structure of PGAM1 and one of the anthraquinone inhibitors 9i with IC50 value of 0.27 μM. The co-crystal structure revealed that F22, K100 and R116 of PGAM1 were critical residues for the binding of inhibitors which further validated the SAR. Consistent with the crystal structure, a competitive assay illustrated that compound 9i was a noncompetitive inhibitor. In addition, compound 9i effectively restrained different lung cancer cells proliferation in vitro. Taken together, this work provides reliable guide for future development of PGAM1 inhibitors and compound 9i may act as a new leading compound for further optimization. |
| Databáze: | OpenAIRE |
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