Design, synthesis characterization and biological evaluation of novel multi-isoform ALDH inhibitors as potential anticancer agents
| Autor: | Jyh Ming Lin, Christopher G. Bazewicz, Raghavendra Gowda, Saketh S. Dinavahi, Robert Chitren, Madhu Babu Battu, Gavin P. Robertson, Krishne Gowda, Manoj K. Pandey, Shantu Amin |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Gene isoform
Cell Survival Aldehyde dehydrogenase Antineoplastic Agents Apoptosis 01 natural sciences Lipid peroxidation 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Cancer stem cell Drug Discovery Animals Humans Protein Kinase Inhibitors Cells Cultured 030304 developmental biology ALDH2 Cell Proliferation Pharmacology chemistry.chemical_classification 0303 health sciences biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry General Medicine Cell Cycle Checkpoints Aldehyde Dehydrogenase 0104 chemical sciences ALDH1A1 Isoenzymes Molecular Docking Simulation Enzyme chemistry Drug Design Cancer research biology.protein Drug Screening Assays Antitumor |
| Zdroj: | European journal of medicinal chemistry. 187 |
| ISSN: | 1768-3254 |
| Popis: | 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 IC50s 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 IC50s 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect