Design, synthesis, and biological evaluation of β-carboline 1,3,4-oxadiazole based hybrids as HDAC inhibitors with potential antitumor effects
- Bioorg Med Chem Lett. 2022 May 15:64:128663. doi: 10.1016/j.bmcl.2022.128663.
- 1. Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, PR China; School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
- 2. Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, PR China; School of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
- 3. Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, PR China.
- 4. Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, PR China; School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
- 5. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
- 6. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
- 7. Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, PR China; School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].
A series of novel β-carboline 1,3,4-oxadiazole based hybrids were designed, synthesized, and tested for cytotoxicity and HDAC inhibition. Among the target compounds, compound ZDLT-1 displayed high inhibitory activity for class I HDACs 1, 2, and 3, and potent anti-proliferative activity against HCT116 cells with an IC50 value of 0.173 ± 0.018 μM, it also exhibited better inhibitory activity with an IC50 value of 6 nM for HDAC6 than SAHA (IC50 = 15 nM). Furthermore, the pharmacological experiment of Hoechst staining, colony formation, cell Apoptosis assay, and wound healing scratch assay indicated that compound ZDLT-1 was a potent cytotoxic agent against HCT116 cells with cell Apoptosis induction. Further, in silico prediction of physicochemical properties, drug-likeness, and ADME parameters suggested that compound ZDLT-1 is a promising Anticancer agent. Taken together, the high potency cytotoxicity and class I HDACs inhibitory activity of compound ZDLT-1, which with the β-carboline 1,3,4-oxadiazole based hybrids as potent Anticancer agents could be nominated for further modification and optimization.