Novel hydroxamic acids incorporating 1-((1H-1,2,3-Triazol-4-yl)methyl)-3-hydroxyimino-indolin-2-ones: synthesis, biological evaluation, and SAR analysis

Abstract

A series of seventeen novel hydroxamic acids incorporating 1-((1H-1,2,3-triazol-4-yl)methyl)-3-hydroxyimino-indolin-2-ones was designed and synthesized. Biological evaluation showed that these hydroxamic acids potently inhibited a class-I isoform of HDACs (HDAC2) with IC 50 values in low micromolar range. Several compounds also exhibited good cytotoxicity. Two compounds, 5e and 5f, emerged as the most potent HDAC2 inhibitors with cytotoxicity up to 8-fold more potent than SAHA in three human cancer cell lines, including SW620 (colon cancer), PC3 (prostate cancer) and AsPC-1 (pancreatic cancer). A molecular modeling approach has been carried out which revealed some structure-activity relationships. Further investigation on absorption, distribution, metabolism, excretion and toxicity (ADMET) suggested that compounds 5e and 5f, while showing potent HDAC2 inhibitory bioactivity, hold desirable characteristics for anticancer compounds.

Novel (E)-3-(1-substituted-1H-indazol-5-yl)-N-hydroxypropenamides as histone deacetylase inhibitors: design, synthesis and structure–activity relationships

“…Docking simulation of all the synthesized compounds was performed by using the Molecular Operating Environment package (MOE software) as previously reported, 34–40 version 2015.10. 41 This study was performed on eight HDAC isoforms to prove the selectivity of all the compounds.…”

Significance of Five-Membered Heterocycles in Human Histone Deacetylase Inhibitors

“…Evaluation against four cancer cell lines showed IC 50 values of SW620 (8.73 µM and 2.06 µM), PC3 (7.98 µM and 2.62 µM), AsPC-1 (4.18 µM and 1.39 µM) and NCI-H23 (5.46 µM and 1.14 µM) for 78 and 79, respectively. Follow up studies by Dung et al [75] yielded compounds 80 and 81 (Figure 21), with potencies better or comparable to SAHA, exhibiting IC 50 values against cancer cell lines of SW620 (0.73 µM and 1.61 µM), PC3 (0.76 µM and 1.74 µM) and AsPC-1 (0.49 µM and 1.49 µM). Further screening and improvements by Dung et al [76] yielded representatives 82 and 83 (Figure 21).…”

Novel 4-Oxoquinazoline-BasedN-Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation

“…Based on the findings of Wu et al, hydroxamic acids should be deprotonated upon its binding to the zinc ion. The receptor was prepared using the QuickPrep module in MOE 2015.10, similar to those reported previously. , During the preparation, solvent and noncomplexed ions were deleted, Protonate3D was used for setting protonation states allowing ASN/GLN/HIS “Flips” in this function, polar hydrogen atoms were added, and all atoms were assigned AMBER FF99 force field. For the docking assays, the flexible ligand-rigid protein settings were applied using the MOE Triangle Matcher placement method, keeping the best 30 poses for conformational analysis.…”