In vivo anticancer potential of hydroxamic acid derivatives

: Notwithstanding the noteworthy advances in its treatment, cancer remains one of the most serious threatens to human across the world. Hydroxamic acid derivatives, the potential inhibitors of histone deacetylases (HDACs), could inhibit cancer cell proliferation, induce cell differentiation, apoptosis and autophagy, and suppress angiogenesis, invasion as well as metastasis through diverse signaling pathways. Thus, hydroxamic acid derivatives exhibit promising activity against cancers and are useful scaffolds in modern anticancer drug discovery. The purpose of the present review article is to summarize the recent developments (Jan. 2011-Jan. 2021) in hydroxamic acid derivatives with insights into their in vivo anticancer potential and mechanisms of action.

Structure-Based Design of Tetrahydroisoquinoline-Based Hydroxamic Acid Derivatives Inhibiting Human Histone Deacetylase 8

We have designed new human histone deacetylase 8 (HDAC8) inhibitors using structure-based molecular design. 3D models of HDAC8–inhibitor complexes were prepared by in situ modification of the crystal structure of HDAC8 co-crystallized with the hydroxamic acid suberoylanilide (SAHA) and a training set (TS) of tetrahydroisoquinoline-based hydroxamic acid derivatives (DAHTs) with known inhibitory potencies. A QSAR model was elaborated for the TS yielding a linear correlation between the computed Gibbs free energies (GFE) of HDAC8–DAHTs complexation (∆∆Gcom) and observed half-maximal enzyme inhibitory concentrations (IC50exp). From this QSAR model a 3D-QSAR pharmacophore (PH4) was generated. Structural information derived from the 3D model and breakdown of computed HDAC8–DAHTs interaction energies up to individual active site residue contributions helped us to design new more potent HDAC8 inhibitors. We obtained a reasonable agreement ∆∆Gcom and values: (pIC50exp = – 0.0376 × ∆∆Gcom + 7.4605, R2 = 0.89). Similar agreement was established for the PH4 model (pIC50exp = 0.8769 × + 0.7854, R2 = 0.87). A comparative analysis of the contributions of active site residues guided the choice of fragments used in designing a virtual combinatorial library (VCL) of DAHT analogs. The VCL of more than 17 thousand DAHTs was screened by the PH4 and furnished 229 new DAHTs. The best-designed analog displayed predicted inhibitory potency up to 110 times higher than that of DAHT1 (IC50exp = 0.047 µM). Predicted pharmacokinetic profiles of the new analogs were compared to current per oral anticancer compounds. This computational approach, which combines molecular modelling, pharmacophore generation, analysis of HDAC8–DAHTs interaction energies and virtual screening of a combinatorial library of DAHTs resulted in a set of proposed new HDAC8 inhibitors. It can thus direct medicinal chemists in their search for new anticancer agents.

N-Alkenylation of hydroxamic acid derivatives with ethynyl benziodoxolone to synthesize cis-enamides through vinyl benziodoxolones

Ethynyl benziodoxolone enabled the chemoselective N-functionalization of O-alkyl hydroxamic acids derived from amino acids and pharmaceuticals. The synthesized cis-vinyl benziodoxolone was derivatized to hydroxamic acid-derived enamides.

Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies

Coumarin-hydroxamic acid derivatives 7a–k were herein designed with a dual purpose: as antiproliferative agents and fluorescent probes. The compounds were synthesized in moderate yields (30–87%) through a simple methodology, biological evaluation was carried out on prostate (PC3) and breast cancer (BT-474 and MDA-MB-231) cell lines to determine the effects on cell proliferation and gene expression. For compounds 7c, 7e, 7f, 7i and 7j the inhibition of cancer cell proliferation was similar to that found with the reference compound at a comparable concentration (10 μM), in addition, their molecular docking studies performed on histone deacetylases 1, 6 and 8 showed strong binding to the respective active sites. In most cases, antiproliferative activity was accompanied by greater levels of cyclin-dependent kinase inhibitor p21, downregulation of the p53 tumor suppressor gene, and regulation of cyclin D1 gene expression. We conclude that compounds 7c, 7e, 7f, 7i and 7j may be considered as potential anticancer agents, considering their antiproliferative properties, their effect on the regulation of the genes, as well as their capacity to dock to the active sites. The fluorescent properties of compound 7j and 7k suggest that they can provide further insight into the mechanism of action.