Hydroxamic Acid-Based Histone Deacetylase (HDAC) Inhibitors Bearing a Pyrazole Scaffold and a Cinnamoyl Linker

Abstract

Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, recent studies have demonstrated that epigenetic mechanisms are also implicated in the insurgence and development of cancer. Patterns of the epigenetic component include DNA methylation and histone modifications. Acetylation of histones is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalance of these two enzymatic systems is known to be a key factor in tumor progression. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors (HDACIs) are being investigated to act as cancer chemotherapeutics. Herein, we report the synthesis, docking studies and biological activity of a series of hydroxamic acid-based HDACIs bearing an N1-aryl or N1-H pyrazole nucleus as surface recognition motif and a cinnamoyl group as a linker to the hydroxamic acid zinc-binding group (ZBG). Some of the tested compounds exhibited inhibitory properties towards HDACs and antiproliferative activity against neuroblastoma SH-SY5Y tumor cell line both at micromolar concentrations.

In Vitro Antimalarial Activity of Inhibitors of the Human GTPase Rac1

“…Commercially available inhibitors of Rac1 guanosine nucleotide exchange activity or inhibitors of the interaction between Rac1 and its GEFs were purchased from Aobious (ZINC69391), Focus Biomolecules (MLS000532223), EMD Millipore (Aza-1), Tocris (NSC23766), Merck (EHop-016, ML141, and Rac1 inhibitor II), and Enamine (compound 4). Compounds 3 and 3′ were synthesized by adapting protocols reported in the literature ( 56 , 57 ), as described in Fig. S2 in the supplemental material.…”

Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring

“…¼ <260 C with decomposition. 1 [1,3]dioxol-5-yl)acetamido)benzyl)-N-hydroxybenzamide (18). 17 (100 mg, 0.21 mmol, 1 equiv.)…”

“…The most signicant structural modication was obtained by switching the ZBG to position 2, affording 5, which, to the best of our knowledge, is the most active quinazoline inhibitor reported so far (IC 50 ¼ 12 nM). 13 Based on these premises and relying on our previous work on HDAC6 inhibitors, 2,[15][16][17][18][19] in this study we report the computational design and the synthesis of two structurally novel derivatives containing an aminotriazoloquinazoline (11a) and aminotriazole scaffold (18). The two synthesized compounds were tested in vitro to evaluate their inhibitory activity against HDAC6.…”

Hydroxamic Acid Derivatives: From Synthetic Strategies to Medicinal Chemistry Applications

“…The subsequent deprotection of hydroxylamine depends on the nature of the protecting group. The silyl ethers are efficiently removed by treatment with 2–3 equiv of tetra- n -butylammonium fluoride (TBAF) in THF or TFA (25% in DCM) at room temperature, while O -benzyl hydroxamates can be deprotected by catalytic hydrogenation with quantitative yields. The trityl group is effectively removed in TFA, while hydroxamic acid, such as THP ether can be deprotected by treatment with catalytic TsOH in MeOH or with fluoride sources (selectfluor) …”