Synthesis and anticancer activities of thieno[3,2-d]pyrimidines as novel HDAC inhibitors

A series of thieno[3,2-d]pyrimidines bearing a hydroxamic acid moiety as novel HDAC inhibitors were designed and synthesized. The structures of the new synthesized compounds were confirmed using IR, ¹H, ¹³C NMR spectrum. Compounds 11–13 showed potent inhibitory activities against HDACs with IC₅₀ values at 0.38, 0.49 and 0.61 μM. Most of target compounds displayed strong anti-proliferative activity by a MTT assay on three human cancer cell lines including HCT-116, MCF-7 and HeLa. Compound 11, having potent inhibitory activities against HDACs, induced apoptosis and G2/M cell cycle arrest in HCT-116 cell line.     

Design,synthesis and anticancer evaluation of acridine hydroxamic acid derivatives as dual Topo and HDAC inhibitors

Multitarget inhibitors design has generated great interest in cancer treatment. Based on the synergistic effects of topoisomerase and histone deacetylase inhibitors, we designed and synthesized a new series of acridine hydroxamic acid derivatives as potential novel dual Topo and HDAC inhibitors. MTT assays indicated that all the hybrid compounds displayed good antiproliferative activities with IC₅₀ values in low micromolar range, among which compound 8c displayed potent activity against U937 (IC₅₀?=?0.90?μM). In addition, compound 8c also displayed the best HDAC inhibitory activity, which was several times more potent than HDAC inhibitor SAHA. Subsequent studies indicated that all the compounds displayed Topo II inhibition activity at 50?μM. Moreover, compound 8c could interact with DNA and induce U937 apoptosis. This study provides a suite of compounds for further exploration of dual Topo and HDAC inhibitors, and compound 8c can be a new dual Topo and HDAC inhibitory anticancer agent.     

Synthesis and biological evaluation of piperamide analogues as HDAC inhibitors

Two natural piperamides (piperlonguminine and refrofractamide A) and their derivatives were synthesized and evaluated for inhibitory activity against histone deacetylases, as well as the HCT-116 human colon cancer cell line. The preliminary structure activity relationship was discussed. Compounds featuring a hydroxamic acid moiety exhibited moderate HDAC activity and in vitro cytotoxicity.     

Fluorescent analogs of peptoid-based HDAC inhibitors: Synthesis,biological activity and cellular uptake kinetics

Fluorescent tagging of bioactive molecules is a powerful tool to study cellular uptake kinetics and is considered as an attractive alternative to radioligands. In this study, we developed fluorescent histone deacetylase (HDAC) inhibitors and investigated their biological activity and cellular uptake kinetics. Our approach was to introduce a dansyl group as a fluorophore in the solvent-exposed cap region of the HDAC inhibitor pharmacophore model. Three novel fluorescent HDAC inhibitors were synthesized utilizing efficient submonomer protocols followed by the introduction of a hydroxamic acid or 2-aminoanilide moiety as zinc-binding group. All compounds were tested for their inhibition of selected HDAC isoforms, and docking studies were subsequently performed to rationalize the observed selectivity profiles. All HDAC inhibitors were further screened in proliferation assays in the esophageal adenocarcinoma cell lines OE33 and OE19. Compound 2, 6-((N-(2-(benzylamino)-2-oxoethyl)-5-(dimethylamino)naphthalene)-1-sulfonamido)-N-hydroxyhexanamide, displayed the highest HDAC inhibitory capacity as well as the strongest anti-proliferative activity. Fluorescence microscopy studies revealed that compound 2 showed the fastest uptake kinetic and reached the highest absolute fluorescence intensity of all compounds. Hence, the rapid and increased cellular uptake of 2 might contribute to its potent anti-proliferative properties.     

Synthesis and biological activity of cyclotetrapeptide analogues of the natural HDAC inhibitor FR235222

In the course of our ongoing efforts to discover new and more effective HDAC inhibitors useful for the development of promising anticancer candidates, we have recently undertaken a molecular modelling study on a small collection of FR235222 analogues, synthesized by us in the frame of a structure–activity relationship investigation, made in order to identify the key structural elements essential for the activity. Progress made in structure elucidation of HDAC active site, together with accurate docking calculations, provided new structural insights useful for a further refinement of the tetrapeptide scaffold which should assure an optimal interaction between the synthetic ligands and the biological target. Following the computer aided suggestions we synthesized six new cyclotetrapeptide analogues of the lead compound (3–8), bearing a carboxylic or an hydroxamic acid functionality as Zn binding moiety. Herein we describe their synthesis and their inhibition activity on different HDAC isoforms.     

Design,synthesis, molecular docking,anti-Proteus mirabilis and urease inhibition of new fluoroquinolone carboxylic acid derivatives

New hydroxamic acid, hydrazide and amide derivatives of ciprofloxacin in addition to their analogues of levofloxacin were prepared and identified by different spectroscopic techniques. Some of the prepared compounds revealed good activity against the urease splitting bacteria, Proteus mirabilis. The urease inhibitory activity was investigated using indophenol method. Most of the tested compounds showed better activity than the reference acetohydroxamic acid (AHA). The ciprofloxacin hydrazide derivative 3a and levofloxacin hydroxamic acid 7 experienced the highest activity (IC₅₀ = 1.22 μM and 2.20 μM, respectively). Molecular docking study revealed high spontaneous binding ability of the tested compounds to the active site of urease.     

Utilization of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinone as a cap moiety in design of novel histone deacetylase inhibitors

A series of novel 5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one derivatives bearing a hydroxamic acid, 2-aminoanilide and hydrazide moieties as zinc-binding group (ZBG) were designed, synthesized and evaluated for the HDAC inhibition activity and antiproliferative activity. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds IVa, IVb, IXa and IXb exhibited significant anti-proliferative activity against the three cell lines tested compared to SAHA as a reference. Compound IVb is equipotent inhibitor for HDAC1 and HDAC2 as SAHA. It is evident that the presence of free hydroxamic acid group is essential for Zn binding affinity with maximal activity with a linker of aliphatic 6 carbons. Docking study results revealed that compound IVb could occupy the HDAC2 binding site and had the potential to exhibit antitumor activity through HDAC inhibition, which merits further investigation.     

Design and synthesis of aryl ether and sulfone hydroxamic acids as potent histone deacetylase (HDAC) inhibitors

A series of novel hydroxamic acid based histone deacetylases (HDAC) inhibitors with aryl ether and aryl sulfone residues at the terminus of a substituted, unsaturated 5-carbon spacer moiety have been synthesized for the first time and evaluated. Compounds with meta- and para-substitution on the aryl ring of ether hydroxamic acids 19c, 20c, 19e, 19f and 19g are potent HDAC inhibitors with activities at low nanomolar levels.     

Development of novel ferulic acid derivatives as potent histone deacetylase inhibitors

Histone deacetylase inhibitors (HDACIs) offer a promising strategy for cancer therapy. The discovery of potent ferulic acid-based HDACIs with hydroxamic acid or 2-aminobenzamide group as zinc binding group was reported. The halogeno-acetanilide was introduced as novel surface recognition moiety (SRM). The majority of title compounds displayed potent HDAC inhibitory activity. In particular, FA6 and FA16 exhibited significant enzymatic inhibitory activities, with IC₅₀ values of 3.94 and 2.82 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against a panel of human cancer cells. FA17 displayed promising profile as an antitumor candidate. The results indicated that these ferulic acid derivatives could serve as promising lead compounds for further optimization.     

Synthesis, enzymatic inhibition, and cancer cell growth inhibition of novel delta-lactam-based histone deacetylase (HDAC) inhibitors

delta-Lactam-based hydroxamic acids, inhibitors of histone deacetylase (HDAC), have been synthesized via ring closure metathesis of key diene intermediates followed by conversion to hydroxamic acid analogues. The hydroxamic acids 12a, 12b, and 17c showed potent inhibitory activity in HDAC enzyme assay. The hydroxamic acid 12b exhibited growth inhibitory activity on five human tumor cell lines, showing good sensitivity on the MDA-MB-231 breast tumor cell.     

Quinolone-based HDAC inhibitors

Abstract

HDAC inhibitors emerged as promising drug candidates in combating wide variety of cancers. At present, two of the compounds SAHA and Romidepsin were approved by FDA for cutaneous T-cell lymphoma and many are in various clinical phases. A new quinolone cap structure was explored with hydroxamic acid as zinc-binding group (ZBG). The pan HDAC inhibitory and antiproliferative activities against three human cancer cell lines HCT-116 (colon), NCI-H460 (lung) and U251 (glioblastoma) of the compounds (4a–4w) were evaluated. Introduction of heterocyclic amines in CAP region increased the enzyme inhibitory and antiproliferative activities and few of the compounds tested are metabolically stable in both MLM and HLM.     

Toward an HDAC6 inhibitor: synthesis and conformational analysis of cyclic hexapeptide hydroxamic acid designed from alpha-tubulin sequence

A cyclic hexapeptide hydroxamic acid inhibitor for HDAC6 has been designed and synthesized on the basis of the facts that alpha-tubulin is the substrate of HDAC6 and of the excellent inhibitory activity of cyclic tetrapeptide hydroxamic acids (CHAPs) for HDACs. Unexpectedly, cyclic hexapeptide hydroxamic acid showed very low HDAC inhibitory activity. To explain the low activity, we have carried out conformation analysis and compared it to the crystal structure of alpha-tubulin. The conformation around the acetylated lysine of the cyclic hexapeptide substrate or the aminosuberate hydroxamic acid [Asu(NHOH)] of cyclic hexapeptide inhibitor is different from that around alpha-tubulin's lysine-40. The difference in the conformation seems to cause some steric hindrance at the capping site resulting in poor binding capacity.     

Design,synthesis, docking studies and biological evaluation of novel chalcone derivatives as potential histone deacetylase inhibitors

A group of novel chalcone derivatives comprising hydroxamic acid or 2-aminobenzamide group as zinc binding groups (ZBG) were synthesized. The structure of the prepared compounds was fully characterized by IR, NMR and elemental microanalyses. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds 4a and 4b exhibited significant anti-proliferative activity against the three cell lines compared to SAHA as reference drug and displayed promising profile as anti-tumor candidates. The results indicated that these chalcone derivatives could serve as a promising lead compounds for further optimization as antitumor agents.     

Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors

Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC₅₀ values of 40: HDAC1, 0.0038 μM; HDAC2, 0.0082 μM; HDAC3, 0.015 μM; HDAC8, 0.0060 μM; HDAC4, 0.058 μM; HDAC9, 0.0052 μM; HDAC6, 0.058 μM). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process.     

Design, synthesis, and evaluation of isoindolinone-hydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors

We designed and synthesized hydroxamic acid derivatives bearing a 4-(3-pyridyl)phenyl group as a cap structure, and found that they exhibit potent histone deacetylase (HDAC) inhibitory activity. A representative compound, 17a, showed more potent growth-inhibitory activity against pancreatic cancer cells and greater upregulation of p21(WAF1/CIP1) expression than the clinically used HDAC inhibitor suberoylanilide hydroxamic acid (Zolinza).     

Epigenetic modifier-induced biosynthesis of novel acetylenic sterols from Cladosporium colocasiae

The addition of an HDAC inhibitor, suberoylanilide hydroxamic acid (SBHA), to the culture medium of Cladosporium colocasiae, dramatically altered its metabolic profiles. Analysis of the culture broth extract led to the isolation of two new acetylenic sterols (1–2). The isolated compounds were further evaluated for their cytotoxic and antibacterial activities. Compound 1 showed activity against Bacillus subtilis, affording a zone of inhibition of 12 mm at 100 μg/disk. However, none of them showed noticeable growth inhibitory effects.     

Induction of funitatin A,a new polyketide from the Yellow River wetland-derived fungus Talaromyces funiculosus

A new, highly modified fatty acid ester, funitatin A (1), was isolated from the Yellow River wetland-derived fungus Talaromyces funiculosus HPU-Y01 cultivated with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). The structure of 1 was established by analysis of NMR and HRESIMS data. Compound 1 featured a rare dimeric cyclopaldic acid structure and showed promising antimicrobial activity against both Proteus species and Escherichia coli with MIC values of 3.13 μM.     

Design,synthesis and evaluation of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones as histone deacetylase inhibitors and antitumor agents

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized several series of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones (4a-h, 8a-d, 10a-d). Biological evaluation showed that these hydroxamic acids were generally cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer). It was found that the N-hydroxypropenamides (10a-d) were the most potent, both in term of HDAC inhibition and cytotoxicity. Several compounds, e.g. 4e, 8b-c, and 10a-c, displayed up to 4-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in term of cytotoxicity. These compounds also comparably inhibited HDACs with IC₅₀ values in sub-micromolar range. Docking experiments on HDAC2 isozyme revealed some important features contributing to the inhibitory activity of synthesized compounds, especially for propenamide analogues. Importantly, the free binding energy computed was found to have high quantitative correlation (R² ∼ 95%) with experimental results.     

Design,synthesis and biological evaluation of di-substituted cinnamic hydroxamic acids bearing urea/thiourea unit as potent histone deacetylase inhibitors

A novel class of di-substituted cinnamic hydroxamic acid derivatives containing urea or thiourea unit was designed, synthesized and evaluated as HDAC inhibitors. All tested compounds demonstrated significant HDAC inhibitory activities and anti-proliferative effects against diverse human tumor cell lines. Among them, 7l exhibited most potent pan-HDAC inhibitory activity, with an IC₅₀ value of 130 nM. It also showed strong cellular inhibition against diverse cell lines including HCT-116, MCF-7, MDB-MB-435 and NCI-460, with GI₅₀ values of 0.35, 0.22, 0.51 and 0.48 μM, respectively.     

Design,synthesis and preliminary bioactivity studies of 1,2-dihydrobenzo[d]isothiazol-3-one-1,1-dioxide hydroxamic acid derivatives as novel histone deacetylase inhibitors

Histone deacetylase (HDAC) is a clinically validated target for antitumor therapy. In order to increase HDAC inhibition and efficiency, we developed a novel series of saccharin hydroxamic acids as potent HDAC inhibitors. Among them, compounds 11e, 11m, 11p exhibited similar or better HDACs inhibitory activity compared with the approved drug SAHA. Further biological evaluation indicated that compound 11m had potent antiproliferative activities against MDA-MB-231 and PC-3.