Design, synthesis, biological evaluation and molecular docking study of arylcarboxamido piperidine and piperazine-based hydroxamates as potential HDAC8 inhibitors with promising anticancer activity.

HDAC8 has been established as one of the vital targets as far as the cancer is concerned. Different compounds having potential HDAC inhibitory activity have been approved by USFDA. However, none of these compounds are selective towards specific HDAC isoform. In this current study, some new hydroxamate derivatives with alkylpiperidine and alkylpiperazine linker moieties have been designed, synthesized and biologically evaluated. All these compounds are effective HDAC8 inhibitors comprising more or less similar cytotoxic potential against different cancer cell lines. It is observed that the piperazine scaffold containing compound is more active than the compound with piperidine scaffold for exerting HDAC8 inhibitory activity. Moreover, the 4-quinolyl cap group is better than the biphenyl group which is better than the benzyl group for producing higher HDAC8 inhibition as well as cytotoxicity. These compounds displayed selective HDAC8 inhibition over HDAC3. Moreover, these compounds showed an increased caspase3/7 activity suggesting their anticancer potential through modulation of apoptotic pathways. Molecular docking study with three potent compounds was performed with both HDAC3 and HDAC8 enzymes to understand the selectivity profile of these compounds. Compound containing 4-quinolyl cap group with alkyl piperazinyl urea linker moiety has been emerged out as the lead molecule that may be further modified to design more effective and selective HDAC8 inhibitors in future.

Design, synthesis and biological evaluation of 2-(3,4-dimethoxyphenyl)-6 (1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine analogues as antiproliferative agents.

Two series of forty five novel 2-(3,4-dimethoxyphenyl)-6-(1,2,3,6-tetrahydropyridin-4-yl) imidazo[1,2-a]pyridine analogues (IPA 1-22, IPS 1-22 and IP-NH) have been designed, synthesized and structures confirmed by 1H NMR, 13C NMR, mass spectrometry. Furthermore, single crystal was developed for IPS-13. All the final derived conjugates were evaluated for their in vitro antiproliferative activity against a panel of diverse cancer cell lines viz., A549 (lung cancer), HeLa (cervical cancer), B16F10 (melanoma) and found to show potent anticancer activity on the tested cell lines. Many of them showed the IC50 values in the range 2.0-20.0 µM. The most active compounds (IPA 5,6,8,9,12,16,17,19 and IPS 7,8,9,22) from IPA and IPS series were screened to determine their cytotoxicity on HEK-293 (human embryonic kidney) normal cell line and were found to be nontoxic to normal human cells. The molecular interactions of the derivatised conjugates were also supported by molecular docking simulations. These derivatives may serve as lead structures for development of novel potential anticancer drug candidates.

HDAC3 is a potential validated target for cancer: An overview on the benzamide-based selective HDAC3 inhibitors through comparative SAR/QSAR/QAAR approaches.

Deacetylation of histones by histone deacetylase 3 (HDAC3) is involved in apoptosis, cellular progression and DNA damage. Due to the overexpression of HDAC3 in a variety of cancers, it is implicated to be a crucial validated target for cancer. Therefore, HDAC3 selective inhibitors have roles to play in combating these cancers. Nowadays, compounds comprising benzamide functionality as zinc binding group (ZBG) have been emerged out to be highly effective and selective HDAC3 inhibitors. In this article, QSAR and QAAR studies have been conducted on diverse benzamide-derived HDAC3 inhibitors as the first initiative to explore the designing strategies of higher active and selective HDAC3 inhibitors over HDAC1 and HDAC2. QSAR models reveal that molecular size and shape along with the steric effect should have to be optimized to achieve higher HDAC3 inhibition. QAAR models reflect that modification/substitution at the benzamide scaffold should be optimized in such a way so that these molecules possess lower steric bulk along with nonpolar features for achieving higher HDAC3 selectivity over HDAC1 and HDAC2. However, the importance of spiro hydrophobic cap group, as well as electron withdrawing fluorine group at the benzamide scaffold, should be well-accounted for retaining higher HDAC3 selectivity over HDAC1. Moreover, less polar and less hydrophobic benzamides are preferred for HDAC3 selectivity over HDAC2. This detailed structural exploration will surely unveil a new vista of designing highly potent and selective benzamide-based HDAC3 inhibitors that may be a crucial weapon to battle against a variety of cancers.

Design, synthesis and biological screening of 2-aminobenzamides as selective HDAC3 inhibitors with promising anticancer effects.

Histone deacetylases (HDACs) have been found as a potential target for anticancer therapy. A number of HDAC inhibitors have been used pre-clinically and clinically as anticancer agents. In the current study, we have designed and synthesized compound 12a by combining the scaffolds of CI-994 and BG45. Moreover, the structure of compound 12a was optimized and a series of 2-aminobenzamide derivatives were synthesized further. These compounds were tested for their HDAC inhibitory activity and found to be efficient HDAC inhibitors. Compound 26c showed 11.68-fold HDAC3 selectivity over pan HDACs, better than the prototype HDAC3 inhibitor BG45. Most of these compounds exhibited antiproliferative activity in both B16F10 and HeLa cell lines. Particularly, compound 26c exhibited better antitumor efficacy in the cell lines compared to the prototype inhibitors CI-994 and BG45. It was also found to promote apoptosis as well as induced significant cell growth arrest in the G2/M phase of cell cycle in B16F10 melanoma cells. This work may provide significant insight regarding structural information to design newer small molecule HDAC3 inhibitors to fight against the target specific malignancies in future.

Evaluation of Anti-Tumor Efficacy of Vorinostat Encapsulated Self-Assembled Polymeric Micelles in Solid Tumors.

Vorinostat (VOR), a potent HDAC inhibitor, suffers from low solubility and poor absorption, which hinders its successful application in therapy, especially in the treatment of solid tumors. In this study, an effort to improve the physicochemical characteristics of VOR was made by encapsulating it in PEG-PLGA copolymeric micelles. VOR-loaded PEG-PLGA micelles (VOR-PEG-PLGA) were produced by thin-film hydration and physicochemically characterized. The PEG-PLGA micelles had an average size of 124.06 ± 2.6 nm, polydispersity index of 0.27 ± 0.1, and entrapment efficiency of 90 ± 2.1%. Micelles were characterized by TEM, DSC, and drug release studies. The drug release occurred in a sustained manner up to 72 h from PEG-PLGA micelles. In the in vitro cell-based studies using human breast cancer (MDA MB 231) and murine melanoma (B16F10) cell lines, VOR-PEG-PLGA micelles exhibited superior cellular internalization, enhanced cytotoxic activity, and greater apoptosis compared to free drug. Percent cell killing of 54.9% for VOR-PEG-PLGA-treated cells was observed after 24 h compared to 36% for free VOR in MDA MB 231 cell line. Further, significant tumor suppression was witnessed in B16F10 tumor-bearing mice treated with VOR-PEG-PLGA micelles with a 1.78-fold reduction in tumor volume compared to free VOR-treated animals. Overall, the VOR-PEG-PLGA micelles improved the biopharmaceutical properties of VOR, which resulted in enhanced anti-tumor efficacy. Therefore, the newly developed nano-formulation of VOR could be considered as an effective treatment option in solid tumors.

Discovery of Novel 2-Amino-5-(Substituted)-1,3,4-Thiadiazole Derivatives: New Utilities for Colon Cancer Treatment.

BACKGROUND: Colon cancer is one of the most widespread disease, the mortality rate is high due to cancer metastasis and the development of drug resistance. In this regards, new chemotherapeutic agents with specific mechanisms of action and significant effect on patient's survival are the new era for the colon cancer drug development. OBJECTIVE: The main objective of present study was to design, synthesize of a novel series of 1,3,4-thiadiazole derivatives (VR1 to VR35) and screen them against HT-29 human colon cancer cell line. METHOD: Newly 1,3,4-thiadiazole scaffold were designed, synthesized and further, characterized by FTIR, NMR (1H and 13C), MS and elemental analyses. Before the synthesis, molecular dynamic simulation and ADME studies were performed to find out the most potent lead compounds. Later, SRB assay using HT-29 cells and ELISA assays were performed to explore activity and molecular targets of VR24 and VR27 and find out whether in silico data had a similar pattern in the molecular level. RESULTS: The results of docking study revealed that both VR24 and VR27 had interaction energy >-5 kcal/mol with various assigned molecular targets and the ligand-protein complexes were found to be stable with IL-6. The computational analysis of molecules showed good ADMET profiling. Later, the in vitro anticancer study was conducted where VR24 and VR27 were found to be active against HT-29 cells (GI50<10 µM). Finally, ELISA assays revealed that both the compounds had higher inhibition properties to various biomarker of colon cancer like IL-6 and COX-2. CONCLUSION: Collectively, these result suggested that VR24 and VR27 inhibited the assigned molecular targets, imparting their ameliorative effects against colon cancer. Due to these encouraging results, we concluded that both VR24 and VR27 may be effective against colon cancer therapy in future.

p-TSA-promoted syntheses of 5H-benzo[h] thiazolo[2,3-b]quinazoline and indeno[1,2-d] thiazolo[3,2-a]pyrimidine analogs: molecular modeling and in vitro antitumor activity against hepatocellular carcinoma.

In our efforts to address the rising incidence of hepatocellular carcinoma (HCC), we have made a commitment to the synthesis of novel molecules to combat Hep-G2 cells. A facile and highly efficient one-pot, multicomponent reaction has been successfully devised utilizing a p-toluenesulfonic acid (p-TSA)-catalyzed domino Knoevenagel/Michael/intramolecular cyclization approach for the synthesis of novel 5H-benzo[h]thiazolo[2,3-b]quinazoline and indeno[1,2-d] thiazolo[3,2-a]pyrimidine analogs bearing a bridgehead nitrogen atom. This domino protocol constructed one new ring by the concomitant formation of multiple bonds (C-C, C-N, and C=N) involving multiple steps without the use of any metal catalysts in one-pot, with all reactants effi-ciently exploited. All the newly synthesized compounds were authenticated by means of Fourier transform infrared spectroscopy, liquid chromatography-mass spectrometry, proton nuclear magnetic resonance spectroscopy, and carbon-13 nuclear magnetic resonance spectroscopy, together with elemental analysis, and their antitumor activity was evaluated in vitro on a Hep-G2 human cancer cell line by sulforhodamine B assay. Computational molecular modeling studies were carried out on cancer-related targets, including interleukin-2, interleukin-6, Caspase-3, and Caspase-8. Two compounds (4A and 6A) showed growth inhibitory activity comparable to the positive control Adriamycin, with growth inhibition of 50% <10 µg/mL. The results of the comprehensive structure-activity relationship study confirmed the assumption that two or more electronegative groups on the phenyl ring attached to the thiazolo[2,3-b]quinazoline system showed the optimum effect. The in silico simulations suggested crucial hydrogen bond and π-π stacking interactions, with a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and molecular dynamics, in order to explore the molecular targets of HCC which were in complete agreement with the in vitro findings. Considering their significant anticancer activity, 4A and 6A are potential drug candidates for the management of HCC.

Polymeric micelles of suberoylanilide hydroxamic acid to enhance the anticancer potential in vitro and in vivo.

AIM: To improve the bioavailability and anticancer potential of suberoylanilide hydroxamic acid (SAHA) by developing a drug-loaded polymeric nanomicellar system. METHODS: SAHA-loaded Poly(ethylene glycol)-block-poly(caprolactone) (PEG-PCL) micelles were developed, and physico-chemically characterized. In vitro cellular uptake, viability and apoptosis-inducing ability of the SAHA-PEG-PCL micelles were investigated. In vivo anticancer activity was evaluated in C57BL/6 mice-bearing tumor. RESULTS: The SAHA-PEG-PCL micelles had optimum size (∼130 nm) with an entrapment efficiency of approximately 67%. The SAHA-PEG-PCL induced stronger cell cycle arrest in G2/M phase leading to higher rate of apoptosis compared to free SAHA. SAHA-PEG-PCL demonstrated significant tumor suppression compared to free SAHA in vivo. CONCLUSION: The physicochemical properties and the antitumor efficacy of SAHA were improved by encapsulating in polymeric micelles.

Synthesis and anti-cancer activity of 1,4-disubstituted imidazo[4,5-c]quinolines.

The synthesis and anti-cancer activity evaluation of fused imidazoquinoline compounds is reported in this paper. Yb(OTf)3 has been utilized as a catalyst for the synthesis of 1,4-diaryl substituted imidazo[4,5-c]quinolines via a modified Pictet-Spengler approach. The desired imidazole ring was synthesized from imines using TosMIC (toluenesulfonylmethyl isocyanide) and subsequently functionalized at the C-4 position yielding an imidazoquinoline skeleton. Importantly, the final step was carried out without the aid of any prefunctionalization to obtain the resultant compounds in good yields. The synthesized compounds, when screened for anti-cancer activity, revealed the highest activity with 4-(2-bromophenyl)-1-phenyl-1H-imidazo[4,5-c]quinoline (IC50: 103.3 µM).