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The article discusses the role of histone acetyltransferase enzymes (HATs) and histone deacetylases (HDACs) in regulating epigenetic processes that affect gene transcription and genomic stability. HDACs, in particular, have been the focus of drug discovery for cancer therapy, with several inhibitors already approved. Current research is focused on developing selective inhibitors for different subtypes of HDACs. The article also explores the use of protein degradation through proteolysis targeting chimera (PROTAC) as a new approach for inhibiting physiological processes. The Special Issue highlights various studies on the development and biological characterization of HDAC and HAT inhibitors, as well as their therapeutic efficacy in combination with other drugs. [Extracted from the article]

Pursuing on our efforts toward searching for efficient hCA IX and hCA XII inhibitors, herein we report the design and synthesis of new sets of benzofuran-based sulphonamides (4a,b, 5a,b, 9a–c, and 10a–d), featuring the zinc anchoring benzenesulfonamide moiety linked to a benzofuran tail via a hydrazine or hydrazide linker. All the target benzofurans were examined for their inhibitory activities toward isoforms hCA I, II, IX, and XII. The target tumour-associated hCA IX and XII isoforms were efficiently inhibited with KIs spanning in ranges 10.0–97.5 and 10.1–71.8 nM, respectively. Interestingly, arylsulfonehydrazones 9 displayed the best selectivity toward hCA IX and XII over hCA I (SIs: 39.4–250.3 and 26.0–149.9, respectively), and over hCA II (SIs: 19.6–57.1 and 13.0–34.2, respectively). Furthermore, the target benzofurans were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Only benzofurans 5b and 10b possessed selective and moderate growth inhibitory activity toward certain cancer cell lines. [ABSTRACT FROM AUTHOR]

On account of their significance as apoptosis inducing agents, merging indole and 3-hydrazinoindolin-2-one scaffolds is a logic tactic for designing pro-apoptotic agents. Consequently, 27 hybrids (6a-r, 9a-f and 11a-c) were synthesised and evaluated for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines. SAR studies unravelled that N-propylindole derivatives were the most active compounds such as 6n (MCF-7; IC50=1.04 µM), which displayed a significant decrease of cell population in the G2/M phase and significant increase in the early and late apoptosis by 19-folds in Annexin-V-FTIC assay. Also, 6n increased the expression of caspase-3, caspase-9, cytochrome C and Bax and decreased the expression of Bcl-2. Moreover, compounds 6i, 6j, 6n and 6q generated ROS by significant increase in the level of SOD and depletion of the levels of CAT and GSH-Px in MCF-7. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a-p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC50 = 6.70, 6.40 and 6.70 µM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC50 = 120 and 150 nM, respectively). Collectively, these data demonstrated that 6e might be a potential lead compound for the development of effective anti-TNBC agents. [ABSTRACT FROM AUTHOR]

In our endeavor towards the development of potent anticancer agents, two different sets of biphenylurea-indolinone conjugates, 5a–s and 8a,b were synthesized. The in vitro cytotoxicity of the synthesized compounds was examined in two human cancer cell lines, namely MCF-7 breast cancer and PC-3 prostate cancer cells using the sulforhodamine B (SRB) colorimetric assay. In particular, the MCF-7 cancer cell line was more susceptible to the synthesized compounds. Compound 5o (IC50 = 1.04 ± 0.10 μM) emerged as the most active member in this study against MCF-7, with 7-fold increased activity compared to the reference drug, doxorubicin (IC50 = 7.30 ± 0.84 μM). Compounds 5l, 5q and 8b also exhibited superior cytotoxic activity against MCF-7 with IC50 values of 1.93 ± 0.17, 3.87 ± 0.31 and 4.66 ± 0.42 μM, respectively. All of the tested compounds were filtered according to the Lipinski and Veber rules and all of them passed the filters. Additionally, several ADME descriptors for the synthesized compounds 5a–s and 8a,b were predicted via a theoretical kinetic study performed using the Discovery Studio 2.5 software. [ABSTRACT FROM AUTHOR]

Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins. [ABSTRACT FROM AUTHOR]

In our endeavor towards the development of effective anticancer agents, a novel series of pyridine-ureas 8a–n were synthesized. All the newly prepared derivatives were evaluated in vitro for their growth inhibitory activity towards the proliferation of breast cancer MCF-7 cell line. Compounds 8e and 8n were found to be the most active congeners against MCF-7 cells (IC50 = 0.22 and 1.88 µM after 48 h treatment; 0.11 and 0.80 µM after 72 h treatment, respectively) with increased activity compared to the reference drug doxorubicin (IC50 = 1.93 µM). Moreover, eight selected pyridines 8b, 8d, 8e, 8i, 8j and 8l–n were evaluated for their in vitro anticancer activity according to the US-NCI protocol. Pyridines 8b and 8e proved to be the most effective anticancer agents in the NCI assay with mean inhibition = 43 and 49%, respectively. Both 8b and 8e exhibited anti-proliferative activity against all tested cancer cell lines from all subpanels growth inhibition (GI for 8b; 12–78%, GI for 8e; 15–91%). Pyridines 8b and 8e were screened in vitro for their inhibitory activity against VEGFR-2. Both compounds inhibited VEGFR-2 at micromolar IC50 values 5.0 ± 1.91 and 3.93 ± 0.73 µM, respectively. The most active pyridines were filtered according to the Lipinski and Veber rules and all of them passed these filters. Finally, several ADME descriptors were predicted for the active pyridines through a theoretical kinetic study. [ABSTRACT FROM AUTHOR]

A series of chalcone-based diarylpyrazoles containing a phenylsulphone or carbonitrile moiety was synthesized. Thus, 3-acetylpyrazoles 6a-c and 10a-c were used as useful substrates in facile synthesis of functional pyrazoles 7a-f and 11a-f, respectively. The anti-inflammatory activity and ulcerogenic effect were evaluated and some of the obtained products possessed a significant anti-inflammatory activity. 1-[1-(3-Methylphenyl)-5-phenyl-4-(phenylsulfonyl)-1H-pyrazol-3-yl]ethanone (6b) showed a high activity when compared with indomethacin as reference drug with lower gastrointestinal (GI) profile. Furthermore, molecular docking studies were performed in order to rationalize the obtained biological results. [ABSTRACT FROM AUTHOR]