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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
HDACis are broadly classified into six main classes according to their structure (Gottesfeld and Pandolfo, 2009). They are: (a) hydroxamic acids (trichostatin-A [TSA], suberoylanilide hydroxamic acid [SAHA], PXD101); (b) benzamides; (c) cyclic peptides and depsipeptides; (d) short-chain fatty acids (propionic acid, butyric acid, valeric acid, caproic acid and valproic acid); (e) sulfur-containing compounds (diallyl disulfide [DADS], diallyl trisulfide [DATS], sulforaphane [SFN]); (f) phenolic compounds (benzoic acid and cinnamic acid derivatives); and (g) hybrid molecules (Figure 8.3 and Table 8.1).
Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
RNR catalyzes the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates by replacing a 2′-OH functionality with hydrogen. Its enzymatic activity is attributed to the formation of a tyrosyl free radical from tyrosine and iron atoms at the active site. Other hydroxamic acid–based derivatives have been investigated as inhibitors (e.g., didox and trimidox) but have not progressed. Interestingly, gemcitabine possesses some RNR inhibitory properties in addition to its other mechanisms of action.
Synthetic Approaches to Inhibitors of Isoprenoid Biosynthesis
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Pedro Merino, Loredana Maiuolo, Ignacio Delso, Vincenzo Algieri, Antonio De Nino, Tomas Tejero
The presence of a hydroxamate group may enhance the capability for metal chelation (Petrillo and Ondetti, 1982), improving the ionic and/or metal coordination with the active site of Farnesyl Protein Transferase (FPT). The preparation of N-methyl substituted hydroxamic acids (117) was performed starting from aspartic acid derivate (108) and N-methyl-O-benzyl-hydroxylamine hydrochloride (109) (Scheme 2.29) (Bianco et al., 1999). Reagents and conditions: (i) CD1, iPr2NEt. (ii) 1N NaOH, MeOH, (iii) EDC, HOBT, iPr2NEt, HVLS-OMe. (iv) Na2CO3 (1.0), 2:01 MeOH, H2O. (v) H2, 10% Pd/C, MeOH. (vi) anhydrous HCl/dioxane, EtOAc, 75%. (vii) H2, 10% Pd/C, MeOH.
Histone deacetylase inhibitors as a potential new treatment for psoriatic disease and other inflammatory conditions
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Jehan Mohammad Nazri, Katerina Oikonomopoulou, Elvin D. de Araujo, Dziyana Kraskouskaya, Patrick T. Gunning, Vinod Chandran
There are four main classes of HDAC inhibitors according to chemical structure (Figure 2) that include: i) Hydroxamic acids (such as Trichostatin A (TSA), suberoyl anilide bishydroxamic acid (SAHA/Vorinostat), and ITF2357 (Givinostat)); ii). Short-chain fatty acids (including butyrate, sodium phenylbutyrate (PheBut), and valproic acid (VPA)); iii) Benzamides (like MS-275 (Entinostat) and CI-994 (Tacedinaline)); and iv) Cyclic peptides (such as Romidepsin (FK228)). Over the last several years, these HDAC inhibitors have been intensely investigated as anti-cancer agents with the United States Food and Drug Administration (US FDA) having approved Vorinostat, Romidepsin, Panobinostat, and Belinostat for the treatment of cancer while many others are still in various stages of preclinical development and clinical trials.
Have molecular hybrids delivered effective anti-cancer treatments and what should future drug discovery focus on?
Published in Expert Opinion on Drug Discovery, 2021
This review describes the advances in the designed and developed anti-cancer hybrids. The most promising and potent hybrids eventually approved and/or under clinical trials are discussed. The detailed information about the approved drugs/clinical candidates was obtained through FDA, CDER [10] and from National Library of Medicine internal dataset compilation [11]. The rate of success along with future perspective has also been revealed. A number of anti-cancer hybrids currently in development are outlined, along with a description of mechanism of action and clinical trial phase. The focus will not only on the early stage of discovery and lead optimization but also on the final stage of bringing the drug into market. For the sake of clarity and conciseness, a few significant anticancer pharmacophoric units are chosen for the designed hybrids, to make a classified article. The hybrids chosen for validating hybridization technique are classified into various sections based on their most relevant pharmacophoric unit including (i) nitrogen mustard- (ii) carbazole- (iii) pyrimidine- (iv) quinoline/quinazoline- (v) indole- (vi) hydroxamic acid- and (vii) ferrocene-based hybrids.
How do we improve histone deacetylase inhibitor drug discovery?
Published in Expert Opinion on Drug Discovery, 2020
The dynamic status of histone acetylation is under the control of histone deacetylases (HDACs) and histone acetyltransferases (HATs), which play an important role in the regulation of gene expression. While HATs mediate the acetylation of lysine residue associated with gene transcription, HDACs have the opposite effect, and deacetylation leads to a more condensed chromatin structure; this, in turn, leads to transcriptional repression of the gene [1]. Histone deacetylases are often dysregulated and have been recognized as a crucial factor in numerous diseases, including cancer, neurodegenerative and inflammatory diseases [2]. High expression of HDAC8 is correlated with poor survival and advanced disease in neuroblastoma [3]. While high expression levels of HDAC1, 2, and 3 have been shown to be associated with poor patient outcomes in gastric and ovarian cancers [4,5], HDACis have pleiotropic cellular effects including the arrest of cell growth, cell cycle progression, and the induction of apoptosis [6]. Numerous HDACis are nowadays at various stages of clinical trial development for the treatment of cancers. The natural hydroxamate Trichostatin A has served as a lead compound, for the development of the first approved HDACi vorinostat (SAHA). To date, five HDACis have been approved for the treatment of cutaneous T-cell lymphoma. These drugs can be classified into three chemical families: the class of hydroxamic acids such as vorinostat, panobinostat, and belinostat; the class of cyclic peptides such as romidepsin; and the class of o-amino anilides such as chidamide.