Conformationally locked calixarene-based histone deacetylase inhibitors

Alkyl- and arylamidocalix[4]arene derivatives 1-11 have been designed and theoretically evaluated by docking studies as potential histone deacetylase inhibitors (HDACi). On the basis of the trimodal distribution of the calculated inhibition constants (K(i)), five alkyl- or arylamido derivatives (3, 7, 8, 9, and 11) were synthesized and tested. A qualitative accordance between the experimental results and the theoretical predictions was obtained, confirming that appropriately substituted arylamidocalix[4]arenes are active HDACi.     

Polymer-assisted, multi-step solution phase synthesis and biological screening of histone deacetylase inhibitors

The polymer-assisted solution phase synthesis (PASP) of an array of histone deacetylase (HDAc) inhibitors is described. HDAc inhibitors have considerable potential as new anti-proliferative agents. Selected compounds were shown to inhibit both human endothelial cell proliferation, and the formation of tubules (neovascularisation) in an in vitro model of angiogenesis.     

Phosphorus-based SAHA analogues as histone deacetylase inhibitors

[structure: see text] Three analogues of suberoyl anilide hydroxamic acid (SAHA) with phosphorus metal-chelating functionalities were synthesized as inhibitors of histone deacetylases (HDACs). The compounds showed weak activity for HeLa nuclear extracts (IC(50) = 0.57-6.1 mM), HDAC8 (IC(50) = 0.28-0.41 mM), and histone-deacetylase-like protein (HDLP, IC(50) = 0.33-1.9 mM), suggesting that the transition state of HDAC is not analogous to zinc proteases. Antiproliferative activity against A2780 cancer cells (IC(50) = 0.11-0.12 mM), comparable to SAHA (0.15 mM), was observed.     

Structural biasing elements for in-cell histone deacetylase paralog selectivity

We use the structural dissection of two 1,3-dioxanes with in-cell histone deacetylase (HDAC) paralog selectivity to identify key elements for selective HDAC inhibitors. We demonstrate that o-aminoanilides are inactive toward HDAC6 while apparently inhibiting deacetylases that act upon histone substrates. This finding has important clinical implications for the development of HDAC inhibitor-based treatments that do not interfere with microtubule dynamics associated with HDAC6. We also show that suberoylanilide hydroxamic acid (SAHA) alone is a nonparalog-selective HDAC inhibitor and that the 1,3-dioxane diversity appended to SAHA is essential for HDAC6 paralog selectivity.     

Fully automated multi-step solution phase synthesis using polymer supported reagents: preparation of histone deacetylase inhibitors

The first fully automated multi-step polymer assisted solution phase (PASP) synthesis is described. An array of histone deacetylase (HDAc) inhibitors was prepared by an unattended 4-5 step sequence incorporating in-line 'catch and release' purification.     

Conformational analogues of Oxamflatin as histone deacetylase inhibitors

Conformational analogues of the hydroxamic acid Oxamflatin compounds, have been synthesised to enable evaluation of the impact of varying the linking section on histone deacetylase inhibition. Preliminary testing indicates treatment of leukaemia cells with each of the analogues leads to significant inhibition of histone deacetylase and reduction in cell growth and proliferation.     

Design,synthesis, and biological evaluation of novel histone deacetylase 6 selective inhibitors

Histone deacetylase 6 (HDAC6) is distinguished from other HDACs by its ability to deacetylate α-tubulin and HSP90, and was reported to be related to a variety of human diseases, such as cancers, neurodegenerative diseases, and immunological disorders. The discovery of novel HDAC6 selective inhibitors is important directions of this research field. In this paper, on the basis of a Bcl-2/HDAC6 dual target inhibitor 7g reported by us previously, a novel type of HDAC6 inhibitors was obtained by removing the binding capability to Bcl-2 protein and the subsequent systematical optimization. Among them, compounds Ⅵ-9, Ⅵ-10 and Ⅵ-11 (IC₅₀ = 3.2 ～ 3.9 nM, SI = 20.6 ～ 38.7) showed the best inhibitory activities against and excellent selectivity to HDAC6. These compounds displayed growth inhibitory selectivity to human multiple myeloma cell line over normal cell line, which indicated potential lower toxicity to normal cells and tissues.     

Facile synthesis of colorimetric histone deacetylase substrates

Here we report a simple procedure for generating colorimetric histone deacetylase (HDAC) substrates by solid-phase peptide synthesis based on racemization-free couplings of amino acid chlorides. We demonstrate the applicability of these substrates in HDAC assays.     

Total synthesis of spiruchostatin A, a potent histone deacetylase inhibitor

The total synthesis of spiruchostatin A was accomplished, unambiguously confirming its structure. Key steps included the use of the Nagao thiazolidinethione auxiliary for a diastereoselective acetate aldol reaction and as an activated acylating agent for amide formation, and macrolactonization by the Yamaguchi protocol. Spiruchostatin A is shown to have biological activity similar to that of FK228, a potent histone deacetylase (HDAC) inhibitor in clinical trials. The spiruchostatin A analogue, epimeric at the beta-hydroxy acid, is inactive, highlighting the importance of stereochemistry at this position for interactions with HDACs.     

Microsporins A and B: new histone deacetylase inhibitors from the marine-derived fungus Microsporum cf. gypseum and the solid-phase synthesis of microsporin A

Two new cyclic peptides, microsporins A and B (7 and 8), were isolated from culture extracts of the marine-derived fungus Microsporum cf. gypseum obtained from a sample of the bryozoan Bugula sp. collected in the U.S. Virgin Islands. The structures of the new compounds were determined by extensive interpretation of 2D NMR data and by chemical methods. Microsporins A and B are potent inhibitors of histone deacetylase and demonstrate cytotoxic activity against human colon adenocarcinoma (HCT-116), as well as against the National Cancer Institute 60 cancer cell panel. The total synthesis of microsporin A on solid-phase is also reported.     

Total synthesis and molecular target of largazole, a histone deacetylase inhibitor

Full details of the concise and convergent synthesis (eight steps, 19% overall yield), its extension to the preparation of a series of key analogues, and the molecular target and pharmacophore of largazole are described. Central to the synthesis of largazole is a macrocyclization reaction for formation of the strained 16-membered depsipeptide core followed by an olefin cross-metathesis reaction for installation of the thioester. The biological evaluation of largazole and its key analogues, including an acetyl analogue, a thiol analogue, and a hydroxyl analogue, suggested that histone deacetylases (HDACs) are molecular targets of largazole and largazole is a class I HDAC inhibitor. In addition, structure-activity relationship (SAR) studies revealed that the thiol group is the pharmacophore of the natural product. Largazole's HDAC inhibitory activity correlates with its antiproliferative activity.     

Design,synthesis, and biological evaluation of N-hydroxycinnamamide/salicylic acid hybrids as histone deacetylase inhibitors

Novel histone deacetylase(HDAC) inhibitors 9a–l were designed and synthesized by coupling the carboxyl group of salicylic acid(SA) with N-hydroxycinnamamides through various alkylol amines, and their in vitro biological activities were evaluated. The N-hydroxycinnamamide/SA hybrids 9b–f and 9h showed good to moderate anti-tumor activities. Notably, compound 9e had a greater potency, comparable to vorinostat(SAHA), in human colon carcinoma cells, which was probably, or at least partially, attributable to the positive effects of the chain length noted in alkylol amines. Furthermore, the HDAC inhibitory activities of 9e against Hela cell nuclear were also similar to that of vorinostat(SAHA), while the tested compounds 9c–f did not exhibit any isoform selectivity in the inhibition of HDACs. In addition, compound 9e could selectively inhibit tumor cells, but not inhibit non-tumor cell proliferation in vitro. Our findings suggest that the N-hydroxycinnamamide/SA hybrids may hold significant promise as therapeutic agents for the intervention of human cancers.     

亲电酮类HDAC抑制剂的3D-QSAR和分子对接研究

组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitor,HDACi)是近年来治疗癌症的重要靶向药物,其中羟氨酸类,苯甲酰胺类多种药物已进入临床试验阶段,但对于亲电酮类HDACi还有待于进一步研究,本研究应用比较分子力场分析法(comparative molecular field analy...