We report the design, synthesis, and biological evaluation of a new series of largazole analogues in which a 4-methylthiazoline moiety was replaced with a triazole and tetrazole ring, respectively. Compound 7 bearing a tetrazole ring was identified to show much better selectivity for HDAC1 over HDAC9 than largazole (10-fold). This work could serve as a foundation for further exploration of selective HDAC inhibitors using a largazole molecular scaffold.KEYWORDS: HDAC inhibitor, peptides, macrocycles, largazole, click chemistry H istone deacetylases (HDACs) are a family of enzymes that catalyze the deacetylation of lysine side chains in chromatin, and thereby, these enzymes are involved in a wide range of biological processes such as cell differentiation, proliferation, angiogenesis, and apoptosis.1−4 Up to now, 18 members of the human HDAC family have been identified, which are divided into four distinct classes on the basis of their size, number of catalytic active sites, subcellular localization, and sequence homology to yeast counterparts. 5−7 Class I HDACs (1−3 and 8), class IIa HDACs (4, 5, 7, and 9), class IIb HDACs (6 and 10), and class IV HDACs (11) 1) 19 and romidepsin (FK228) (Figure 1), 20 have been approved by the U.S. Food and Drug Administration (FDA) for cutaneous T-cell lymphoma (CTCL). In most cases, the reported HDAC inhibitors consist of three distinct structural motifs: the Zn(II) binding moiety, a spacer moiety, and a recognition cap group. It should be noted that the cap region is a key factor in current HDACi design because topological differences are observed in the corresponding "cap" regions of HDAC isozymes.Largazole 3 is a natural macrocyclic depsipeptide reported by Luesch and co-workers in 2008, which show promising HDAC1 inhibitory activity and selectivity. 21 These excellent properties of largazole have attracted significant attention and make it a becoming lead molecule for further structural optimization in pursuit of molecules of higher potency or selectivity. Recently, several research groups have completed total synthesis and structure−activity relationship (SAR) studies of largazole.22−37 Among them, only two groups focused mostly on the alteration or elimination of the methyl group of 4-methylthiazoline moiety. 35,36 On the basis of their results, we envisioned that the 4-methylthiazoline moiety is not essential for the potency of largazole, and modification of it is tolerable. By analyzing molecular modeling of the largazole complex with HDAC1 structure, we revealed that the 4-methylthiazoline residue has hydrophobic interactions with the side chains of Phe 150 of the HDAC1, and these interactions may be crucial for HDAC class/isoform selectivity of largazole (Figure 2). Click chemistry has been widely applied in organic
Main observation and conclusion A phytochemical investigation on the seeds of Sophora alopecuroides led to obtaining fourteen structurally diverse matrine‐based alkaloids (1—14), including eight new ones (1, 6, 8—12, 14). Notably, alopecuroide F (1) represents the first dimeric matrine‐type skeleton assembled via unprecedent C‐13–C‐12' connection. The new structures were determined through extensive spectroscopic data (UV, OR, HRESIMS, 1D, and 2D NMR), ECD calculations, and three instances, verified by X‐ray crystallography. Biologically, all alkaloids were evaluated for cytotoxicity against four human cancer cell lines (HepG2, A549, THP‐1, and MCF‐7) and anti‐inflammatory activities for two pro‐inflammatory cytokines (TNF‐α and IL‐6). Alopecuroide F (1) can inhibit TNF‐α and IL‐6 productions in a dose‐dependent manner, with IC50 values of 35.6 ± 0.5 and 41.7 ± 0.8 μmol/L, respectively.
Four new alkaloids (1–4) belonging to rare examples of bis-amide matrine-type were isolated from the seeds of sophora alopecuroides. Their structures including absolute configuration were determined by extensive spectroscopic analysis, electronic circular dichroism (ECD) interpretation, and X-ray diffraction crystallography. Chemically, bis-amide matrine-type alkaloids can provide new molecular template for structural modification. Compounds 3–4 displayed obvious anti-inflammatory effects based on the inhibition of two key pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in a dose-dependent manner, with IC50 values from 35.6 to 45.8 μm.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.