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Review
. 2020 Aug 13:11:992.
doi: 10.3389/fphar.2020.00992. eCollection 2020.

Natural Products Impacting DNA Methyltransferases and Histone Deacetylases

Sergi Herve Akone  1   2 , Fidele Ntie-Kang  3   4   5 , Fabian Stuhldreier  6 , Monique Bassomo Ewonkem  1 , Alexandre Mboene Noah  7 , Simon Eitel Misse Mouelle  1 , Rolf Müller  2
Affiliations
Review

Natural Products Impacting DNA Methyltransferases and Histone Deacetylases

Sergi Herve Akone et al. Front Pharmacol. .

Abstract

Epigenetics refers to heritable changes in gene expression and chromatin structure without change in a DNA sequence. Several epigenetic modifications and respective regulators have been reported. These include DNA methylation, chromatin remodeling, histone post-translational modifications, and non-coding RNAs. Emerging evidence has revealed that epigenetic dysregulations are involved in a wide range of diseases including cancers. Therefore, the reversible nature of epigenetic modifications concerning activation or inhibition of enzymes involved could be promising targets and useful tools for the elucidation of cellular and biological phenomena. In this review, emphasis is laid on natural products that inhibit DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) making them promising candidates for the development of lead structures for anticancer-drugs targeting epigenetic modifications. However, most of the natural products targeting HDAC and/or DNMT lack isoform selectivity, which is important for determining their potential use as therapeutic agents. Nevertheless, the structures presented in this review offer the well-founded basis that screening and chemical modifications of natural products will in future provide not only leads to the identification of more specific inhibitors with fewer side effects, but also important features for the elucidation of HDAC and DNMT function with respect to cancer treatment.

Keywords: DNA methyltransferases; cancer; epigenetics; histone deacetylases; inhibition; natural products.

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Figures

Figure 1
Figure 1
Structures of DNA methyltransferases inhibitors.
Figure 2
Figure 2
Common features of HDAC inhibitors.
Figure 3
Figure 3
Structures of linear HDAC inhibitors. The colors are representative of different parts shown in Figure 2.
Figure 4
Figure 4
Structures of cyclic tetrapeptides. The colors are representative of different parts shown in Figure 2.
Figure 5
Figure 5
Structures of cyclic depsipeptides. The colors are representative of different parts shown in Figure 2. The black color is representative of the product moiety.
Figure 6
Figure 6
Structures of the non Zinc-binding HDACs.
Figure 7
Figure 7
H-bond interactions between Genistein and binding site amino acid residues in the DNMT1 cavity. H-bond between genistein and DNMT1 are shown (distance <3.2 Å) as red dotted lines that include the names of the residues and distances (Reproduced with permission).
Figure 8
Figure 8
Modeling docking poses towards the homology model of showing the interaction of curcumin (2) and its two analogs (50–51) (A) and tetrahydrocurcumin (52, B) within the catalytic domain of DNMT1. The catalytic Cys1126, and anchoring Glu1668, Arg1312 are shown in the catalytic domain, (Reproduced with permission).
Figure 9
Figure 9
3D view of the docking pose of reduced PsA (A) and its synthetic analogue (B) to HDAC1 (PDB ID: 4BKX). The ligands are shown in orange and green, respectively. Important parts of the enzyme for interaction are shown in magenta sticks, while Zn2+ ion is shown as a light-yellow sphere (Reproduced with permission).
See this image and copyright information in PMC

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