Design, Synthesis and Conformational Studies of Cyclic Tetrapeptides having βγ Fused Turns as HDAC Inhibitors

Abstract

Histone deacetylases (HDACs) belong to a class of major targets for the development of anticancer drugs for which cyclic peptide-based molecules are attracting wide attention. Here we show the synthesis, conformational and in silico analysis of tetrahydrofuran amino acid (TAA) based 15-membered cyclic tetrapeptides (CTPs) containing hydroxamic acid side chain as potential HDAC inhibitors. NMR based solution studies in protected and deprotected forms reveal that the macrocycles are stabilized by 10-membered β-turn as well as a 7-membered γ-turn. This type of fused structures within the same macrocycle is not frequently sighted. Our initial in silico docking results indicated that the hydroxamic acid protected CTPs show promising binding with the class-1 HDACs. We also noticed that the C-chain with hydroxamic functional group attached on the ornithine sidechain did not affect the core structure of the peptide ring. Moreover, some of these cyclic tetrapeptides with hydroxamic acid side chain exhibited an induction of acetylation of histones on preliminary cell-based experiments. Our initial results provide an insight into the development of HDAC inhibitors based on the CTPs with novel βγ fused turns which have not been explored yet.

Conformation Based in silico Studies of Cyclic Tetrapeptides with βγ Fused Turns as Thrombin Inhibitors

“…Conformational and Molecular Dynamics (MD) studies : Detailed solution conformational studies were carried out for cyclic tetrapeptides (CTPs) in DMSO‐ d 6 with 2–10 mM concentrations to investigate their structural and conformational preferences in the solution. Sequential assignment of all proton resonances was performed as previously described [10] . All cyclic tetrapeptides (CTPs) are similar in the backbone, however different on the side chain protective groups of Orn reside.…”

“…The nOe intensities were converted to distances as described earlier [10] . The detailed protocol for the MD simulation is listed in the experimental section in the Supporting Information.…”

“…The nOe intensities were converted to distances as described earlier. [10] The detailed protocol for the MD simulation is listed in the experimental section in the Supporting Information. The MD studies showed results similar to what was observed in our previous study where we used this fused turn system to design a HDAC inhibitor.…”

“…Sequential assignment of all proton resonances was performed as previously described. [10] All cyclic tetrapeptides (CTPs) are similar in the backbone, however different on the side chain protective groups of Orn reside. All the amide protons were resonating between δ 6.0 ppm to δ 8.5 ppm scale.…”

“…[20] A library of designed cyclic peptides with guanidine functionality has been reported by Heinis group as human thrombin inhibitors. [21] Based on that concept and the model cyclic peptides reported by our group (Figure 1), [10,22] we have designed tetrahydrofuran amino acid containing cyclic tetrapeptides 1 A-B and 2 A-B with guanidine functionality in the side chain (Figure 2). These cyclic tetrapeptides were derived from our previously reported model cyclic peptides.…”