Design, Synthesis, and Molecular Docking Study of New Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors Combining Resin Acids and Adamantane Moieties

Abstract

In this paper, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their inhibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds were able to inhibit TDP1 at micromolar concentrations (0.19-2.3 µM) and demonstrated low cytotoxicity in the T98G glioma cell line. The effect of the terpene fragment, the linker structure, and the adamantane residue on the biological properties of the new compounds was investigated. Based on molecular docking results, we suppose that adamantane derivatives of resin acids bind to the TDP1 covalent intermediate, forming a hydrogen bond with Ser463 and hydrophobic contacts with the Phe259 and Trp590 residues and the oligonucleotide fragment of the substrate.

Keywords: TDP1; adamantane; resin acid; tyrosil-DNA-phosphodiesterase 1.

Figure 1

Structures of known TDP1 inhibitors.

Figure 2

Structures of natural-based TDP1 inhibitors and their IC₅₀ values.

Figure 3

Design strategy for new abietylamine-based compounds.

Scheme 1

General procedure for the synthesis of compounds 1–12.

Figure 4

Individual cytotoxicity of studied compounds in the T98G and SNB19 glioma cell lines. * Compounds 7 and 8 formed visible micelles when stock solutions were dissolved in a cell growth medium, as shown by light microscopy. The cytotoxicity of these compounds was studied; however, the concentrations of their solutions may be significantly different from those indicated in dilutions.

Figure 5

Cytotoxicities of combinations of studied compounds with temozolomide in T98G glioma cell line.

Figure 6

Position of the resin acid derivative 1 in the molecular model of human TDP1 intermediate, ΔG^calc = –9.0 kcal/mol. (A) Inhibitor’s interactions with a covalently bound DNA fragment and TDP1 residues. The oligonucleotide is shown in orange, His263 in green, and hydrophobic Phe259 and Trp590 in yellow. The dotted line indicates a hydrogen bond. (B) Van der Waal’s representation of the modeled TDP1–inhibitor complex.