Design, Synthesis and Cancer Cell Growth Inhibition Evaluation of New Aminoquinone Hybrid Molecules

Abstract

Molecular hybridization has proven to be a successful multi-target strategy in the design and development of new antitumor agents. Based on this rational approach, we have planned hybrid molecules containing covalently linked pharmacophoric units, present individually in compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II and ROCK1. Seven new molecules, selected by docking calculation of the complexes with each of the proteins taken into consideration, have been efficiently synthesized starting from 2,3-dichloro-1,4-naphtoquinone or 6,7-dichloro-5,8-quinolinquinone. By screening the full National Cancer Institute (NCI) panel, including 60 human cancer cell lines, four molecules displayed good and sometimes better growth inhibition GI₅₀ than the ROCK inhibitor Y-27632, the Topo II inhibitor podophyllotoxin and the tubulin inhibitor combretastatin A-4. The relative position of N,N heteroatoms in the structures of the tested compounds was crucial in affecting bioactivity and selectivity. Furthermore, compound 3 (2-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(3,4,5-trimethoxyphenoxy)naphthalene-1,4-dione) emerged as the most active in the series, showing a potent and selective inhibition of breast cancer BT-549 cells (GI₅₀ < 10 nM).

Keywords: 3,4,5-trimethoxyphenyl group; antitumor activity; cytotoxicity; docking calculation; hybrid molecules; naphtoquinones; quinolinequinones.

Figure 1

Design strategy of the target hybrid molecules.

Scheme 1

Synthesis of molecules 1a–c, 3a–c and 3. Reagents and conditions: (a) K₂CO₃, DMSO, r.t. 48 h; (b) piperidine, CH₂Cl₂, r.t. 24 h; (c) N1,N1-dimethylethane-1,2-diamine, CH₂Cl₂, r.t. 24 h; (d) 2-(piperazin-1-yl)ethan-1-ol, CH₂Cl₂, r.t. 24 h. Arbitrary numbering is for convenience.

Figure 2

Dose response curves at NCI fixed protocol: (a) for compound 1b on the indicated central nervous system (CNS) cancer cell lines, and (b) for compound 3 on the indicated breast cancer cell lines. The curves were obtained at five concentrations (log dilutions from 10^–4 to 10^–8 M). The concentrations of each compound, which inhibited 50% of cancer cell growth (GI₅₀), were deduced and are the values reported in Table 1.