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).
Highlights
Cancer is one of the prominent causes of death worldwide, and there is an urgent need to introduce new therapeutic agents due to resistance and severe side effects shown by the currently available drugs
Other representative examples are given by colchicine and podophyllotoxin (Figure 1) [6], which make this pharmacophore a peculiar structural motif among the effective tubulin inhibitors studied in the last decades, with a special value in the design of new antitumor drugs
Naphthoquinone and quinolinequinones cores are other representative chemical scaffolds for the development of antitumor agents, which are present in structures of natural and synthetic bioactive products [9,10]
Summary
Cancer is one of the prominent causes of death worldwide, and there is an urgent need to introduce new therapeutic agents due to resistance and severe side effects shown by the currently available drugs. A hybrid molecule usually contains two or more pharmacophore scaffolds present in single therapeutically active agents, connected together in a new single structure by covalent bonds. The selection of these moieties is based on the strategy of combining structures and pharmacological activities of known drugs and bioactive natural or synthetic compounds [1]. The aim of this strategy is to obtain new therapeutic agents that are able to reduce undesirable side effects of the parent drugs, and to display a modified selectivity profile, a higher affinity and a better therapeutic effect than the administration of a combination of the single-target drugs [2]. It is understandable that the investigation of new hybrid anticancer drugs has recently become of great therapeutic interest
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