Unexpected One-Pot Synthesis of Highly Conjugated Pentacyclic Diquinoid Compounds

Abstract

A new class of pentacyclic diquinoid compounds has been synthesized with a facile one-pot reaction of two molecules of 2-hydroxynaphthoquinone and 1-bromoalkanes in the presence of ferrocene. These molecules were isolated as enol tautomers that exhibit intramolecular hydrogen bond and extended electronic conjugation as proved by the intense absorption spectrum with a broad band between 400 and 600 nm. The spectroscopic and electrochemical characterization of this new class of compounds has been performed. One of the synthesized diquinoid derivatives showed a significant cytotoxicity with IC 50 values of 25−50 μM against Cisplatin-Resistant SKOV3 and colon carcinoma SW480 cell lines. The results of our study provide a valuable tool to a one-pot synthesis of highly conjugated polyquinones, analogous to important biological systems, with significant antitumoral activity. ■ INTRODUCTIONNaphthoquinone-based molecules are ubiquitous in plants, having key roles in several transformations.1 Vitamin K derivatives, for example, are naphthoquinones involved in biological processes such as the catalysis of the cyclic photophosphorylation pathways 2 and the decarboxylation of glutamic acid.3 Moreover, in the photosynthetic system, quinones act as the final electron acceptors in reaction centers after sunlight harvesting process. The understanding of the photosynthetic mechanism has stimulated the synthesis of artificial mimicking models, based on electron transfer processes. Accordingly, the donor and acceptor moieties used in such models are mainly inspired by the pigments found in photosynthetic reaction centers.4 Therefore, quinones have often been used as acceptor moieties together with easily oxidizable compounds, such as porphyrin or ferrocene derivatives, in donor−acceptor dyads mimicking natural photosynthesis. 5In this paper we described a new and unexpected synthesis of highly coniugated pentacyclic diquinoid compounds. Although our initial aim was not the diquinones formation, we studied these products because of their interesting absorption properties and in view of their relevance in many fields, and in particular in medical applications. 6For example, a quinoid tricyclic derivative with antibiotic properties, the hipposudoric acid (Chart 1a), was isolated from the skin secretion of hippopotamus after a sequence of extraction processes. 7 The chemical synthesis of hypposudoric acid is possible, but only with a difficult, time-consuming multistep route, 7b as usually occurs for the synthesis of natural poliquinonoid compounds.8 Due to its absorption spectrum in the visible region, hipposudoric acid appears to be produced to

A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism

“…KuQuinones are a new class of pentacyclic di-quinoid compounds that have recently been discovered and synthesized with a facile one-pot reaction [17]. The polycyclic system can be considered a naphthoquinone derivative and its name is due to the structural similarities with vitamin K. In this work the Et-KuQ has been reacted with the human Top1 enzyme.…”

“…Extended electronic conjugation is proved by the intense absorption spectrum with a broad band between 400 and 600 nm. These molecules were isolated as enol tautomers stabilized by the intramolecular hydrogen bond with the nearest carbonyl group, as shown in the crystal structure of the Et-KuQ derivative [17]. The strong hydrogen-bond interaction is evidenced by the very high value of the chemical shift (18 ppm) of the enolic hydrogen in the 1 H NMR spectrum.…”

“…This structure permits us to provide an interpretation of the effect of the compound during the religation process. In fact, the deprotonated oxygen molecules of Et-KuQ that represent a strong hydrogen acceptor site [17] and that can then help the deprotonation process that the hydroxyl group of the 5′ DNA terminal must undergo to reseal the cleaved DNA strand, are at an average distance from the DNA O5′ of 6.7 Å (Figure 7). In the crystal structure of the covalent enzyme–DNA binary complex the distance between the DNA O5′ and the Nζ Lys 532 , that is considered the proton acceptor site, is 7.2 Å [4,6].…”

“…The Et-KuQ was synthesized as previously described [17]. CPT (Sigma) and Et-KuQ were dissolved in DMSO to a final concentration of 4 and 0.5 mg/ml, respectively, and stored at −20°C.…”

“…In this work, in the search for a new topoisomerase poison, we have investigated the interaction of the enzyme with Et-KuQ (1-ethylKuQuinone) (Figure 1), a pentacyclic-diquinoid synthetic compound [17]. The results indicate that Et-KuQ inhibits cleavage and enhances religation in the presence of CPT.…”