SYNTHESIS AND CYTOTOXIC ACTIVITY OF GERANYLMETHOXYHYDROQUINONE DERIVATIVES

Abstract

The new synthetic geranyl-2,4-methoxyhydroquinone 1 and the known geranyl-4,5-methoxyhydroquinone 2 were prepared by Electrophilic Aromatic Substitution (EAS) reactions between geraniol and 1,3,5-trimethoxyphenol using BF 3 ∙Et 2 O as a catalyst. Furthermore, the new geranylmethoxyhydroquinones derivatives (3-6) were obtained by chemical transformations of 1 and 2. The compounds have been evaluated for their cytotoxic activities against PC-3 human prostate cancer cell line, MCF-7 and MDA-MB-231 human breast cancer cells lines and dermal human fibroblasts DHF. IC 50 values for compounds 1 and 5 ranged in the 80 µM level. 3-6 , sponges 7-10 , alcyonaceans 11 , gorgonaceans 12 , and ascidians belonging to the genus Aplidium 13-18 . These substances present a terpenoid portion ranging from one to nine isoprene units. On the other hand, different studies of the structure activity relation (SAR) in a series of nonmethoxylated and methoxylated prenylated quinones with side chains containing from one to eight isoprene units reported that the optimum length of the side-chain is two isoprene units and in the para-position relative to the methoxy-group 19, 20 . Additionally, these authors informed that all tested quinones (3-Demethylubiquinone Q2 and its synthetic derivatives) have inhibited of JB6 Cl41 cell transformation and p53 activity and induction of apoptosis, AP-1 and NF-kB activity. Due to the importance that showed by these compounds in the mentioned biological activities, in this work we describe the synthesis and cytotoxic activity of geranylmethoxyhidroquinones derivatives (1-6). The new synthetic geranyl-2,4-dimethoxyhydroquinone 1 and known geranyl-4,5- dimethoxyhydroquinone 2 were synthesized using the strategy of Electrophilic Aromatic Substitution (EAS) reactions, according to the reported protocol 21-23 . The geranylmethoxyhidroquinones derivatives (3-6) are synthetic analogs of 1 and 2, while the known compound 5 is analogous to the marine natural product verapliquinone A. All the compounds were evaluated in vitro against various human cancer cells lines in order to analyse the influence of the molecular structure on the cytotoxic activity. Scheme 1. Synthesis of 2,4,5-trimethoxyphenol 9 (a) MCPBA/CH2Cl2, r.t. 1.87 g, 86%; (b) CH3OH/Et3N, r.t. 2.45 g, 78%.