Novos derivados do lapachol 2, nor-lapachol 3 e da lausona 4 foram sintetizados através do deslocamento nucleofílico das metoxinaftoquinonas 2a, 3a e 4a pela poliamina (PA) N 1 -Boc-N 5 -Bn-espermidina 1a. Os produtos, 2b, 3b e 4b, respectivamente, foram obtidos em bons rendimentos e caracterizados por métodos espectroscópicos e analíticos. Os ensaios preliminares de inibição das enzimas topoisomerases (topo) I e II-α mostraram-se promissores: todos os compostos (1a 2b, 3b e 4b) inibiram a atividade catalítica da enzima topo II-α na dose de 2 μM. Considerando que somente a PA 1a não inibiu a atividade da enzima na dose de 0,2 μM, as naftoquinonas apresentam-se como fragmentos em potencial para melhorar a atividade de PAs. Nenhum dos compostos inibiu a topo I na dose de 200 μM.Novel derivatives of lapachol 2, nor-lapachol 3 and lawsone 4 have been synthesized by nucleophilic displacement of the methoxynaphthoquinones 2a, 3a and 4a with the polyamine (PA) N 1 -Boc-N 5 -Bn-spermidine 1a. The respective products 2b-4b were obtained in good yields and characterized by spectroscopic and analytical methods. The inhibitory action of these naphthoquinone-PA conjugates on DNA-topoisomerases (topo) I and II-α was evaluated by relaxation assay of supercoiled DNA plasmid. All compounds (1a 2b, 3b and 4b) presented significant inhibition of topo II-α catalytic activity at the 2 μM dose. Considering that only PA 1a did not inhibit the enzyme catalytic activity at the 0.2 μM dose, the appended naphthoquinone moiety acts as a "value added" fragment. Compounds 1a 2b, 3b and 4b did not inhibit the enzyme DNA-topo I at the 200 μM dose.Keywords: spermidine, lapachol, lawsone, nor-lapachol, DNA-topoisomerase II-α
IntroductionPolyamines (PAs) spermidine, spermine and putrescine occur in the cells of living organisms where they fulfill an array of physiological roles. 1 Because they are involved in optimum growth and replication of various cell types, and are present in higher concentrations in rapidly proliferating cells 2 they were identified as potential targets for the development of anticancer drugs. Initial efforts were focused on the design and synthesis of selective inhibitors of the PA biosynthetic enzymes however their action was not sufficient to inhibit tumor growth. 3 The discovery that tissues with a high demand of PAs contain active polyamine transporter (PAT) for importing exogenous PAs 4 redirected the focus of interest to the PA uptake system from the cellular environment, and several potent inhibitors became known. 5 Anticancer therapies have tried to use the PAT to convey citotoxic and genotoxic agents to rapidly proliferating cells. 6 440 Cunha et al. J. Braz. Chem. Soc. Currently, the most actively pursued approach is based on tumor growth inhibition by cytotoxic structural analogues of the natural PAs, however the PA transport system also offers the possibility to improve transport and accumulation by tumors of compounds which are tethered to PA structures. One of the recent strategies involved the grafting o...