Synthesis of novel naphthoquinone-spermidine conjugates and their effects on DNA-topoisomerases I and II-alpha

Abstract

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...

F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System

“…Based on this, polyamine vectorization was proposed as a valuable strategy to increase the selectivity of anticancer agents. The literature reports several examples of polyamine conjugates with cytotoxic drugs, such as chlorambucil (17), nitroimidazoles (18), aziridines (19), acridines (20), enediyenes (21), anthracenes (16), naphtoquinones (22), camptothecin (23), and protoberberine (24). All these conjugated drugs are DNA-interacting agents used to develop a general strategy by exploiting both the transport mechanism and the high affinity of polyammonium cations for DNA.…”

Novel 2-(R-phenyl)amino-3-(2-methylpropenyl)-[1,4]-naphthoquinones: synthesis, characterization, electrochemical behavior and antitumor activity

“…The presence of an amino group in quinones has led to interesting biologically active compounds. [7][8][9][10][11][12] Biological activity of quinones is often related to their electrochemical behavior. 13 The ability to accept one or two electrons to form the corresponding radical anion (Q •-) or dianion (Q 2-) species is believed to induce formation of reactive oxygen species, responsible for the oxidative stress in cells.…”

“…19 Nor-lapachol is obtained from lapachol by the Hooker oxidation 20 and has been used as a substrate for the synthesis of several active compounds. [9][10][11][12] The incorporation of polyamines to this quinone, for example, has led to significant increase in the DNA topoisomerase II-a inhibition, compared to the original naphthoquinone. 13,14 Furthermore, arylamino derivatives of nor-a and nor-b lapachones present potent antitumor 11 and trypanocide activities.…”

Antitumoral activity of new polyamine-naphthoquinone conjugates

“…Indeed, interference of ROS in the association of cytochrome c with cardiolipin at the inner mitochondrial membrane facilitates the release of the proapoptotic cytochrome c and induction of apoptosis (27). In a previous study (14) we showed that while coupling of spermidine group to naphthoquinones led to an increase in their cytotoxic activity, it did not change the ability of conjugates 5a-c to inhibit DNA topoisomerases. Here we demonstrated that this coupling also did not block the ability of 5c to generate ROS.…”

“…1) and showed that the resulting 1,4-naphthoquinone-polyamine conjugates 5a-c are potent inhibitors of DNA-topoisomerase II-α (14). Herein we describe the preparation of novel unprotected derivatives 6a-c and the evaluation of the cytotoxicity of both protected and unprotected 1,4-naphthoquinone-polyamines 5a-c and 6a-c against human lines of leukemia (HL-60), lung cancer (GLC4), melanoma (MV-3), Burkitt lymphoma (Daudi) and a mouse breast tumor (Ehrlich carcinoma).…”