Cytotoxic, trypanocidal activities and physicochemical parameters of nor-²-lapachone-based 1,2,3-triazoles

Abstract

A atividade citotóxica de cinco derivados 1,2,3-triazólicos da nor-β-lapachona e do precursor azidonaftoquinona, foi avaliada contra seis linhagens de células neoplásicas: SF-295 (sistema nervoso central), , MDAMB-435 (melanoma), HL-60 (leucemia), PC-3 (próstata) e B-16 (melanoma murino). Valores de IC 50 entre 0,43 e 9,48 μM foram obtidos. A 3-(4-(1-hidróxicicloexil)-1H-1,2,3-triazol-1-il)-2,2-dimetilnaftol[1,2-b]furan-4,5-dione apresentou-se altamente citotóxica contra MDAMB-435, com IC 50 menor do que o encontrado para doxorubicina (controle positivo). Na tentativa de obter correlação entre parâmetros físico-químicos (potencial de redução e clog P) e atividade citotóxica, estudos eletroquímicos foram realizados em tampão acetato, pH 4,5, em eletrodo de carbono vítreo, e valores de log P calculados (clog P). Apesar da ausência de interação estrutural conjugativa entre o sistema quinônico e o anel triazólico, observou-se a influência do anel heterocíclico no comportamento voltamétrico, com deslocamento anódico dos potenciais de redução. Não se verificou correlação entre os parâmetros eletroquímicos (Ep Ic ) e a atividade citotóxica. Por outro lado, a comparação de Ep Ic com atividades tripanocidas, já descritas, reafirmou a tendência de maior atividade biológica para quinonas mais eletrofílicas (> Ep Ic ). Apesar da ausência de correlação direta, foi possível verificar que clog P influencia a atividade citotóxica: quanto menor a lipofilia (< clog P), menor a citotoxicidade (> IC 50 ).The cytotoxicities of five nor-β-lapachone-based 1,2,3-triazoles and the precursor azidonaphthoquinone were assayed against six neoplasic cancer cell lines: SF-295 (central nervous system), , , HL-60 (leukaemia), PC-3 (prostate) and B-16 (murine melanoma). IC 50 values ranging from 0.43 to 9.48 μM were obtained. 3-(4-(1-hydroxycyclohexyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione proved highly cytotoxic to MDAMB-435, with IC 50 even lower than the one from doxorubicin (positive control). In an attempt to correlate physicochemical parameters (reduction potentials and calculated log P) with cytotoxic activity, electrochemical studies were conducted in acetate buffer, pH 4.5, using a vitreous carbon electrode and calculated log P values were obtained. Despite the absence of a structural conjugative interaction between the two systems (quinone and triazole), the heterocyclic group was found to influence the voltammetric behaviour, as indicated by anodic shifts in the reduction potentials. No correlation was found between Ep Ic and cytotoxicity. In contrast, a comparison of Ep Ic with previously reported trypanocidal activities reconfirmed the trend for higher activity coupled with better quinone electrophilicity (> Ep Ic ). A leading term in the correlation of cytoxicity, despite the absence of a linear correlation, was the calculated log P: the lower the lipophilicity, the lower the cytoxicity (> IC 50 ).Keywords: lapachones, cytotoxicity, reduction potentials, clog P, naphthoquinone-triazoles, trypanocidal agen...

Synthesis and antitumor activity of selenium-containing quinone-based triazoles possessing two redox centres, and their mechanistic insights

“…Since the synthesis of arylamino substituted lapachones and azidoquinones are well established in our group [25,40,42], compounds 13 and 14 were prepared as shown in Scheme 3. Following click methodology, compounds 13 and 14 were reacted with selenium-containing azide and alkyne, respectively, to furnish the naphthoquinones 15 and 16 in 70% and 80% yield, respectively.…”

“…Nor-β-lapachone and derivatives are among the most potent compounds from the lapachol group [25,26]. Recently, we demonstrated [50] the cytotoxicity and genetic toxicity of nor-β-lapachone in human lymphocytes, HL-60 leukaemia, and immortal normal murine V79 fibroblasts ranging from 2.5 and 5 μM.…”

“…Previous studies from our laboratory revealed that compounds 50-53 (Figure 1) can be considered as prototypes possessing potent antitumor activities against diverse cancer cells [25,26]. To deepen our knowledge about the mechanism of action of compounds 50-53 and compare the previously reported structures with selenium-containing lapachone-based 1,2,3-triazoles, we examined their potential NQO1-dependent cytotoxicities using a set two-hour exposure, with or without the NQO1 inhibitor, dicoumarol.…”

“…In the last few years, our group has been intensively dedicated to the synthesis and evaluation of lapachones against cancer cell lines [25,26]. We discovered a series of lapachones with modified C-rings (Scheme 1a) with potent activity against cancer lineages [27].…”

Cytotoxicity of lapachol metabolites produced by probiotics

“…Although lapachol has been licensed in Brazil for general clinical practice as a carcinostatic drug (Da Silva J unior et al 2009), and several studies regarding its anticancer properties have been reported, it is stated that high doses of lapachol are required to achieve therapeutic efficacy, resulting in high side effects in patients (Sunassee et al 2013). Because of this, the use of lapachol as coadjuvant in the treatment of certain cancer types has been stopped (Hussain et al 2007).…”