Activité antiproliférative et docking moléculaire des dérives naphthoquinoniques et acides carboxyliques indaniques du lapachol issu de source naturelle

Abstract

β-lapachone 9, α-lapachone 8 and 2-acetylfuronaphthoquinone 10 are examples of analogs derived from lapachol 4, a natural product, that show superior antitumor activity compared to lapachol (Hussain & Green, 2017). The present work aims at the synthesis of new lapachol derivatives with high antitumoral potential. We present in this work the phytochemical study of plants from the Bignoniaceae family from which seventeen compounds were isolated, including lapachol. Subsequently, the semisynthesis of the lapachol derivatives was carried out, according to the following three objectives:Firstly, the chemical transformations of lapachol were aimed at obtaining derivatives which are structurally related to β-lapachone, α-lapachone and 2-acetylfuronaphthoquinone with potentially enhanced biological activities. This approach resulted in the synthesis of nine derivatives. Secondly, the chemical transformations of lapachol were aimed at finding out how changes in the stereochemistry and electronics of the core structures influence bioactivity. These derivatives were obtained as racemic and stereoselectively, through the Sharpless stereoselective epoxidation reaction. This approach resulted in the synthesis of thirteen derivatives. Thirdly, in a pharmacomodulation approach aimed at removing the quinone groups which are usually associated with acute cytotoxicity, immunotoxicity and carcinogenesis of quinones (Bolton et al., 2000), orthoquinones were converted to indan carboxylic acids via benzylic acid rearrangement and phenazines via Schiff base reaction. This approach resulted in the synthesis of sixteen derivatives.The anti-proliferative activity of forty three derivatives of lapachol were evaluated on a panel of human cancer cells including in vitro models for cancers typically associated with dismal prognosis, such as BE(2)-C, Kelly, SKNSH, CHLA-90 (all neuroblastoma), A549 (non-small cell lung cancer), SKMEL-28 (melanoma), and U373 (glioblastoma). Of these derivatives, fifteen were the most active and had one- or multiple-digit micromolar antiproliferative activity. The most potent derivatives were those incorporating β-naphthoquinone and α-naphthoquino[2,3-b]furan skeletons. However, the most interesting analog evaluated was 1,3 di-one 76 with an indeno[1,2-b]pyran skeleton obtained via benzilic acid rearrangement with decarboxylation. It demonstrated potent cytotoxic activity and eliminated virtually all cells in culture without producing resistant populations (close to 0% cell viability) at concentrations just slightly exceeding its IC50 value. Considering the good activity associated to this 1,3 di-one (76) and the fact that this scaffold has not been the object of any cancer studies, we performed in this study an in-silicio approach by molecular docking to find out which targets and active sites might be involved in its activity. Some proteins were selected for this docking but it appears that the biological activity associated with the compound 76 is not from the inhibition of one of the proteins selected in the context of this virtual screening. However, this study makes it possible to justify the apoptotic activity of five of the fifteen compounds tested on cancer cells by the inhibition of the VEGFR2, CDK2, CDK6 and Topoisomerase 1 proteins.The current investigation identified several new lead compounds that could be used as starting points for anti-cancer drug discovery.