Chloroformate-mediated ring cleavage of indole alkaloids leads to re-engineered antiplasmodial agents.

Natural product ring distortion strategies have enabled rapid access to unique libraries of stereochemically complex compounds to explore new chemical space and increase our understanding of biological processes related to human disease. Herein is described the development of a ring-cleavage strategy using the indole alkaloids yohimbine, apovincamine, vinburnine, and reserpine that were reacted with a diversity of chloroformates paired with various alcohol/thiol nucleophiles to enable the rapid synthesis of 47 novel small molecules. Ring cleavage reactions of yohimbine and reserpine produced two diastereomeric products in moderate to excellent yields, whereas apovincamine and vinburnine produced a single diastereomeric product in significantly lower yields. Free energy calculations indicated that diastereoselectivity regarding select ring cleavage reactions from yohimbine and apovincamine is dictated by the geometry and three-dimensional structure of reactive cationic intermediates. These compounds were screened for antiplasmodial activity due to the need for novel antimalarial agents. Reserpine derivative 41 was found to exhibit interesting antiplasmodial activities against Plasmodium falciparum parasites (EC50 = 0.50 µM against Dd2 cultures), while its diastereomer 40 was found to be three-fold less active (EC50 = 1.78 µM). Overall, these studies demonstrate that the ring distortion of available indole alkaloids can lead to unique compound collections with re-engineered biological activities for exploring and potentially treating human disease.

Green synthesis of colloidal gold nanoparticles using latex from Hevea brasiliensis and evaluation of their in vitro cytotoxicity and genotoxicity.

Latex extracted from Hevea brasiliensis tree has been used as a green alternative for preparing gold nanoparticles (Au NPs); however, no study evaluating the cytotoxic and genotoxic potential of Au NPs synthesised using H. brasiliensis has been published. The present study aimed to synthesise and characterise colloidal Au NPs using latex from H. brasiliensis and to evaluate their in vitro cytotoxicity and genotoxicity. Ideal conditions for the green synthesis of Au NPs were studied. In vitro cytotoxicity and genotoxicity of Au NPs in CHO-K1 cells was also evaluated. Our findings indicated that the ideal synthesis conditions of pH, temperature, reduction time, and concentrations of latex and HAuCl4 were 7.0, 85°C, 120 min, 3.3 mg/mL, and 5.0 mmol/L, respectively. LC5024 h of Au NPs was 119.164 ± 5.31 µg/mL. Lowest concentration of Au NPs tested presented minimal cytotoxicity and genotoxicity. However, high concentrations of Au NPs promoted DNA damage and cell death via apoptosis. On the basis of these findings, the authors optimised the use of an aqueous solution of H. brasiliensis latex as a reducing/stabilising agent for the green synthesis of Au NPs. Low concentrations of these NPs are biocompatible in normal cell types, suggesting that these NPs may be used in biological applications.