Strategies towards the N-glycosylation of indolocarbazole alkaloids and interaction with model cell membranes

• Grant number: 14/25784-7
• Support Opportunities: Research Grants - Visiting Researcher Grant - International
• Start date: March 24, 2015
• End date: March 23, 2016
• Field of knowledge: Physical Sciences and Mathematics - Physics - Condensed Matter Physics
• Principal Investigator: Osvaldo Novais de Oliveira Junior
• Grantee: Osvaldo Novais de Oliveira Junior
• Visiting researcher: Varala Ravi
• Visiting researcher institution: Rajiv Gandhi University of Knowledge Technologies (RGUKT), India
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 13/14262-7 - Nanostructured films from biologically-relevant materials, AP.TEM

Abstract

This Project is aimed at synthesizing compounds from the indolocarbazole family, which are expected to be potent therapeutic agents against cancer, to be used in experiments that simulate the interaction with model membranes made with Langmuir monolayers. Indolocarbazoles (ICZs) have various biological activities, but the greatest interest is focused on compounds that possess antitumor and neuroprotective properties. Compounds whose basic structure is the pyrroloindolocarbazole system with one N-glycosidic bond, such as rebeccamycin, act by DNA topoisomerase I inhibition (attractive target for cancer chemotherapy), whereas those with two N-glycosidic bonds, e.g. staurosporine, are mainly protein kinase C (PKC) inhibitors. In general, the indolocarbazole acceptor is a weaker nucleophile than the bis(indoly1)-maleimide or indole acceptor, which limits the direct application of many established glycosylation methodologies to the indolocarbazole aglycones. In the work proposed here, two stauroporine derivatives, K-252c and K-252d, will be synthesized in gram scale upon exploiting the expertise of the invited researcher. So far, only few derivatives have been achieved by the modification around the ICZ and carbohydrate skeleton. This proposal will be the first of its kind wherein totally diverse ICZ analogues will be achieved. The compounds synthesized will then be used in Langmuir monolayer experiments by other members of the Polymer Group. (AU)