Development of synthetic approaches to 3-acyl-5-hydroxytetramic acids and their application in the total synthesis of intergramycin

• Applicant: Dr. Evgeny V. Prusov
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 257019435

Natural products and natural products derived drugs have found a widespread application in the treatment of bacterial infections and cancer diseases. By contrast, much less natural product derived antiviral compounds are currently in the clinic and thus some attractive opportunities may lie in the discovery and development of such medicines. Recently, the secondary metabolite integramycin isolated from the bacterial strain Actinoplanes sp. was characterized as inhibitor of HIV integrase, which is the essential enzyme for virus replication. Based on the pharmacophoric similarity of tetramic acid to diketoacids, one can propose that the inhibitory activity of integramycin arises from formation of its ternary complex with viral DNA and integrase. Owing to its interesting biological properties and complex molecular architecture, integramycin pose several intriguing biochemical questions and synthetical challenges. Particularly interesting here is the biosynthetic origins of the tetramic acid fragment and octalin core. We aim to address these questions in conjunction with total synthesis of integramycin. The main objectives of this proposal are to develop a new method of introduction the hydroxylated tetramic acid fragment into natural product structures by oxidation of the corresponding enolates or singlet oxygen cycloaddition, to investigate the applicability of intermolecular Diels-Alder reaction for the construction of octalin core and to accomplish the first synthesis of integramycin. Utilizing the knowledge obtained in these studies, a series of simplified and structurally modified analogs of integramycin can be produced and biologically evaluated using in vitro integrase assays in order to gain preliminary information regarding structure-activity relationships and pharmacophores of integramycin.

• DFG Programme: Research Grants