Project Details
Projekt
Design and synthesis of novel archazolids: Development of simplified analogues
Applicant
Professor Dr. Dirk Menche
Subject Area
Organic Molecular Chemistry - Synthesis and Characterisation
Term
from 2014 to 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 159663715
The polyketide natural products archazolid A and B constitute novel types of particularly efficient (IC50 in the low nanomolar and subnanomolar range) and specific inhibitors of V-ATPases, both in vitro and in vivo. During the first funding period of this Forschergruppe, they have been shown to demonstrate potent antitumor activity in mice, which renders them highly attractive compounds for further preclinical advancement. However this has been severely hampered by the low availability from their natural source and the structural complexity that impedes a large scale access by total synthesis. Within the interdisciplinary approach of this Forschergruppe this project proposes the design and synthesis of simplified archazolids as improved antitumor agents. The first part of the project will develop innovative archazolid derivatives as chemical tools to analyse in more detail the in vivo interactions of these potent macrolides at a molecular level. Based on these studies the design and synthesis of carefully selected archazolid analogues will then be pursued. Particular emphasis will be placed on the development of equipotent but more readily available analogues. Structural simplification will rely on a rational approach based on a detailed in silico analysis of target inhibitor interactions. These compounds will be obtained either by a modular, total synthesis or based on derivatization of the parent natural products themselves. All analogues will then be thoroughly evaluated for their antitumor potential within this Forschergruppe.
DFG Programme
Research Units
