Synthese des Cyclohepta[e]hydrindan-Kerns des marinen Homoverrucosan-Diterpenoids Gagunin E und Evaluation von Homoverrucosanoid-abgeleiteten Estern als MDR-Modulatoren

Andreas Schäfer, Technische Universität Dortmund, Technische Universität Dortmund
2018
The present thesis describes the synthesis of the A−B-cis,B−C-trans annulated cyclohepta[e]hydrindane core of a gagunin E analogue featuring a fully elaborated B−C ring segment. The marine homoverrucosane diterpenoid gagunin E was isolated by Shin and co-workers in 2002 from a sponge of the genus Phorbas. Biological studies demonstrated that gagunin E exhibits a notable LC50 value (0.03 μg/mL) against the human leukemia cell-line K562. The tricarbocyclic scaffold was assembled starting from an
more » ... d starting from an adaptable A ring building block by a (4+2)-cycloaddition for annulation of the B ring. A ring-closing metathesis served for construction of the seven-membered C ring. The angular methyl groups were attached by electrophilic cyclopropanation−ring opening. Principles for the natural product-like functionalization of the homoverrucosane scaffold were delineated that could guide future synthetic efforts toward the gagunins. A library based on the most active lead compound was made accessible by esterification of the terpenols with commercially available acids. The members of the compound library of non-natural homoverrucosanoid-derived esters were examined as modulators of the membrane transporter proteins ABCB1 (P-gp), ABCG2 (BCRP), and ABCC1 (MRP1), which are involved in the formation of multidrug resistance (MDR) in cancer chemotherapy. Structure−activity relationship studies revealed that specific molecular constitution and configuration as well as general lipophilicity of the homoverrucosane scaffold are important factors for effective molecular recognition. The presence of an unmasked alcohol at C6 and a quinoline-6-carboxylic acid ester at C4 are most beneficial for binding to ABCB1 and ABCG2.
doi:10.17877/de290r-18900 fatcat:honztstrejc4ngcewnqer47whm