Abstract
The synthesis of the A-B-cis,B-C-trans-annulated cyclohepta[e]hydrindane core of a gagunin E analogue is reported in detail. The tricarbocyclic scaffold was assembled starting from an easily accessible 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. A library based on the most active lead compound was made accessible by esterification of the terpenols with commercially available acids. A transannular etherification reaction gave access to tetracyclic derivatives of the synthetic inhibitors. 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Survival / drug effects
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Cells, Cultured
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Dogs
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Dose-Response Relationship, Drug
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Drug Resistance, Multiple / drug effects*
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Esters / chemical synthesis
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Esters / chemistry
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Esters / pharmacology*
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Humans
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Molecular Conformation
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Multidrug Resistance-Associated Proteins / metabolism
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / metabolism
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Polycyclic Compounds / chemical synthesis
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Polycyclic Compounds / chemistry
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Polycyclic Compounds / pharmacology*
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Structure-Activity Relationship
Substances
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ABCB1 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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Antineoplastic Agents
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Esters
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Multidrug Resistance-Associated Proteins
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Neoplasm Proteins
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Polycyclic Compounds
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multidrug resistance-associated protein 1