The Ko family of fumitremorgin C analogs are potent and selective ABCG2 inhibitors. However, the most potent
Ko compounds carry an ester linkage in their side-chain that makes them chemically and metabolically less stable.
We have synthesized 16 tricyclic and 28 tetracyclic novel analogs devoid of ester linkages and tested them for ABCG2
inhibition potency and specificity. Unlike in the tricyclic analog group, potent ABCG2 inhibitory compounds were found
among the tetracyclic analogs. The most potent compounds carried the 3S,6S,12aS configuration. We observed a marked
stereospecificity as compounds with the 3S,6S,12aS configuration were at least 18-fold more potent inhibitors than their
diastereoisomeric pairs with a 3S,6R,12aS configuration. This stereospecificity was not observed in ABCB1 and ABCC1
inhibition. Therefore, a single chiral center confers specificity for ABCG2 over ABCB1 and ABCC1. This is quite unexpected
considering the large multivalent drug binding site these transporters harbor.
Keywords: ABCG2 reversal, cancer, fumitremorgin C analogs, indolyl diketopiperazines, inflammatory diseases, multidrug
resistance, structure-activity relationships
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