Synthesis and ABCG2 Inhibitory Activity of Novel Fumitremorgin C Analogs – Specificity and Structure Activity Correlations

Author(s): Orsolya Szolomajer-Csikos, Erzsebet Beery, Levente Kosa, Zsuzsanna Rajnai, Marton Jani, Anasztazia Hetenyi, Katalin Tauber Jakab, Peter Krajcsi, Gabor K Toth.

Journal Name: Medicinal Chemistry

Volume 9 , Issue 4 , 2013

Become EABM
Become Reviewer


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

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2013
Page: [494 - 509]
Pages: 16
DOI: 10.2174/1573406411309040003
Price: $58

Article Metrics

PDF: 24