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

Abstract

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.

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…In addition, 77 was the most effective inhibitor of BCRP, with very low activity against P-gp or other known drug transporters [168,170]. In addition, the stereospecificity was shown to be very critical in the Ko family, for example, compounds having the 3S,6S,12αS configuration were 18 times more potent than those with 3S,6R,12αS configuration in inhibiting BCRP; however, this stereoselective effect was not observed in P-gp and MRP-1 [171]. 3S,6S,12αS configuration were 18 times more potent than those with 3S,6R,12αS configuration in inhibiting BCRP; however, this stereoselective effect was not observed in P-gp and MRP-1 [171].…”

“…In addition, the stereospecificity was shown to be very critical in the Ko family, for example, compounds having the 3S,6S,12αS configuration were 18 times more potent than those with 3S,6R,12αS configuration in inhibiting BCRP; however, this stereoselective effect was not observed in P-gp and MRP-1 [171]. 3S,6S,12αS configuration were 18 times more potent than those with 3S,6R,12αS configuration in inhibiting BCRP; however, this stereoselective effect was not observed in P-gp and MRP-1 [171]. The first synthesis of 74 was reported by Hino et al who prepared N-propyl-7-methoxy-β-carboline as the key intermediate [172].…”

“…The reaction was performed by the Pictet-Spengler condensation of the hydroxyethyl functionalized polystyrene resin linked L-tryptophan with excess of aldehyde Scheme 15a [163,169]. 3S,6S,12αS configuration were 18 times more potent than those with 3S,6R,12αS configuration in inhibiting BCRP; however, this stereoselective effect was not observed in P-gp and MRP-1 [171]. The first synthesis of 74 was reported by Hino et al who prepared N-propyl-7-methoxy-β-carboline as the key intermediate [172].…”

Investigation of the Pharmacokinetics of the ABCG2 Transporter Inhibitor Ko134 in Mice by a Newly Developed and Validated HPLC Method

“…propionic acid tert-butyl ester) was synthetized as published previously [19]. 1-Isobutyl-2,3,4,9-tetrahydro-1H--carboline-3-carboxylic acid acetate (internal standard, IS) was purchased from Sigma-Aldrich (Budapest, Hungary).…”

“…3). The basic pharmacokinetic parameters of Ko134 in mice calculated with the PKSolver 2.0 software in the noncompartmental approach [19] are listed in Table 3. As shown in (Fig.…”