The most common solid tumors show intrinsic multidrug resistance (MDR) or inevitably acquire suchwhen treated with anticancer drugs. In this work, we describe the discovery of a peripherally restricted, potent, competitive NMDA receptor antagonist 1l by a structure-activity-study of the broad-acting ionotropic glutamate receptor antagonist 1a. Subsequently, we demonstrate that 1l augments the cytotoxic action of sorafenib in murine hepatocellular carcinoma (HCC) cells. The underlying biological mechanism was shown to be interference with the lipid signaling pathway, leading to reduced expression of MDR transporters and therebyan increased accumulation of sorafenib in the cancer cells. Interference with lipid signaling pathwaysby NMDA receptor inhibition is a novel and promising strategy for reversing transporter-mediated chemoresistance in cancer cells.
Competitive antagonists for ionotropic
glutamate receptors (iGluRs)
are highly valuable tool compounds for studying health and disease
states in the central nervous system. However, only few subtype selective
tool compounds are available and the discovery of antagonists with
novel iGluR subtype selectivity profiles remains a profound challenge.
In this paper, we report an elaborate structure–activity relationship
(SAR) study of the parental scaffold 2,3-trans-3-carboxy-3-phenyl-proline
by the synthesis of 40 new analogues. Three synthetic strategies were
employed with two new strategies of which one being a highly efficient
and fully enantioselective strategy based on C(sp3)–H activation
methodology. The SAR study led to the conclusion that selectivity
for the NMDA receptors was a general trend when adding substituents
in the 5′-position. Selective NMDA receptor antagonists were
obtained with high potency (IC50 values as low as 200 nM)
and 3–34-fold preference for GluN1/GluN2A over GluN1/GluN2B-D
NMDA receptors.
Discovery
of chemical tools for the ionotropic glutamate receptors
continues to be a challenging task. Herein we report a diversity-oriented
approach to new 2,3-trans-l-proline analogs
whereby we study how the spatial orientation of the distal carboxylate
group influences the binding affinity and receptor class and subtype
selectivity. In total, 10 new analogs were synthesized and 14 stereoisomers
characterized in binding assays at native rat ionotropic glutamate
receptors, and at cloned human homomeric kainic acid (KA) receptor
subtypes GluK1–3. The study identified isoxazole analogs 3d,e, which displayed selectivity in binding
at native N-methyl-d-aspartate (NMDA) receptors
over native α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) and KA receptors, in the high nanomolar to low micromolar
range. Furthermore, analogs 3i-A/B showed a preference
in binding affinity for GluK3 over GluK1,2. Finally, analog 3j displayed high nanomolar affinity for native NMDA receptors
as well as for homomeric GluK3 receptors.
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