ABSTRACT
P-glycoprotein (Pgp) modulators are promising agents for overcoming multidrug resistance (MDR) in cancer chemotherapy. In this study, via structural optimization of our lead compound S54 (nonsubstrate allosteric inhibitor of Pgp), 29 novel pyxinol amide derivatives bearing an aliphatic heterocycle were designed, synthesized, and screened for MDR reversal activity in KBV cells. Unlike S54, these active derivatives were shown to transport substrates of Pgp. The most potent derivative 4c exhibited promising MDR reversal activity (IC50 of paclitaxel = 8.80 ± 0.56 nM, reversal fold = 211.8), which was slightly better than that of third-generation Pgp modulator tariquidar (IC50 of paclitaxel = 9.02 ± 0.35 nM, reversal fold = 206.6). Moreover, the cytotoxicity of this derivative was 8-fold lower than that of tariquidar in human normal HK-2 cells. Furthermore, 4c blocked the efflux function of Pgp and displayed high selectivity for Pgp but had no effect on its expression and distribution. Molecular docking revealed that 4c bound preferentially to the drug-binding domain of Pgp. Overall, 4c is a promising lead compound for developing Pgp modulators.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1 , Amides , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Molecular Docking Simulation , Humans , Drug Resistance, Multiple/drug effects , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Structure-Activity Relationship , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Drug Resistance, Neoplasm/drug effects , Molecular Structure , Dose-Response Relationship, Drug , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Drug Screening Assays, Antitumor , Cell Proliferation/drug effectsABSTRACT
The P-glycoprotein (Pgp) is a major transporter involved in multidrug resistance (MDR) of cancer cells leading to chemotherapy failure. In our previous study, we demonstrated that the amide derivatives of pyxinol are promising modulators against Pgp-mediated MDR in cancer. In the present study, we designed and synthesized novel pyxinol derivatives linked to amino acid residues. We evaluated MDR (paclitaxel (Ptx) resistance) reversal potency of forty pyxinol derivatives in KBV cells and analyzed their structure-activity relationships. Half of our derivatives sensitized KBV cells to Ptx at non-toxic concentrations, among which the pyxinol compound bearing a methionine residue (3c) exhibited the best activity in MDR reversal. Compound 3c was found to possess high selectivity toward Pgp and sensitize the KBV cells to Pgp substrates by blocking the efflux function of Pgp. This manifestation may be attributed to its high binding affinity with Pgp, as suggested by docking studies. Overall, the biological profile and ease of synthesizing these pyxinol derivatives render them promising lead compounds for further development for Pgp-mediated MDR.