Methoxylation of 3 ',4 '-aromatic side chains improves P-glycoprotein inhibitory and multidrug resistance reversal activities of 7,8-pyranocoumarin against cancer cells
ABSTRACT The overexpression of P-glycoprotein (Pgp), an ATP-driven membrane exporter of hydrophobic xenobiotics, is one of the major causes of multidrug resistance (MDR) in cancer cells. Through extensive screening we have found that the extracts of Peucedanum praeruptorum Dunn. and one of the major components (+/-)-praeruptorin A (PA) may reverse Pgp-mediated multidrug resistance. Studies on novel PA derivatives have shown that (+/-)-3'-O,4'-O-dicinnamoyl-cis-khellactone (DCK) is more active than PA or verapamil and is a non-competitive inhibitor of Pgp. Here, we report that methoxylation of the cinnamoyl groups on DCK may further enhance its bioactivity. The structure-activity relationship is demonstrated by comparing two new pyranocoumarins (+/-)-3'-O,4'-O-bis(3,4-dimethoxycinnamoyl)-cis-khellactone (DMDCK) and (+/-)-3'-O,4'-O-bis(4-methoxycinnamoyl)-cis-khellactone (MMDCK). While the co-existence of 3- and 4-methoxy groups on cinnamoyl remarkably enhanced the Pgp-inhibitory activity, the lone existence of the 4-methoxy group on cinnamoyl reduced the activity. Contrary to DCK, DMDCK promoted the binding of UIC2 antibody to Pgp which signifies a conformational change of Pgp similar to that induced by transport substrates. While DCK moderately stimulated the basal Pgp-ATPase activity, DMDCK inhibited the activity. A pharmacophore search with verapamil-based template revealed that four functional groups of DMDCK could be simultaneously involved in interaction with Pgp whereas for DCK or MMDCK only three groups were involved. It is speculated that the additional 3-methoxy group on cinnamoyl allows DMDCK to interact more efficiently with Pgp substrate site(s). If DMDCK was tightly bind to Pgp substrate site(s) the complexes could be inactive with regard to transportation and ATP hydrolysis could also be inhibited.
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ABSTRACT: By methods of differential-thermal analysis and X-ray-phase analysis it is proved that the Bi2Te3-Bi2Se3 section is a system with a continuous series of solid solutions, with the formation of Bi2Te2Se compound below the solidus line. The formation of this compound has been confirmed both in experiment and by thermodynamic analysis. It has been found that after zone melting the temperature values of the liquidus and solidus lines correlate with those obtained for equilibrium systems and mentioned in the literature. The boundary has been identified for the existence of Bi2Te3-xSex solid solutions, which lies at ∼14 mole % Bi2Se3 (Bi2Te2.58Se0.42). Thermodynamic analysis shows chemical interactions (reactions) resulting in the formation of Bi2Te2Se. It has been found that in the two-phase zone, the Seebeck coefficient values dramatically change in a jumping manner, with the points of extremum located on the boundaries of the two-phase zone. In the zone of Bi2Te2Se compound occurrence (33.3 mole % Bi2Se3) the values of the Seebeck coefficient and power factor are minimal.
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ABSTRACT: Multidrug resistance-associated protein 2 (MRP2/ABCC2) is mainly expressed in the apical phase of barrier membranes. It functions as a critical efflux pump in the biliary excretion of endogenous substances, such as conjugated bilirubin and bile salts, as well as many structurally diverse xenobiotics and their metabolites. Due to its important role in defining ADME/Tox properties, efforts have emerged to build the structure-activity relationship (SAR) for MRP2/ABCC2 at early stages of drug discovery process. MRP2/ABCC2 is a member of the integral membrane protein family whose high-resolution crystal structure has not been described. To overcome the obstacle of lacking detailed structural depiction, various molecular modeling approaches have been applied to derive the structural requirements for binding interactions with MRP2/ABCC2 protein, including two-dimensional (2D) and three-dimensional (3D) quantitative SAR (QSAR) analysis, pharmacophore models, and homology modeling of the transporter. Here we summarize recent progresses in understanding the SAR of MRP2/ABCC2 recognition of substrates and/or inhibitors, and describe some of the useful in vitro tools for characterizing the interactions with the transporter.The AAPS Journal 07/2009; 11(3):406-13. DOI:10.1208/s12248-009-9117-0 · 3.91 Impact Factor
- Chinese Journal of Natural Medicines 01/2010; 7(6):465-475. DOI:10.3724/SP.J.1009.2009.00465