Methoxylation of 3 ',4 '-aromatic side chains improves P-glycoprotein inhibitory and multidrug resistance reversal activities of 7,8-pyranocoumarin against cancer cells

Research & Development Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China.
Bioorganic & medicinal chemistry (Impact Factor: 2.79). 05/2008; 16(7):3694-703. DOI: 10.1016/j.bmc.2008.02.029
Source: PubMed


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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    • "Unlike Pd-la mechanism, DCK directly inhibited Pgp by a noncompetitive mechanism without inhibiting Pgp expression [31]. In a further study by Fong et al. [32], methoxy substitution of the aromatic rings significantly enhanced the interaction between Pgp and pyranocoumarins and influenced Pgp-MDR reversing action. (±)-3′-O, 4′-O-bis(3, 4-Dimethoxycinnamoyl)-cis-khellactone (DMDCK) was found as a good Pgp modulator because of higher Pgp-MDR reversing activity and relatively lower cytotoxicity. "
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    ABSTRACT: Praeruptorins belonging to the angular-type pyranocoumarins are bioactive constituents that have been isolated from some Peucedanum species such as P. praeruptorum, which is used in traditional Chinese medicine for treatment of cold, cough, upper respiratory infections, and so forth. Many reports have demonstrated that the beneficial pharmacological effects of P. praeruptorum root on cardiovascular, pulmonary, immune, and nervous system diseases were attributed to the presence of praeruptorins. The aim of this review is to explain the recent efforts of scientists in pharmacological screening of natural and synthetic praeruptorin derivatives, studying the mechanisms of some praeruptorins action, pharmacokinetics, toxicity, and relevant structure-activity relationships. Based on reported data about the pharmacological properties of praeruptorins and semisynthetic derivatives of them, it is hopeful that in the near future more studies focus on the discovery of the new application and therapeutic uses of these bioactive compounds and understanding the specific mechanisms of them. The present discusses the reports on molecular and biological activities of praeruptorins of the genus Peucedanum, from 1976 onwards.
    Full-text · Article · Nov 2013
    • "Both stereoisomers of DMDCK had four functional groups (two hydrophobic points and two HB acceptor points) simultaneously involved in the interaction with Pgp, implying a higher binding affinity and Pgp modulating activity. Results of the pharmacophore search provide an explanation on structural bases for MDR reversing activity of these pyranocoumarins derivatives [121] [122]. Furthermore, pyranocoumarins are as effective as verapamil, a calcium voltage channel blocker, in enhancing doxorubicin accumulation. "
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    ABSTRACT: Natural as well as synthetic coumarins have recently drawn much attention due to its broad pharmacological activities. Many coumarins and their derivatives exert anti-coagulant, anti-tumor, anti-viral, anti-inflammatory and anti-oxidant effects, as well as anti-microbial and enzyme inhibition properties. The recognition of key structural features within coumarin family is crucial for the design and development of new analogues with improved activity and for the characterization of their mechanism of action and potential side effects. The different substituents in the coumarin nucleus strongly influence the biological activity of the resulting derivatives. Although some coumarins have been already characterized to evoke a particular biological activity, the challenge would be the design and synthesis of new derivatives with high specific activity for other pharmacological targets and define their mechanism of action to achieve new therapeutic drugs. The present review highlights the current progress in the development of coumarin scaffolds for drug discovery as novel anti-cancer agents. The major challenges about coumarins include the translation of current knowledge into new potential lead compounds and the repositioning of known compounds for the treatment of cancer.
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