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: 2.82). 05/2008; 16(7):3694-703. DOI: 10.1016/j.bmc.2008.02.029
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: A simple synthesis and biologic evaluation of trans-3,4,5-trimethoxycinnamamides 10a–e and 11 as novel antinarcotic agents is described. The synthetic key strategies involve condensation reaction and coupling reaction to generate trans-3,4,5-trimethoxycinnamamides 10a–e and 11. They were evaluated for free radical scavenging, inhibitory action for neurotoxicity in cultured neurons, and antinarcotic activity in mice. It was found that compounds 10a, 10d, and 10e displayed significant inhibitory action of the glutamate-induced neurotoxicity and 10a–e and 11 showed high antinarcotic activity in mice.
    Medicinal Chemistry Research 01/2013; · 1.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    BioMed research international. 01/2013; 2013:343808.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Drug resistance is a major impediment for cancer treatment, to overcome it we designed and synthesized sixteen coumarins bearing hydrazide-hydrazone moiety and evaluated them against human drug-resistant pancreatic carcinoma (Panc-1) cells and drug-sensitive (hepatic carcinoma; Hep-G2 and leukemia; CCRF) cell lines in vitro. The 6-brominated coumarin hydrazide-hydrazone derivatives (BCHHD) 7c, 8c and 10c were more potent than doxorubicin (DOX) against resistant Panc-1 cells. BCHHD 7c showed significant cytotoxicity against all tested cells (IC50: 3.60-6.50 μM) on comparison with all other coumarin hydrazide-hydrazone derivatives (CHHD), whereas BCHHD's 8c and 10c showed significant antiproliferative activity only against resistant Panc-1 cells with IC50 of 2.02 μM and 2.15 μM, respectively. All the investigated BCHHD's were able to activate caspases 3/7 and they could induce apoptosis in resistant Panc-1 cells. Microarray analysis showed that BCHHD 7c induced the expression of apoptotic- and cell cycle arrest (G2/M)- genes in resistant Panc-1 cells. Moreover, BCHHD 7c induced the up-regulation of CDKN1A, DDIT4, GDF-15 and down-regulation of CDC2, CDC20, CDK2 genes. Based on our results, we conclude that 7c could be a potent anticancer drug to overcome drug resistance in cancer and it could be highly beneficial for patients in the clinic.
    European Journal of Medicinal Chemistry 02/2014; 76C:539-548. · 3.43 Impact Factor