P-糖蛋白抑制剂及其构效关系研究进展

摘要/Abstract

摘要： P-糖蛋白(P-glycoprotein,P-gp)是一种ATP依赖性的跨膜转运蛋白,可将多种结构和药效不同的化合物排出细胞。P-gp具有重要的病理生理功能,既影响药物的体内过程,也是肿瘤产生多药耐药的主要原因之一。因此,开发P-gp的抑制剂对于药物代谢动力学行为的调节及逆转肿瘤多药耐药具有重要意义。本文总结了近年来P-gp抑制剂开发及构效关系(structure-activity relationship, SAR)的研究进展,这对进一步筛选及合成理想的P-gp抑制剂有重要的指导作用。

关键词: P-糖蛋白, 多药耐药, 构效关系

Abstract: P-glycoprotein (P-gp) is an important ATP-dependent transmembrane transporter, which can pump out a large number of structural and functional diverse compounds. P-gp plays a prominent role in physiological and pathological functions. It is not only crucial to drug disposition, but also one of the main causes of multidrug resistance (MDR). Therefore, developing P-gp inhibitors is significant to researches on modulation of drug pharmacokinetics and reversion of multidrug resistance. In this paper, we summarize studies on structure-activity relationship of P-gp inhibitors, which will give us important information for screening and synthesizing desirable P-gp inhibitors in the future.

Key words: P-glycoprotein, Multidrug resistance, Structure-activity relationship

中图分类号:

R969

温晓舟, 周芳, 吴晓兰, 王广基. P-糖蛋白抑制剂及其构效关系研究进展[J]. 中国临床药理学与治疗学, 2010, 15(7): 814-820.

WEN Xiao-zhou, ZHOU Fang, WU Xiao-lan, WANG Guang-ji. Research advance on P-glycoprotein inhibitors and the structure-activity relationship[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2010, 15(7): 814-820.

参考文献

[1] Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter[J]. Annu Rev Biochem, 1993,62: 385-427.
[2] Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance[J]. Nat Rev Cancer, 2005,5(4):275-284.
[3] Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters[J]. J Nat Rev Cancer, 2002,2(1):48-58.
[4] Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants[J]. Biochimicaet Biophysica Acta, 1976,455(1):152-162.
[5] Gottesman MM, Pastan I. The multidrug transporter, a double-edged sword[J]. J Biol Chem, 1988,263(25):12163-12166.
[6] Rosenberg MF, Kamis AB, Collaghan R, et al. Three-dimensional structures of the mammalian multidrug resistance P-glycoprotein demonstrate major conformational changes in the transmembrane domains upon nucleotide binding[J]. J Biol Chem, 2003,278(10):8294-8299.
[7] Sauna ZE, Smith MM, Muller M, et al. The mechanism of action of multidrug-resistance-linked P-glycoprotein[J]. J Bioenerg Biomembr, 2001,33(6):481-491.
[8] Ambudkar SV, Sarfaty CK, Sauna ZE,et al. P-glycoprotein: from genomics to mechanism[J]. Oncogene, 2003,22(47):7468-7485.
[9] Loo TW, Bartlett MC, Clarke DM. Methanethiosulfonate derivatives of rhodamineand verapamil aetivate human P-glycoprotein at different sites[J]. J Biol Chem, 2003,278(50):50136-50141.
[10] Aller SG, Yu J, Ward A, et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding[J]. Science, 2009,323(5922):1718-1722.
[11] Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: Implications for drug delivery and activity in cancer chemotherapy[J]. Mol Carcinogen, 1995,13(3):129-134.
[12] McDevitt CA, Callaghan R. How can we best use structural information on P-glycoprotein to design inhibitors[J] ? Pharm Ther, 2007, 113(2):429-441.
[13] Wang RB, Kuo CL, Lien LL, et al. Structure-activity relationship: analyses of p-glycoprotein substrates and inhibitors[J]. J Clin Pharm Ther, 2003,28(3):203-228.
[14] Bielder JL, Riehm H. Cellular resistance to actinomycin D in Chinese Hamster cells in vitro: cross-resistance, radioautotrophic, and cytogenic studies[J]. Cancer Res, 1970,30(4),1174-1184.
[15] Bain LJ, McLachlan JB, LeBlanc GA. Structure-activity relationships for xenobiotic transport substrates and inhibitory ligands of P-glycoprotein[J]. Environ Health Perspect, 1997, 105(8):812-818.
[16] Bain LJ, LeBlanc GA. Interaction of structurally diverse pesticides with the human MDR1 gene product P-glycoprotein[J]. Toxicol Appl Pharmacol, 1996,141(1):288-298.
[17] Perez-Victoria JM, Perez-Victoria FJ, Conseil G, et al. High-afinity binding of silybin derivatives to the nucleotide-binding domain of a Leishmania tropica P-glycoprotein-like transporter and chemosensitization of a multidrug-resistant parasite to daunomycin[J]. Antimicrob Agents Ch, 2001,45(2):439-446.
[18] Ramu A, Ramu N. Reversal of multidrug resistance by phenothiazines and structurally related compounds.Cancer Chemother[J]. Pharmacol, 1992,30(3):165-173.
[19] Dzubák P, Hajdúch M, Gazák R, et al. New derivatives of silybin and 2,3-dehydrosilybin and their cytotoxic and P-glycoprotein modulatory activity[J]. Bioorgan Med Chem, 2006,14(11):3793-3810.
[20] Ueda K, Okamura N, Hirai M, et al. Human P-glycoprotein transports cortisol, aldosterone,and dexamethasone, but not progesterone[J]. J Biol Chem, 1992,267(34):24248-24252.
[21] Chiba P, Ecker G, Schmid D, et al. Structural requirements for activity of propafenone-type modulators in P-glycoprotein-mediated multidrug resistance[J]. Mol Pharmacol, 1996,49(6):1122 -1130.
[22] Teodori E, Dei S, Garnier-Suillerot A, et al. Exploratory chemistry toward the identification of a new class of multidrug resistance reverters inspired by pervilleine and verapamil models[J]. J Med Chem, 2005,48(23):7426-7436.
[23] McDevitt CA, Callaghan R. How can we best use structural information on P-glycoprotein to design inhibitors[J] ? Pharmacol Ther, 2007,113(2):429-441.
[24] Kitagawa S, Nabekura T, Takahashi T, et al. Structure-activity relationships of the inhibitory effects of flavonoids on P-glycoprotein-mediated transport in KB-C2 Cells[J]. Biol Pharm Bull, 2005,28(12):2274-2278.
[25] Kitagawa S. Inhibitory effects of polyphenols on P-glycoprotein- mediated transport[J]. Biol Pharm Bull, 2006,29(1):1-6.
[26] Conseil G, Baubichon-Cortay H, Dayan G, et al. Flavonoids: a class of modulators with bifunctional interactions at vicinal ATP-and steroid-binding sites on mouse P-glycoprotein[J]. Proc Nati Acad Sci USA, 1998,95(17):9831-9836.
[27] Lespine A, Martin S, Dupuy J, et al. Interaction of macrocyclic lactones with P-glycoprotein:Structure-af?nity relationship[J]. Eur J pharm Sci, 2007,30(1):84-94.
[28] Lee Y, Yeo H, Liu SH, et al. Increased anti-P-glycoprotein activity of baicalein by alkylation on the A ring[J]. J Med Chem, 2004,47(22):5555-5566.
[29] Choi CH, Kim JH, Kim SH.Reversal of P-glycoprotein-mediated MDR by 5,7,3',4',5'-pentamethoxyflavone and SAR[J]. Biochem Biophys Res Commun, 2004,320(3):672-679.
[30] Ohtani H, Ikegawa T, Honda Y, et al. Effects of various methoxyflavones on vincristine uptake and multidrug resistance to vincristine in P-gp-overexpressing K562/ADM cells[J]. Pharm Res, 2007,24(10):1936-1943.
[31] Ford JM, Prozialeck WC, Hait WN.. Structural features determining activity of phenothiazines and related drugs for inhibition of cell growth and reversal of multidrug resistance[J]. Mol Pharmacol, 1989,35(1):105-115.
[32] Ford JM, Briggemann EP, Pastan I, et al. Cellular and biochemical characterization of thioxanthenes for reversal of multidrug resistance in human and murine cell lines[J]. Cancer Res, 1990,50(6):1748-1756.
[33] Chen B, Dong Y, Zhang P, et al. Effect of tetrandrine and droloxifene on the reversion of drug resistance of K562/A02 cell line and induction of apoptosis[J]. Zhonghua Zhong Liu Za Zhi, 2002,24(6):526-528.
[34] Tsakovska IM. QSAR and 3D-QSAR of phenothiazine type multidrug resistance modulators in P388/ADR Cells[J]. Bio Med Chem, 2003,11(13):2889-2899.
[35] 张景红, 李红玉.雄黄微生物提取液对K562/ADM细胞P-糖蛋白和多药耐药基因表达的影响[J].中国临床药理学与治疗学, 2009,14(8):855-860.
[36] Choi JS, Choi BC, Kang KW. Effect of resveratrol on the pharmacokinetics of oral and intravenous nicardipine in rats: possible role of P-glycoprotein inhibition by resveratrol[J]. Pharmazie, 2009,64(1):49-52.
[37] Zheng Y, Zhou F, Wu X, et al. 23-Hydroxybetulinic acid from Pulsatilla chinensis (Bunge) Regel synergizes the antitumor activities of doxorubicin in vitro and in vivo[J]. J Ethnopharmacol, 2010, [Epub ahead of print].
[38] Li W, Nan L, Ji Y, et al. Studies on influence factors of gnsenoside Rg1 and Rb1 absorption in intestines of rats[J]. Zhongguo Zhong Yao Za Zhi, 2009,34(20):2627-2632.