HYDROPHOBIC INTERACTION OF 2-TRIFLUOROMETHYL-N10-SUBSTITUTED PHENOXAZINES WITH BOVINE SERUM ALBUMIN AND REVERSAL OF DRUG RESISTANCE IN BACTERIAL CELLS
Keywords:
Hydrophobic interaction, Phenoxazines, Bacterial drug resistance, Bovine serum albuminAbstract
Objective: The objective of this study was to report the hydrophobic interaction of 2-trifluoromethyl-N10-substituted phenoxazines with bovine serum albumin and reversal of drug resistance in bacterial cells.
Methods: Binding of six compounds, 10-[3'-N-morpholinopropyl]-2-trifluoromethyl phenoxazine (1C), 10-[4'-N-morpholinobutyl]-2-trifluoromethyl phenoxazine (2C), 10-[3'-N-pyrrolidinopropyl]-2-trifluoromethyl phenoxazine (3C), 10-[4'-N-pyrrolidinobutyl]-2-trifluoromethyl phenoxazine (4C), 10-[N-piperidinoacetyl]-2-trifluoromethyl phenoxazine (5C), and 10-[N-pyrrolidinoacetyl]-2-trifluoromethyl phenoxazine (6C), to bovine serum albumin (BSA) has been measured by gel filtration and equilibrium dialysis methods. The binding of these compounds to BSA has been characterized by percentage of bound drug (β), the association constant (K), the apparent binding constant (k) and free energy (∆Fo). The binding of phenoxazine derivatives to BSA, a serum protein that binds and transports small molecules, is correlated with their partition coefficients. Further, the ability of the phenoxazines (1C-6C) on the antibacterial activity of five antibiotics, kanamycin, spectinomycin, gentamycin, streptomycin and benzylpenicillin was examined for their ability to reverse the resistance of E. coli K12 MG 1655 and E. coli ST 58.
Results: The results of displacing experiments reveal that the phenoxazine benzene rings and tertiary amines attached to the side chain of phenoxazine moiety are bound to a hydrophobic region on the albumin molecule. Among the compounds examined the butyl series seems to possess better reversing ability, suggesting that the activity could be related to lipophilicity and the extent of binding to BSA.
Conclusions: Phenoxazines are bound to albumin by hydrophobic interactions of their benzene rings. The alkyl side chain, particularly butyl chain of phenoxazines intensifies the interaction of phenoxazines with BSA. The compound that binds to a greater extent with protein possesses more activity for reversing of drug resistance.
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Laursen JB, Nielsen J. Phenazine natural products: biosynthesis, synthetic analogues, and biological activity. Chem Rev 2004;104:1663-86.
Chunhua L, Yaoyao L, Haoxin W, Baomin, Yuemao S. A new phenoxazine derivative isolated from marine sediment actinomycetes, Nocardiopsis. Drug Discoveries Ther 2013;7(3):101-4.
Nakachi T, Tabuchi T, Takasaki A, Arai S, Miyazawa K, Tomoda A. Anticancer activity of phenoxazines produced by bovine erythrocytes on colon cancer cells. Oncol Rep 2010;23:1517-22.
Prinz H, Chamasmani B, Vogel K, Böhm KJ, Aicher B, Gerlach M, et al. N-benzoylated phenoxazines and phenothiazines: synthesis, antiproliferative activity, and inhibition of tubulin polymerization. J Med Chem 2011;54:4247-63.
Boehringer CF, Soehne. Reaction of pyrylium salts with amines of the benzimidazole series. Chem Abstr 1964;60:1712.
Rogers WP, Craig JC, Warwick GP. Chemical constitution and anthelminthic activity of cyclic analogues of phenothiazine. Br J Pharmacol 1955;10:340-2.
Thimmaiah KN, Horton JK, Qian XD, Beck WT, Houghton JA, Houghton PJ. Structural determinants of phenoxazine type compounds required to modulate the accumulation of vinblastine and vincristine in multidrug-resistant cell lines. Cancer Commun 1990;2(7):249–59.
Thimmaiah KN, Horton JK, Sheshadri R, Israel M, Houghton JA, Houghton PJ. Synthesis and chemical characterization of N-substituted phenoxazines directed toward reversing vinca alkaloid resistance in multidrug-resistant cancer-cells. J Med Chem 1992;35:3358-64.
Horton JK, Thimmaiah KN, Harwood FC, Kuttesch JF, Houghton PJ. pharmacological characterization of N-substituted phenoxazines directed toward reversing vinca alkaloid resistance in multidrug-resistant cancer-cells. Mol Pharmacol 1993;44:552-9.
Eregowda GB, Kalpana HN, Ravi Hegde, Thimmaiah KN. Synthesis and analysis of structural features of phenoxazine analogues needed to reverse vinblastine resistance in multidrug resistant (MDR) cancer cells. Indian J Chem 2000;39B:243-59.
Eregowda GB, Krishnegowda G, Kalpana HN, Channu BC, Dass C, Horton JK, et al. Structural requirements for activity of phenoxazines for reversal of drug resistance in cancer cells. Asian J Chem 1999;11(3):878-05.
Thimmaiah KN, Jayashree BS, Germain GS, Houghton PJ, Horton JK. Characterization of 2-chloro-N10-substituted phenoxazines for reversing multidrug resistance in cancer cells. Oncol Res 1998;10:29-41.
Thimmaiah KN, Easton JB, Germain GS, Morton CL, Kamath S, Buolamwini JK, et al. Identification of N10-substituted phenoxazines as potent and specific inhibitors of Akt signaling. J Biol Chem 2005;280(36):31924-35.
Kandagal PB, Ashoka S, Seetharamappa J, Shaikh SMT, Jadegoud Y, Ijare OB. Study of the interaction of an anticancer drug with human and bovine serum albumin: Spectroscopic approach. J Pharm Biomed Anal 2006;41:393-9.
Thomas F, Rochaix P, White Koning M, Hennebrlle I, Sarini J, Benlyazid A, et al. Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma. Eur J Cancer 2009;45(13):2316-23.
Ferenc Z, Zsolt B, David M, Peter H, Imre P, Attila B, et al. Evaluation of drug–human serum albumin binding interactions with support vector machine aided online automated docking. Struct. Bioinf 2011;27(13):1806-13.
Rasoulzadeh F, Asgari D, Naseri A, Rashidi MR. Spectroscopic studies on the interaction between erlotinib hydrochloride and bovine serum albumin. DARU 2010;18(3):179-84.
Hu YJ, Liu Y, Sun TQ, Bai AM, Lü JQ, Pi ZB. Binding of anti-inflammatory drug cromolyn sodium to bovine serum albumin. J Mol Struct 2005;750:174-8.
Rasoulzadeh F, Najarpour H, Naseri A, Rashidi MR. Fluorescence quenching study of quercetin interaction with bovine milk xanthine oxidase. Spectrochim Act Part A 2009;72:190-3.
Wang YQ, Zhang HM, Zhang GC, Tao WH, Tang SH. Binding of brucine to human serum albumin. J Mol Struct 2007;830:40-5.
Qiulan Z, Yongnian N, Serge K. Binding interaction of dopamine with bovine serum albumin: a biochemical study. Spectroscopy Lett 2012;45(2):85-92.
Hanwen S, Yuanyuan W, Pan H, Yanli Z, Yunkai L. Characterization of interaction between antitumor drug 5-fluorouracil and human serum albumin by affinity capillary electrophoresis. Asian J Pharm Sci 2012;7(1):75-9.
Krieglstein J, Meiler W, Staab J. Hydrophobic and ionic interactions of phenothiazine derivatives with bovine serum albumin. Biochem Pharmacol 1972;2:985-97.
Jadwiga H, Anna M, Katarzyna KK. Recent advances in multi-drug resistance (MDR) efflux pump inhibitors of gram-positive bacteria S. aureus. Antibiotics 2013;2(1):28-45.
Falagas ME, Bliziotis IA. Pan drug-resistant Gram-negative bacteria: the dawn of the post-antibiotic era. Int J Antimicrob Agents 2007;29:630-6.
Amaral L, Udwadia ZF, vaSoolingen DA. A cheap and effective anti-Mdr/Xdr/Tdr Tb drug is already available. Biochem Pharmacol J 2012;1000:137.
Amaral L, Molnar J. Why and how the old neuroleptic thioridazine cures the XDR-TB patient. Special issue: antituberculosis drugs. Pharmaceuticals 2012;5:1021-31.
Amaral L, Udwadia Z, Abbate E, van Soolingen D. The added effect of Thioridazine in treatment of resistant TB. Int J Tuberculosis Lung Disease 2012;16:1706-8.
Leitner I, Nemeth J, Feurstein T, Abrahim A, Matzneller P, Lagler H, et al. The third-generation P-glycoprotein inhibitor tariquidar may overcome bacterial multidrug resistance by increasing intracellular drug concentration. J Antimicrobial Chemother 2011;66:834-9.
Zamora JM, Pearce HL, Beck WT. Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells. Mol Pharmocol 1988;33:454-62.
Hulshoff A, Perrin JH. Quantitative correlations between albumin binding constants and chromatographic Rm values of phenothiazine derivatives. J Med Chem 1977;20:430-9.
Glasser H, Krieglstein J. Die Eiweißbindung einiger Psychopharmaka mit tricyclischem Ringsystem in Abhängigkeit von ihrer chemischen Konstitution. Naunyn-Schmiedeberg’s. Arch Pharmacol 1970;265:321-34.
Bird AE, Marshal AC. Correlation of serum binding of penicillins with partition coefficients. Biochem Pharmacol 1967;16:2275-90.
Hansch C. Use of homolytic, steric, and hydrophobic constants in a structure-activity study of 1, 3-benzodioxole synergists. J Med Chem 1968;11(5):920-4.
Hansch C, Fujitha T. p-s-p Analysis. A method for the correlation of biological activity and chemical structure. J Am Chem Soc 1964;86:1616-26.
Hansch C, Kiehs K, Lawrence GL. The role of substituent’s in the hydrophobic bonding of phenols by serum and mitochondrial proteins. J Am Chem Soc 1965;87(24):5770-3.
Scholtan W, Shlossmann K, Rosenkranz H. Steroidhormonen und von Steroidguanylhydrazonen a serum albumin. Arzneimittelforschung 1968;18:767-80.
Kauzmann W. Some factors in the interpretation of protein denaturation. Adv Protein Chem 1959;14:1-63.
Bush K, Miller GH. Bacterial enzymatic resistance: β-Lactamases and aminoglycoside-modifying enzymes. Curr Opin Microbial 1998;1:509-15.
Sabatini S, Gosetto F, Serritella S, Manfroni G, Tabarrini O, Iraci N, et al. Pyrazolo [4,3-c][1,2]benzothiazines 5,5-dioxide: a promising new class of Staphylococcus aureus NorA efflux pump inhibitors. J Med Chem 2012;55:3568-72.
Li XZ, Nikqaido H. Efflux-mediated drug resistance in bacteria. Drugs 2009;69:1555-23.
Kohler T, Pechere JC, Plesiat P. Bacterial antibiotic efflux systems of medical importance. Cell Mol Life Sci 1999;56:771-8.
Mahamoud A, Chevalier J, Alibert-Franco S, Kern WV, Pages JM. Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy. J Antimicrob Chemother 2007;59:1223-9.
Poole K, Lomovskaya O. therapeutic strategies-infectious diseases can efflux inhibitors really counter resistance. Drug Discovery Today 2006;3:145-52.
Chandramouli KH, D′ Souza CJM, Thimmaiah KN. Plasmid loss in plasmid-carrying strains of Escherichia coli treated with phenoxazines and an approach to study their DNA binding properties. Nucleotides Nucleic Acids 2008;27(1):70-83.
Wadkins RM, Houghton PJ. Kinetics of transport of dialkyloxacarbocyanines in multidrug-resistant cell lines overexpressing P-glycoprotein: interrelationship of dye alkyl chain length, cellular flux, and drug resistance. Biochemistry 1995;34(11):3858-72.
Martin SK, Oduola AMJ, Milhous WK. Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 1987;235:899-01.
Krogstad DJ, Gluzomon I, Ykyle DE, Oduola AMJ, Martin SK, Milhous WK, et al. Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 1987;238:1283-5.
Cowman AF, Karcz S, Galatis D, Culvenor JG. A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole. J Cell Biol 1991;113:1033-42.
Simon SM, Schindler M. Cell biological mechanisms of multidrug resistance in tumors. Proc Natl Acad Sci USA 1994;91:3497-04.
Imundo L, Barasch J, Prince A, Al-Awaqati Q. Cystic fibrosis epithelial cells have a receptor for pathogenic bacteria on their apical surface. Proc Natl Acad Sci USA 1995;92:3019-23.