Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

The Substantial Improvement of Amphotericin B Selective Toxicity Upon Modification of Mycosamine with Bulky Substituents

Author(s): Edward Borowski, Natalia Salewska, Joanna Boros-Majewska, Marcin Serocki, Izabela Chabowska, Maria J. Milewska, Dominik Ziętkowski and Sławomir Milewski*

Volume 16, Issue 1, 2020

Page: [128 - 139] Pages: 12

DOI: 10.2174/1573406415666181203114629

Price: $65

Abstract

Background: It is assumed that the unfavorable selective toxicity of an antifungal drug Amphotericin B (AmB) can be improved upon chemical modification of the antibiotic molecule.

Objective: The aim of this study was verification of the hypothesis that introduction of bulky substituents at the amino sugar moiety of the antibiotic may result in diminishment of mammalian in vitro toxicity of thus prepared AmB derivatives.

Methods: Twenty-eight derivatives of AmB were obtained upon chemical modification of the amino group of mycosamine residue. This set comprised 10 N-succinimidyl-, 4 N-benzyl-, 5 Nthioureidyl- and 9 N-aminoacyl derivatives. Parameters characterizing biological in vitro activity of novel compounds were determined.

Results: All the novel compounds demonstrated lower than AmB antifungal in vitro activity but most of them exhibited negligible cytotoxicity against human erythrocytes and three mammalian cell lines. In consequence, the selective toxicity of majority of novel antifungals, reflected by the selective toxicity index (STI = EH50/IC50) was improved in comparison with that of AmB, especially in the case of 5 compounds. The novel AmB derivatives with the highest STI, induced substantial potassium efflux from Candida albicans cells at concentrations slightly lower than IC50s but did not trigger potassium release from human erythrocytes at concentrations lower than 100 μg/mL.

Conclusion: Some of the novel AmB derivatives can be considered promising antifungal drug candidates.

Keywords: Antifungal agent, amphotericin B, chemical modification, selective toxicity, hemotoxicity, potassium efflux.

Graphical Abstract
[1]
Hamill, R.J. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs, 2013, 73(9), 919-934.
[http://dx.doi.org/10.1007/s40265-013-0069-4] [PMID: 23729001]
[2]
Borowski, E. Novel approaches in the rational design of antifungal agents of low toxicity. Farmaco, 2000, 55(3), 206-208.
[http://dx.doi.org/10.1016/S0014-827X(00)00024-0] [PMID: 10919084]
[3]
Brajtburg, J.; Powderly, W.G.; Kobayashi, G.S.; Medoff, G.; Medoff, G. Amphotericin B: current understanding of mechanisms of action. Antimicrob. Agents Chemother., 1990, 34(2), 183-188.
[http://dx.doi.org/10.1128/AAC.34.2.183] [PMID: 2183713]
[4]
Anderson, T.M.; Clay, M.C.; Cioffi, A.G.; Diaz, K.A.; Hisao, G.S.; Tuttle, M.D.; Nieuwkoop, A.J.; Comellas, G.; Maryum, N.; Wang, S.; Uno, B.E.; Wildeman, E.L.; Gonen, T.; Rienstra, C.M.; Burke, M.D. Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat. Chem. Biol., 2014, 10(5), 400-406.
[http://dx.doi.org/10.1038/nchembio.1496] [PMID: 24681535]
[5]
Bagiński, M.; Czub, J. Amphotericin B and its new derivatives - mode of action. Curr. Drug Metab., 2009, 10(5), 459-469.
[http://dx.doi.org/10.2174/138920009788898019] [PMID: 19689243]
[6]
Torrado, J.J.; Espada, R.; Ballesteros, M.P.; Torrado-Santiago, S. Amphotericin B formulations and drug targeting. J. Pharm. Sci., 2008, 97(7), 2405-2425.
[http://dx.doi.org/10.1002/jps.21179] [PMID: 17893903]
[7]
Treshchalin, I.D.; Sletta, H.; Borgos, S.E.; Pereverzeva, E.P.; Voeikova, T.A.; Ellingsen, T.E.; Zotchev, S.B. Comparative analysis of antifungal activities in vitro and acute toxicity in vivo of S44HP, an analogue of nystatin obtained by genetic engineering. Antibiot. Khimioter., 2005, 50, 18-22.
[PMID: 16768209]
[8]
Brautaset, T.; Sletta, H.; Nedal, A.; Borgos, S.E.F.; Degnes, K.F.; Bakke, I.; Volokhan, O.; Sekurova, O.N.; Treshalin, I.D.; Mirchink, E.P.; Dikiy, A.; Ellingsen, T.E.; Zotchev, S.B. Improved antifungal polyene macrolides via engineering of the nystatin biosynthetic genes in Streptomyces noursei. Chem. Biol., 2008, 15(11), 1198-1206.
[http://dx.doi.org/10.1016/j.chembiol.2008.08.009] [PMID: 19022180]
[9]
Tevyashova, A.N.; Korolev, A.M.; Trenin, A.S.; Dezhenkova, L.G.; Shtil, A.A.; Polshakov, V.I.; Savelyev, O.Y.; Olsufyeva, E.N. New conjugates of polyene macrolide amphotericin B with benzoxaboroles: synthesis and properties. J. Antibiot. (Tokyo), 2016, 69(7), 549-560.
[http://dx.doi.org/10.1038/ja.2016.34] [PMID: 27005557]
[10]
Wright, J.J.K.; Albarella, J.A.; Krepski, L.R.; Loebenberg, D. N-aminoacyl derivatives of polyene macrolide antibiotics and their esters. J. Antibiot. (Tokyo), 1982, 35(7), 911-914.
[http://dx.doi.org/10.7164/antibiotics.35.911] [PMID: 6757233]
[11]
Grzybowska, J.; Sowiński, P.; Gumieniak, J.; Zieniawa, T.; Borowski, E. N-methyl-N-D-fructopyranosylamphotericin B methyl ester, new amphotericin B derivative of low toxicity. J. Antibiot. (Tokyo), 1997, 50(8), 709-711.
[http://dx.doi.org/10.7164/antibiotics.50.709] [PMID: 9315089]
[12]
Hąc-Wydro, K.; Dynarowicz-Łątka, P.; Grzybowska, J.; Borowski, E. N-(1-piperidinepropionyl)amphotericin B methyl ester (PAME)--a new derivative of the antifungal antibiotic amphotericin B: searching for the mechanism of its reduced toxicity. J. Colloid Interface Sci., 2005, 287(2), 476-484.
[http://dx.doi.org/10.1016/j.jcis.2005.02.038] [PMID: 15925613]
[13]
Volmer, A.A.; Szpilman, A.M.; Carreira, E.M. Synthesis and biological evaluation of amphotericin B derivatives. Nat. Prod. Rep., 2010, 27(9), 1329-1349.
[http://dx.doi.org/10.1039/b820743g] [PMID: 20556271]
[14]
Wilcock, B.C.; Endo, M.M.; Uno, B.E.; Burke, M.D. C2′-OH of amphotericin B plays an important role in binding the primary sterol of human cells but not yeast cells. J. Am. Chem. Soc., 2013, 135(23), 8488-8491.
[http://dx.doi.org/10.1021/ja403255s] [PMID: 23718627]
[15]
Davis, S.A.; Vincent, B.M.; Endo, M.M.; Whitesell, L.; Marchillo, K.; Andes, D.R.; Lindquist, S.; Burke, M.D. Nontoxic antimicrobials that evade drug resistance. Nat. Chem. Biol., 2015, 11(7), 481-487.
[http://dx.doi.org/10.1038/nchembio.1821] [PMID: 26030729]
[16]
Janout, V.; Schell, W.A.; Thévenin, D.; Yu, Y.; Perfect, J.R.; Regen, S.L. Taming amphotericin B. Bioconjug. Chem., 2015, 26(10), 2021-2024.
[http://dx.doi.org/10.1021/acs.bioconjchem.5b00463] [PMID: 26340430]
[17]
Szlinder-Richert, J.; Mazerski, J.; Cybulska, B.; Grzybowska, J.; Borowski, E. MFAME, N-methyl-N-D-fructosyl amphotericin B methyl ester, a new amphotericin B derivative of low toxicity: relationship between self-association and effects on red blood cells. Biochim. Biophys. Acta, 2001, 1528(1), 15-24.
[http://dx.doi.org/10.1016/S0304-4165(01)00166-0] [PMID: 11514093]
[18]
Paquet, V.; Carreira, E.M. Significant improvement of antifungal activity of polyene macrolides by bisalkylation of the mycosamine. Org. Lett., 2006, 8(9), 1807-1809.
[http://dx.doi.org/10.1021/ol060353o] [PMID: 16623556]
[19]
Salewska, N.; Boros-Majewska, J.; Lącka, I.; Chylińska, K.; Sabisz, M.; Milewski, S.; Milewska, M.J. Chemical reactivity and antimicrobial activity of N-substituted maleimides. J. Enzyme Inhib. Med. Chem., 2012, 27(1), 117-124.
[http://dx.doi.org/10.3109/14756366.2011.580455] [PMID: 21612375]
[20]
Park, S.; Hayes, B.L.; Marankan, F.; Mulhearn, D.C.; Wanna, L.; Mesecar, A.D.; Santarsiero, B.D.; Johnson, M.E.; Venton, D.L. Regioselective covalent modification of hemoglobin in search of antisickling agents. J. Med. Chem., 2003, 46(6), 936-953.
[http://dx.doi.org/10.1021/jm020361k] [PMID: 12620071]
[21]
Siatra-Papastaikoudi, T.; Tsotinis, A.; Raptopoluou, C.P.; Sambani, C.; Thomou, H. Synthesis of new alkylaminoalkyl thiosemicarbazones of 3-acetylindole and their effect on DNA synthesis and cell proliferation. Eur. J. Med. Chem., 1995, 30, 107-114.
[http://dx.doi.org/10.1016/0223-5234(96)88215-8]
[22]
Bowman, R.E. N-substituted amino acids. II. The reductive alkylation of amino acids. J. Chem. Soc., 1950, 1346-1349.
[http://dx.doi.org/10.1039/jr9500001346]
[23]
N-substituted second generation derivatives of antifungal antibiotic Amphotericin B and methods of their preparation and application.. U.S. Patent No. 9,745,335;; Patent and Trademark Office: Washington,DC: U.S, . , 1950.
[24]
Franz, R.; Kelly, S.L.; Lamb, D.C.; Kelly, D.E.; Ruhnke, M.; Morschhäuser, J. Multiple molecular mechanisms contribute to a stepwise development of fluconazole resistance in clinical Candida albicans strains. Antimicrob. Agents Chemother., 1998, 42(12), 3065-3072.
[http://dx.doi.org/10.1128/AAC.42.12.3065] [PMID: 9835492]
[25]
Clinical and Laboratory Standards Institute (CLSI), Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard-third edition, in: CLSI Document M27-A3, Clinical and Laboratory Standards Institute, Wayne PA, USA, 2008; National Committee for Clinical Laboratory Standards. 2002. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi. Approved standard, in: NCCLS document M38-A. National Committee for Clinical Laboratory Standards, Wayne, PA, USA, .. 2002.
[26]
Skwarecki, A.S.; Skarbek, K.; Martynow, D.; Serocki, M.; Bylińska, I.; Milewska, M.J.; Milewski, S. Molecular umbrellas modulate the selective toxicity of polyene macrolide antifungals. Bioconjug. Chem., 2018, 29(4), 1454-1465.
[http://dx.doi.org/10.1021/acs.bioconjchem.8b00136] [PMID: 29485855]
[27]
Belakhov, V.V.; Shenin, Y.D. Synthesis and antifungal activity of N-benzyl derivatives of Amphotericin B. Pharm. Chem. J., 2007, 41, 362-366.
[http://dx.doi.org/10.1007/s11094-007-0082-6]
[28]
Solovieva, S.E.; Olsufyeva, E.N.; Preobrazhenskaya, M.N. Chemical modification of antifungal polyene macrolide antibiotics. Russ. Chem. Rev., 2011, 80, 103-126.
[http://dx.doi.org/10.1070/RC2011v080n02ABEH004145]
[29]
Carmody, M.; Murphy, B.; Byrne, B.; Power, P.; Rai, D.; Rawlings, B.; Caffrey, P. Biosynthesis of amphotericin derivatives lacking exocyclic carboxyl groups. J. Biol. Chem., 2005, 280(41), 34420-34426.
[http://dx.doi.org/10.1074/jbc.M506689200] [PMID: 16079135]
[30]
Preobrazhenskaya, M.N.; Olsufyeva, E.N.; Solovieva, S.E.; Tevyashova, A.N.; Reznikova, M.I.; Luzikov, Y.N.; Terekhova, L.P.; Trenin, A.S.; Galatenko, O.A.; Treshalin, I.D.; Mirchink, E.P.; Bukhman, V.M.; Sletta, H.; Zotchev, S.B. Chemical modification and biological evaluation of new semisynthetic derivatives of 28,29-Didehydronystatin A1 (S44HP), a genetically engineered antifungal polyene macrolide antibiotic. J. Med. Chem., 2009, 52(1), 189-196.
[http://dx.doi.org/10.1021/jm800695k] [PMID: 19055412]
[31]
Tevyashova, A.N.; Olsufyeva, E.N.; Solovieva, S.E.; Printsevskaya, S.S.; Reznikova, M.I.; Trenin, A.S.; Galatenko, O.A.; Treshalin, I.D.; Pereverzeva, E.R.; Mirchink, E.P.; Isakova, E.B.; Zotchev, S.B.; Preobrazhenskaya, M.N. Structure-antifungal activity relationships of polyene antibiotics of the amphotericin B group. Antimicrob. Agents Chemother., 2013, 57(8), 3815-3822.
[http://dx.doi.org/10.1128/AAC.00270-13] [PMID: 23716057]
[32]
Szlinder-Richert, J.; Cybulska, B.; Grzybowska, J.; Bolard, J.; Borowski, E. Interaction of amphotericin B and its low toxic derivative, N-methyl-N-D-fructosyl amphotericin B methyl ester, with fungal, mammalian and bacterial cells measured by the energy transfer method. Farmaco, 2004, 59(4), 289-296.
[http://dx.doi.org/10.1016/j.farmac.2003.12.007] [PMID: 15081346]
[33]
Bagiński, M.; Gariboldi, P.; Borowski, E. The role of amphotericin B amino group basicity in its antifungal action. A theoretical approach. Biophys. Chem., 1994, 49(3), 241-250.
[http://dx.doi.org/10.1016/0301-4622(93)E0074-F] [PMID: 8018821]
[34]
Czerwiński, A.; König, W.A.; Zieniawa, T.; Sowiński, P.; Sinnwell, V.; Milewski, S.; Borowski, E. New N-alkyl derivatives of amphotericin B. Synthesis and biological properties. J. Antibiot. (Tokyo), 1991, 44(9), 979-984.
[http://dx.doi.org/10.7164/antibiotics.44.979] [PMID: 1938621]
[35]
Ślisz, M.; Cybulska, B.; Mazerski, J.; Grzybowska, J.; Borowski, E. Studies of the effects of antifungal cationic derivatives of amphotericin B on human erythrocytes. J. Antibiot. (Tokyo), 2004, 57(10), 669-678.
[http://dx.doi.org/10.7164/antibiotics.57.669] [PMID: 15638328]
[36]
Czub, J.; Neumann, A.; Borowski, E.; Bagiński, M. Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives - A molecular dynamics study. Biophys. Chem., 2009, 141(1), 105-116.
[http://dx.doi.org/10.1016/j.bpc.2009.01.001] [PMID: 19185412]
[37]
Matsumori, N.; Sawada, Y.; Murata, M. Mycosamine orientation of amphotericin B controlling interaction with ergosterol: sterol-dependent activity of conformation-restricted derivatives with an amino-carbonyl bridge. J. Am. Chem. Soc., 2005, 127(30), 10667-10675.
[http://dx.doi.org/10.1021/ja051597r] [PMID: 16045354]
[38]
Paquet, V.; Volmer, A.A.; Carreira, E.M. Synthesis and in vitro biological properties of novel cationic derivatives of amphotericin B. Chemistry, 2008, 14(8), 2465-2481.
[http://dx.doi.org/10.1002/chem.200701237] [PMID: 18196508]
[39]
Falci, D.R.; da Rosa, F.B.; Pasqualotto, A.C. Comparison of neph-rotoxicity associated to different lipid formulations of amphotericin B: a real-life study. Mycoses, 2015, 58(2)104-112, 104, 112..
[http://dx.doi.org/10.1111/myc.12283] [PMID: 25590436]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy