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Synthesis and biological evaluation of esterified and acylated derivatives of NH2-(AEEA)5-amphotericin B

The Journal of Antibiotics volume 74, pages 133–142 (2021)Cite this article

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Abstract

Based on NH2-(AEEA)5-amphotericin B (DMR005; AEEA is 8-amino-3,6-dioxaoctanoic acid), a series of novel esterified and acylated derivatives of DMR005 were synthesized. These derivatives were evaluated for their antifungal activities using the broth dilution method, for their hemolytic toxicity with sterile defibrinated sheep blood, and for their self-association through UV–visible spectroscopy. The preliminary screening tests indicated that NH2-(AEEA)5-amphotericin B methyl ester (DMR031) was an ideal compound. The results of minimum inhibitory concentration and time-kill assays showed that antifungal activities of DMR031 (4 μg ml−1) against Candida albicans ATCC10231 and ATCC90028 were reduced by four times compared to these of amphotericin B (AmB) (1 μg ml−1). DMR031 (142 ± 1 mg ml−1) significantly improved the water solubility of AmB as DMR005 did. Preliminary safety assessments of DMR031 were carried out via cell toxicity assay of HEK293T in vitro, which turned out to be much better than AmB. AmB had good efficacy in vivo at a dose of 1 mg ml−1. However, DMR031 still had no efficacy in vivo even at a dose of 16 mg ml−1, merely prolonged the survival time of mice.

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References

  1. Oura M, Sternberg TH, Wright ET. A new antifungal antibiotic, amphotericin B. Antibiot Annu. 1956;3:566–73.

  2. Donovick R, Gold W, Pagano JF, Stout HA. Amphotericins A and B, antifungal antibiotics produced by a streptomycete. I. In vitro studies. Antibiot Annu. 1956;3:579–86.

    CAS  Google Scholar 

  3. Saravolatz LD, Ostrosky-Zeichner L, Marr KA, Rex JH, Cohen SH. Amphotericin B: time for a new “gold standard”. Clin Infect Dis. 2003;37:415–25.

    Article  Google Scholar 

  4. Bartner E, Zinnes H, Moe RA, Kulesza JS. Studies on a new solubilized preparation of amphotericin B. Antibiot Annu. 1957;5:53–8.

    PubMed  Google Scholar 

  5. Deray G. Amphotericin B nephrotoxicity. J Antimicrob Chemother. 2002;9:37–41.

    Article  Google Scholar 

  6. Fanos V, Cataldi L. Amphotericin B-induced nephrotoxicity: a review. J Chemother. 2000;12:463–70.

    Article  CAS  Google Scholar 

  7. Laniado-Laborín R, Cabrales-Vargas MN. Amphotericin B: side effects and toxicity. Rev Iberoam Micol. 2009;26:223–7.

    Article  Google Scholar 

  8. Dupont B. Overview of the lipid formulations of amphotericin B. J Antimicrob Chemother. 2002;49:31–6.

    Article  CAS  Google Scholar 

  9. Hartsel SC, Baas B, Bauer E, Foree LT, Kindt K, Preis H, et al. Heat-induced super-aggregation of amphotericin B modifies its interaction with serum proteins and lipoproteins and stimulation of TNF-alpha. J Pharm Sci. 2001;90:124–33.

    Article  CAS  Google Scholar 

  10. Bonner DP, Mechlinski W, Schaffner CP. Polyene macrolide derivatives. 3. Biological properties of polyene macrolide ester salts. J Antibiot. 1972;25:261.

    Article  CAS  Google Scholar 

  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 Antibioti. 2006;50:709–11.

    Article  Google Scholar 

  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;287:476–84.

    Article  Google Scholar 

  13. And VP, Carreira EM. Significant improvement of antifungal activity of polyene macrolides by bisalkylation of the mycosamine. Org Lett. 2006;8:1807–9.

    Article  Google Scholar 

  14. Zhang JH, Ma J, Dong YZ, Zhao WJ, Feng J. Synthesis and characterization of NH2-(AEEA)n-amphotericin B derivatives. J Antibiot. 2019;72:210–7.

    Article  CAS  Google Scholar 

  15. Espinel-Ingroff A, Fothergill A, Ghannoum M, Manavathu E, Ostrosky-Zeichner L, Pfaller MA, et al. Quality control and reference guidelines for CLSI broth microdilution susceptibility method (M 38-A document) for amphotericin B, itraconazole, posaconazole, and voriconazole. J Clin Microbiol. 2005;43:5243.

    Article  CAS  Google Scholar 

  16. Klepser ME, Ernst EJ, Lewis RE, Ernst ME, Pfaller MA. Influence of test conditions on antifungal time-kill curve results: proposal for standardized methods. Antimicrob Agents Chemother. 1998;42:1207–12.

    Article  CAS  Google Scholar 

  17. Bulmus V, Woodward M, Lin L, Murthy N, Stayton P, Hoffman A. A new pH-responsive and glutathione-reactive, endosomal membrane-disruptive polymeric carrier for intracellular delivery of biomolecular drugs. J Control Release. 2003;93:105–20.

    Article  CAS  Google Scholar 

  18. Higuchi TA, Connors KA. Phase-solubility techniques. In: Advances in analytical chemistry and instrumentation. Manhattan, USA: Jonh Wiley & Sons, INC; 1965.

  19. Jouyban A. Handbook of solubility data for pharmaceuticals. Vol. 3. Florida, USA: CRC Press; 2010. p. 198–202.

  20. Slisz 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. 2004;57:669–78.

    Article  CAS  Google Scholar 

  21. Itai B, Nir O, Vladimir D, Alex MS. Amphotericin B derivatives. USA, US20170319705A1. 2017.

  22. Barwicz J, Christian S, Gruda I. Effects of the aggregation state of amphotericin B on its toxicity to mice. Antimicrob Agents Chemother. 1992;36:2310–5.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by the National Key R&D Program of China (2017YFD0501404).

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Authors and Affiliations

  1. School of Pharmacy, Fudan University, Shanghai, China

    Jinhua Zhang

  2. Shanghai Duomirui Biotechnology Ltd, Shanghai, China

    Yuanzhen Dong, Minwei Chen, Hanqing Tang & Jun Feng

  3. China State Institute of Pharmaceutical Industry, Shanghai, China

    Hongjiang Xu, Wenwen Shangguan, Wenjie Zhao & Jun Feng

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  1. Jinhua Zhang
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Correspondence to Jun Feng.

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Supplementary information

41429_2020_365_MOESM1_ESM.docx

The synthetic methods of Fmoc-DMR005 and the compound properties of esterified and acylated derivatives of DMR005 in detail

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Zhang, J., Dong, Y., Xu, H. et al. Synthesis and biological evaluation of esterified and acylated derivatives of NH2-(AEEA)5-amphotericin B. J Antibiot 74, 133–142 (2021). https://doi.org/10.1038/s41429-020-00365-3

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