Scalable and cost-effective tosylation-mediated synthesis of antifungal and fungal diagnostic 6″-Modified amphiphilic kanamycins.

Autor: Subedi YP; Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT, 84322-0300, USA., Pandey U; Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT, 84322-0300, USA., Alfindee MN; Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT, 84322-0300, USA., Montgomery H; Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT, 84322-0300, USA., Roberts P; Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT, 84322-0300, USA., Wight J; Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT, 84322-0300, USA., Nichols G; Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT, 84322-0300, USA., Grilley M; Department of Biology, Utah State University, 5305 Old Main Hill, Logan, UT, 84322-5305, USA., Takemoto JY; Department of Biology, Utah State University, 5305 Old Main Hill, Logan, UT, 84322-5305, USA., Chang CT; Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT, 84322-0300, USA. Electronic address: tom.chang@usu.edu.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2019 Nov 15; Vol. 182, pp. 111639. Date of Electronic Publication: 2019 Aug 22.
DOI: 10.1016/j.ejmech.2019.111639
Abstrakt: Amphiphilic kanamycins bearing hydrophobic modifications at the 6″ position have attracted interest due to remarkable antibacterial-to-antifungal switches in bioactivity. In this report, we investigate a hurdle that hinders practical applications of these amphiphilic kanamycins: a cost-effective synthesis that allows the incorporation of various connecting functionalities to which the hydrophobic moieties are connected to the kanamycin core. A cost-effective tosylation enables various modifications at the 6″ position, which is scalable to a 90-g scale. The connecting functionalities, such as amine and thiol, were not the dominant factor for biological activity. Instead, the linear chain length played the decisive role. Amphiphilic kanamycin attached with tetradecyl (C14) or hexadecyl (C16) showed strong antifungal and modest antibacterial activities than with shorter chains (C6-C10). However, increases in chain length were closely correlated with an increase in HeLa cell toxicity. Thus, a compromise between the antimicrobial activities and cytotoxicities, for optimal efficacy of amphiphilic kanamycins may contain chain lengths between C8 and C12. Finally, the described synthetic protocol also allows the preparation of a fluorescent amphiphilic kanamycin selective toward fungi.
(Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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