- Discovery of Amphamide, a Drug Candidate for the Second Generation of Polyene Antibiotics
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Amphotericin B (AmB, 1) is the drug of choice for treating the most serious systemic fungal or protozoan infections. Nevertheless, its application is limited by low solubility in aqueous media and serious side effects such as infusion-related reactions, hemolytic toxicity, and nephrotoxicity. Owing to these limitations, it is essential to search for the polyene derivatives with better chemotherapeutic properties. With the objective of obtaining AmB derivatives with lower self-aggregation and improved solubility, we synthesized a series of amides of AmB bearing an additional basic group in the introduced residue. The screening of antifungal activity in vitro revealed that N-(2-aminoethyl)amide of AmB (amphamide, 6) had superior antifungal activity compared to that of the paternal AmB. Preclinical studies in mice confirmed that compound 6 had a much lower acute toxicity and higher antifungal efficacy in the model of mice candidosis sepsis compared with that of AmB (1). Thus, the discovered amphamide is a promising drug candidate for the second generation of polyene antibiotics and is also prospective for in-depth preclinical and clinical evaluation.
- Bychkova, Elena N.,Bykov, Evgeny E.,Efimova, Svetlana S.,Grammatikova, Natalia E.,Isakova, Elena B.,Mirchink, Elena P.,Ostroumova, Olga S.,Pereverzeva, Eleonora R.,Shchekotikhin, Andrey E.,Solovieva, Svetlana E.,Tevyashova, Anna N.,Treshchalin, Ivan D.,Zatonsky, George V.
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p. 2029 - 2044
(2020/09/21)
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- Molecular Imprinting of Carboxylic Acids Employing Novel Functional Macroporous Polymers
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Imprinted network polymers incorporating basic functional groups were developed to assess the binding and specificity of carboxylic acids. The binding affinities were determined using t-BOC-phenylalanine and 2-phenylbutyric acid as templates and substrates. Chiral selectivity for the enantiomers of t-BOC-phenylalanine was found for polymers incorporating adenine or 2-aminopyridine functionality. Chiral selectivity in the case of (R)-(-)-2-phenylbutyric acid was found for the polymer utilizing N-(2-aminoethyl) methacrylamide as the functional monomer. Optimization of binding was achieved by changing polymerization conditions (thermal versus photochemical polymerization, monomer:template ratio) for t-BOC-phenylalanine imprinted polymers employing the N-(2-aminopyridine) methacrylamide monomer.
- Spivak, David,Shea, Kenneth J.
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p. 4627 - 4634
(2007/10/03)
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- Tmob Side Chain-Protected S-Cysteine- and Homo-S-cysteinesulfonamides, their Nα-Protected and Nω-Aminoethylated Derivatives
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The 2,4,6-trimethoxybenzyl (Tmob) group is very suitable for temporary protection of the aminosulfonyl group of S-cysteine- and homo-S-cysteinesulfonamides.Both the introduction and removal of the Tmob-protecting group can be achieved in high yields. 2-Am
- Videnov, Georgi,Aleksiev, Boris,Stoev, Mincho,Paipanova, Tamara,Jung, Guenther
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p. 941 - 946
(2007/10/02)
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- Mono-Protected Diamines. Nα-tert-Butoxycarbonyl α,ω-Alkanediamine Hydrochlorides from Amino alcohols.
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Nα-tert-Butoxycarbonyl α,ω-alkanediamine hydrochlorides 3a-e are prepared from the amino alcohols in yields of 66-87percent.Reaction of the free amine with di-tert-butyl dicarbonate gives the N-tert-Butoxycarbonylamino alcohol 1a-e.One-pot conversion to the azide 2a-e via the mesylate under phase-transfer conditions followed by hydrogenolysis in the presence of chloroform yields the title compounds.
- Mattingly, Phillip G.
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p. 366 - 368
(2007/10/02)
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