“…The free amine, obtained after removal of the Boc protecting group of compound 7 , was reacted with 9 to afford acylurea 10 . Cyclization to produce the uracil moiety was effected by refluxing in aqueous ammonia ,, to afford 11 after benzyl ester formation (Scheme ). 3 …”
Section: Resultsmentioning
confidence: 99%
“…In the course of developing effective and safe antifungal agents, many efforts have been directed toward replacing the amino terminal peptide moiety (R 1 , Figure ) of polyoxins and nikkomycins but with only limited success. − Little work has been done to modify the nucleoside moiety, , or to develop other alternate transport systems. Nucleosides in general, display a broad range of biological activities, in particular, antiviral, antifungal, and antitumor activities …”
Carbocyclic polyoxin C (2) and its alpha-epimer 3 were synthesized in racemic form in an efficient and diastereodivergent fashion from cis-4-(N-tert-butylcarbamoyl)cyclopent-2-en-1-ol (5a). This synthesis features a Pd(0)-catalyzed substitution reaction, a novel, mild reduction of an alpha-nitro ester to an amino acid ester, and an improved procedure for uracil ring formation.
“…The free amine, obtained after removal of the Boc protecting group of compound 7 , was reacted with 9 to afford acylurea 10 . Cyclization to produce the uracil moiety was effected by refluxing in aqueous ammonia ,, to afford 11 after benzyl ester formation (Scheme ). 3 …”
Section: Resultsmentioning
confidence: 99%
“…In the course of developing effective and safe antifungal agents, many efforts have been directed toward replacing the amino terminal peptide moiety (R 1 , Figure ) of polyoxins and nikkomycins but with only limited success. − Little work has been done to modify the nucleoside moiety, , or to develop other alternate transport systems. Nucleosides in general, display a broad range of biological activities, in particular, antiviral, antifungal, and antitumor activities …”
Carbocyclic polyoxin C (2) and its alpha-epimer 3 were synthesized in racemic form in an efficient and diastereodivergent fashion from cis-4-(N-tert-butylcarbamoyl)cyclopent-2-en-1-ol (5a). This synthesis features a Pd(0)-catalyzed substitution reaction, a novel, mild reduction of an alpha-nitro ester to an amino acid ester, and an improved procedure for uracil ring formation.
“…In the search for analogs with more potent and safer antifungal action, structural modifications have been reported, among them, modification of the N-terminal amino acid [111], transposition of the glycyl residue of the nucleoside amino acid [112] or carbocyclic analogs of these antibiotics [113]. Instability of polyoxins and nikkomycins against intracellular proteases has been proposed as one of the causes for the generally observed decrease of in vivo efficacy [114].…”
Section: Chemical Requirements For Polyoxins and Nikkomycins To Act Amentioning
Human mycoses have become a threat to health world-wide. Unfortunately there are only a limited number of antimycotic drugs in use. Promising targets for drugs specific against fungi are those affecting chitin synthesis. Chitin is absent in vertebrates, and is essential for fungal wall integrity. A thorough knowledge of the mechanism of chitin synthesis is required to design specific inhibitors. We review here our current understanding of the process, and the most promising drugs that inhibit it. Chitin is made by chitin synthases requiring specific microvesicles, the chitosomes, for intracellular transport. Fungi contain several chitin synthases, some of which may be essential at a certain stage. This phenomenon is important to take into account for drug design. The most widely studied chitin synthase inhibitors are polyoxins and nikkomycins that probably bind to the catalytic site of chitin synthases. These are not equally susceptible to the drugs. In Saccharomyces cerevisiae the order of sensitivity is: Chs3p>Chs1p>Chs2p. Main problems for their succesful use in vivo are: low permeability, and different susceptibility of fungal species, and variable responses in animal models. Chemical modifications have been proposed to make more potent derivatives. Other synthetic or natural compounds are also promising as possible inhibitors, but their properties are less well known. Rational drug design has proceeded only on the basis of existing inhibitors, because the structure of the active site of chitin synthase is unknown. Undoubtedly, determination of this, and the biosynthetic mechanism will reveal unexpected drug targets in the future.
A scalable and reliable manufacturing process for Nikkomycin Z HCl on a 170 g scale has been developed and optimized. The process is characterized by a 2.3 g/L fermentation yield, 79% purification yield, and >98% relative purity of the final product. This method is suitable for further scale up and cGMP production. The Streptomyces tendae ΔNikQ strain developed during the course of this study is superior to any previously reported strain in terms of higher yield and purity of Nikkomycin Z.
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