Nikkomycin antibiotics

Enzyme preparations from liver or microbial sources were reported to show rather high substrate specificity [76] for the natural phosphorylated acceptor d-(18) but, at much reduced reaction rates, offer a rather broad substrate tolerance for polar, short-chain aldehydes [77-79]. Simple aliphatic or aromatic aldehydes are not converted. Therefore, the aldolase from Escherichia coli has been mutated for improved acceptance of nonphosphorylated and enantiomeric substrates toward facilitated enzymatic syntheses ofboth d- and t-sugars [80,81]. High stereoselectivity of the wild-type enzyme has been utilized in the preparation of compounds (23) / (24) and in a two-step enzymatic synthesis of (22), the N-terminal amino acid portion of nikkomycin antibiotics (Figure 10.12) [82]. 

Figure 10.12 Stereoselective synthesis ofthe amino acid portion of nikkomycin antibiotics and hexulosonic acids using KDPGIc aldolase.

Several groups have reported the isolation of 2 -chloropentostatin (11), an inhibitor of adenosine deaminase, from an Actinomadura strain.Some new nikkomycin antibiotics (12) have been described, which are nucleoside-peptide antibiotics elaborated by a HO... 

Nikkomycins. The nikkomycins (141—159), isolated from S. tendae are nucleoside-peptide antibiotics (1,4,244,245) as shown in Table 8. Nikkomycins X and Z are stmcturaHy identical to neopolyoxins A and C, respectively. Compound (141) is a competitive inhibitor of chitin synthetase. Two new nikkomycins, nikkomycin pseudo-Z and pseudo-J (158, 159), contain a C-glycosidic bond between C-5 of uracil and C-1 of... 

However, not all nucleophiles show the same bias as shown in Scheme 4.5 on addition to the nitroalkene. The product of the addition of potassium phthalimide has 5 (R) stereochemistry (Eq. 4.38).47 This stereoselective addition is applied for the synthesis of other related antibiotics, such as nikkomycine B.48... 

A further interesting example in the context of natural products is shown, in the transformation of the p-lactam 102 into the p-amino ketone 103, Scheme 34, which upon carbonyl reduction provides the amino lactone 104, the cyclized form of the Ai-terminal amino acid residue found in the antibiotic family of nikkomycins, Fig. 6 [101]. 

Asymmetric induction in the aldol reaction of enolsilane and metal enolate nucleophiles with yS-substituted aldehydes gives rise to both excellent yields and good diastereoselectivities (equation 128)507. The best diastereoselectivity was obtained using a trimethylsilyl enolate in the presence of boron trifluoride-etherate (92 8 anti. syn). The key step in the synthesis of the N-terminal amino acid analogue of nikkomycin B and Bx (nucleoside peptide antibiotics) has been performed using this type of methodology508. 

A few other biologically interesting and naturally occurring peptides and amino acids of rather simple structure were synthesized using the Ugi four-component reaction (Figure 12.5) the phosphonic acid antibiotics plumbemycin A 249 and B 250 [126], both epimers of the polychlorinated antihypertensive peptide (+)-demethyldysidenin 251 [127], and the nucleoside antibiotic nikkomycin 252 [128]. 

Nikkomycins Z 94 and X 95, isolated as nucleoside antibiotics from Streptomyces tendae 221 inhibit chitin biosynthesis and have fungicidal and insecticidal properties. 

Several of these bioactive natural products have been successfully developed as therapeutics for clinical use. For example, Cyclosporin A is a fungal decapeptide principally used to suppress immune rejection in organ transplant patients. Mevinolin and compatin both control cholesterol synthesis in human. The search for enzyme- or receptor-targeted microbial products does not limit itself to medical use. Several commercially important antibiotics such as Nikkomycin and Avermectin have been found for agricultural applications in recent years. 

Nikkomycins are nucleoside amide antibiotics produced by Streptomyces tendae Tii 901 and are known to show antifungal, anti-insecticidal, and acaricidal activities. They are competitive inhibitors of chitin synthase. Nikkomycins are produced as a complex mixture, with nikkomycin Z (13) and nikkomycin X (14) representing the major components. ... 

The nucleoside antibiotic nikkomycin Z was brominated using the perhydrolase from Streptomyces aureofaciens Tii241521. Bromination occurred at the 6-position and at the 4,6-positions of the pyridine system of nikkomycin Z. 

The syntheses of the nucleoside antibiotics willardiin (108) and the analog (109) of nikkomycin and sinefugin are based on the Ugi reaction. 

Polyoxin D and nikkomycin Z are Streptomyces derived peptidyl nucleoside antibiotics that have been shown to be competitive inhibitors of chitin synthetase in both fungal and insect in vitro systems [39-44]. Both polyoxin D and nikkomycin Z have structural similarities to the substrate UDP-N-acetylglucosamine, which most likely accounts for the competitive nature of their ability to inhibit chitin... 

Further representatives of the nikkomycin group of antibiotics have been described (see Vol. 19, p.l82), involving more variants in the aminoacid sidechains attached to the 5-amino-allouronic acid core. 

Nikkomycins are a group of peptidyl nucleoside antibiotics produced by Streptomyces tendae Tii901 [318] and Streptomyces ansochromogenes 7100 [319]. Since their structure is similar to that of the chitin synthase substrate... 

Hayashi and co-workers used a similar strategy (Scheme 25) for the formal total synthesis of nikkomycin B (107) (96), a nucleoside peptide antibiotic isolated from the culture broth of Streptomyces tendae. In the key step, propionaldehyde (60), furfural (108), and the TBS-protected aniline 109 were reacted in the presence of... 

The chemistry and biochemistry of polyoxins has been discussed. The structure of the neopolyoxins A, B, and C, which are potent inhibitors of fungal cell-wall chitin synthetase, has been established neopolyoxins A and B are the imidazole nucleosides (18) and (19), respectively, whereas neopolyoxin C is the corresponding uracil-1-yl nucleoside the structure of polyoxin N was also revised, the amino-acid side-chain of (18) being replaced by 2-amino-5-(9-carbamoyl-2-deoxy-L-xyIonic acid. The new antibiotic nikkomycin B also has the structure of (18), although its stereochemistry has not been fully established. Adenomycin has... 

Bruntner C, Lauer B, Schwarz W, Mohrle V, Bor-mann C (1999) Molecular characterization of cotranscribed genes from Streptomyces tendae Tu901 involved in the biosynthesis of the peptidyl moiety of the peptidyl nucleoside antibiotic nikkomycin. Mol Gen Genet 262 102-114... 

Nucleoside antibiotic. Isol. from Strepto-myces tendae. Hydrol. prod, of Nikkomycin J, N-55. Active against insects, phytopathogenic fungi and bacteria. Sol. H2O, Py. 

Nucleoside antibiotic. From Streptomyces tendae. Exhibits lower activity than other Nikkomycins. 

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