Chitin synthetase inhibitors

Chitin synthesis in wing pads of 1-day-old fifth-instar larvae of Locusta is stimulated in vitro by 20-hydroxyecdysone and makisterone A 88), This chitin biosynthesis system requires integrity of the microtubular system and the chitin-synthetase complex. Chitin synthesis can be inhibited in this test system by azadirachtin as well as by colcemid, a microtubular poison, or by diflubenzuron, a chitin synthetase inhibitor. It is also of interest to note that RH5849 stimulates chitin synthesis in wing discs of Plodia interpunctella 89). 

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... 

After injection, when part of the permeability barriers in the larvae is absent, polyoxin D inhibits the glucose incorporation, but less so than difluben-zuron. The conclusion seems obvious that the intrinsic effects of both compounds are practically identical but that polyoxin D is much more hindered by the permeability barriers present in the Pieris brassicae larvae. On the strength of the evidence presented by Misato and co-workers that polyoxin D is a competitive inhibitor of chitin synthetase, a... 

Summarizing, diflubenzuron features mentioned in the introduction of this paper can be completed as follows The new insecticide has favourable environmental properties because it is non-persistent in soils and it has a low biological magnification. It is stable on plants and in insects, hence it has a long residual activity. It represents the best choice from the series of the benzoylphenyl ureas. It is a reversible inhibitor of chitin synthesis in insects, probably by blocking chitin synthetase. 

There are no plasma membrane-bound enzymes whose activities are known to be specifically and sufficiently altered to account for growth Inhibition by the sterol inhibitors at sub-MIC doses. A likely candidate is chitin synthetase, but the activity of this enzyme is not reduced in fact, sterol inhibitor-treated fungi contain more glucosamine polymers than controls. However, the altered deposition of chitin (see above references) may reflect a discontinuity between cytoskeletal elements which are believed to be involved in cell wall formation and the plasma membrane, but it is unlikely that this is at the root of growth inhibition since a wall-less slime mutant of Neurospora crassa is as sensitive as the wild-type strain to propiconazole (57TI Cytochrome oxidase and microsomal ATPase are inhibited by high concentrations (10 5,... 

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... 

Analogues 249 (X = H, OH) of UDP-GlcNAc have been prepared as potential inhibitors of chitin synthetases. The synthetic route involved a C-allyl derivative of GlcNAc, which was elaborated by ozonolysis, Wittig reaction and coupling with the nucleoside, followed by hydrogenation or hydroxylation as appropriate. The corresponding amides were also prepared from 5 -amino-5 -deoxyuridine. Lipophilic amino acid methyl esters and methylamides have been coupled to 0-5 of AZT by carbamate links. The products showed anti-HIV activity, but this was not due to carbamate hydrolysis or to direct inhibition of reverse transcriptase, and the mechanism of action may be one not previously observed with nucleoside antivirals. ... 

Exactly how these various potential regulators are integrated is obscure. The peptide inhibitor might play no part in regulating chitin synthesis, but could serve simply to protect the cytoplasm against unwanted proteolysis by the activating factor. Whatever the real mechanism is, chitin synthetase activity is tightly linked to the cell cycle in yeast and its spatial occurrence is equally closely specified. 

Current biochemical literature is replete with good reasons for undertaking the synthesis of various nucleopeptides. However, there still seems to be a dearth of activity in this field which is so pertinent to some verj fundamental aspects of cell chemistry. Synthetic studies in 1971 ranged from an interesting approach to pyrimidinyl- and purinyl-peptides by the Pandit group to analogs of the new polyoxin (Chart 18) nucleopeptide antibiotics. One of the natural products, polyoxin M, (Chart 18) has been found to be a powerful inhibitor of yeast chitin synthetase, but several analogs prepared without the 5 -carboxyl and/or the 4"-hydroxyl were inactive in terms of antibiotic activity. 

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... 

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