The Polyoxins: Pyrimidine Nucleoside Peptide Antibiotics Inhibiting Fungal Cell Wall Biosynthesis

Isono, Kiyoshi; Suzuki, Saburô

doi:10.3987/s-1979-01-0333

Cited by 116 publications

(42 citation statements)

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“…The first group was the polyoxins (11), which are produced as both dipeptides and tripeptides. Although these inhibit growth of many fungi, activity against Candida albicans was not demonstrated until recently.…”

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confidence: 99%

Relative rates of transport of peptidyl drugs by Candida albicans

McCarthy¹,

Newman²,

Nisbet³

et al. 1985

Antimicrob Agents Chemother

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A variety of peptide drugs are known to be active against Candida albicans; however, little is known about the transport of such igents into the target organism. To provide further information concerning transport of this type, we studied the uptake of two classes of small linear peptides: polyoxins which act intact within the ceil and the m-fluorophenylalanyl (m-F-Phe) peptides which require peptidase cleavage to release m-F-Phe.Competition studies with a specific dipeptide detector (alanyl-a-thiophenylglycine) enabled us to determine Ki values of 2.6 ,uM for nikkomycin Z and 350 ,uM for polyoxin D. Rates of uptake of the peptidyl-nucleosides are approximately 30 times lower than those of the m-F-Phe peptides (apparent maximal velocities: nikkontycin Z, 62 pmol min-' mg (dry weight) of cells'l; M-F-Phe alanine 1.3 nmol min-' mg (dry weight) of cells-'). For both the m-F-Phe peptides and the peptidyl-nucleosides, the affinity of the drug for the transport system is an important determinant of its whole-cell activity.

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mentioning

confidence: 99%

Relative rates of transport of peptidyl drugs by Candida albicans

McCarthy¹,

Newman²,

Nisbet³

et al. 1985

Antimicrob Agents Chemother

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“…Nikkomycins (Table 1) and polyoxins are peptidenucleoside antibiotics which competitively inhibit the chitin synthase of fungi and insects because of their structural similarity to UDP-N-acetylglucosamine (Isono & Suzuki, 1979 Cohen, 1987).…”

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confidence: 99%

Structure-activity relationships of the nikkomycins

Decker

Zähner

Heitsch

et al. 1991

Journal of General Microbiology

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The structure-activity relationships of different nikkomycins were studied to evaluate the structural requirements for a potent chitin synthase inhibitor. We investigated the transport of the nikkomycins via the peptide transport system of the yeast Yarrowia fipoiytica and determined the kinetic parameters for nikkomycin Z uptake [Km = 24 PM, Vmax = 2.2 nmol min-l (mg dry wt)-l]. We demonstrated that the @-methyl group of the N-terminal amino acid of dipeptide nikkomycins protects the molecule against peptidase activity in crude cell-extracts of different fungi. Furthermore, the relationship between inhibition constants for chitin synthase, transport of the nikkomycins via the peptide transport system, susceptibility to degradation by cellular proteases and whole-cell activity of the nikkomycins are discussed.

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“…(＋)-1-deoxynojirimycin（2), 4) polyoxamic acid（3, common structure of polyoxins), 5) anisomycin （4), 6) (-)-swainsonine（5), 7) alexine（6), 3) (-)-galan- Vol. 134 (2014) tinic acid（7, component of antibiotic galantin I), 8,9) calyculin A のアミノ酸部分（8) 10 a) The ratio of isomers was determined by HPLC.…”

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Stereoselective Synthesis of Polyhydroxylated Amines Using (<i>S</i>)-Pyroglutamic Acid Derivatives

Ikota

2014

YAKUGAKU ZASSHI

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Naturally occurring polyhydroxylated amines such as (＋)-1-deoxynojirimycin, polyoxamic acid, anisomycin, (-)-swainsonine, and alexine stereoisomers, which have interesting biological activities including glucosidase-and mannosidase-inhibitory activity, immunoregulatory activity, and antibacterial eŠects, were synthesized stereoselectively starting from (S )-pyroglutamic acid derivatives. a,b-Unsaturated lactams ((S )-5-hydroxymethyl-2-oxo-3-pyrroline derivatives), a,b-unsaturated d-lactone ((S )-4-amino-2-penten-5-olide derivative), and E-oleˆn ((S,E )-methyl-4-amino-5-hydroxypent-2-enoate derivative) from (S )-pyroglutamic acid derivatives were dihydroxylated using OsO 4 in the presence of N-methyl morpholine N-oxide (NMO) to aŠord various chiral building blocks with diŠerent conˆgura-tions. The stereoselectivity of cis-dihydroxylation for a,b-unsaturated lactams and a,b-unsaturated d-lactone was very high, while the stereoselectivity was low for E-oleˆn. Therefore, the double asymmetric induction of E-oleˆn using K 2 OsO 4 with chiral ligands was successively applied to yield high stereoselectivity. (2R,3S )-2-Hydroxymethyl-3-hydroxypyrrolidine and Gaissman-Weiss lactone, important intermediates for the preparation of pyrrolizidine alkaloids, were synthesized from a (3R,4R,5R )-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidinone derivative derived from a,b-unsatulated lactam. (＋)-1-Deoxynojirimycin was synthesized from a (2S,3R,4R )-methyl 4-amino-2,3,5-trihydroxypentanoate derivative of E-oleˆn. (-)-Swainsonine and its stereoisomers were synthesized from (2R,3S,4R)-or (2R,3R,4R )-2-hydroxymethyl-3,4-dihydroxypyrrolidine derivatives of a,b-unsaturated d-lactone or a,b-unsaturated lactam. The key reaction was diastereoselective allylation of the aldehyde derived from the corresponding 2-hydroxymethylpyrrolidine derivatives with various allylation reagents. The high diastereoselectivity could be explained by cyclic chelate formation between metals and the a-aminocarbonyl group or b-alkoxycarbonyl group, in which the nucleophile approaches from the less hindered face. Four alexine stereoisomers were synthesized from (2R,3R,4S,5R )-and (2R,3R,4S,5S )-2,3-dihydroxymethyl-3,4-dihydroxyl pyrrolidine derivatives of a,b-unsaturated lactam.

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The Polyoxins: Pyrimidine Nucleoside Peptide Antibiotics Inhibiting Fungal Cell Wall Biosynthesis

Cited by 116 publications

References 0 publications

Relative rates of transport of peptidyl drugs by Candida albicans

Relative rates of transport of peptidyl drugs by Candida albicans

Structure-activity relationships of the nikkomycins

Stereoselective Synthesis of Polyhydroxylated Amines Using (<i>S</i>)-Pyroglutamic Acid Derivatives

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