The molecular structure of Diazaquinomycin
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Diazaquinomycin
Discovery, producing organism and structure (1,2)
Diazaquinomycins were found while screening for antifolate substances in microorganisms. Diazaquinomycin A inhibited the growth of Gram-positive bacteria. 11,18 -Diacetoxydiazaquinomycin A exhibited antitumor activity against Meth-A fibrosarcoma. The total synthesis of diazaquinomycin A has been reported by two groups. The first total synthesis was achieved by Kelly et al (3).
Physical data (Diazaquinomycin A)
Red crystals. C20H22N2O4; mol wt 354.41. Slightly sol. in DMSO, MeOH, acetone, CHCl3. Insol. in H2O, hexane.
Screening method (4)
Most general microorganisms cannot incorporate folate-related compounds, but some special microorganisms such as Streptococcus sp. and Lactobacillus sp. require folate-related compounds and thus can incorporate them. Antifolates are used clinically as anticancer and antibacterial drugs. To screen the antifolate compounds, we selected a culture broth of soil isolates showing inhibitory activity against a Streptococcus sp. grown in a medium containing a limited amount of pteroate, enough amino acids, bases, and nucleosides, (except thymine and thymidine (TdR)), but lacking inhibitory activity against organisms grown in the same medium supplemented with a sufficient amount of TdR.
Diazaquinomycin D
Biological activity (1,5,6,)
1) Antimicrobial activities
Diazaquinomycin A inhibited the growth of Gram-positive bacteria (MIC: 3.13–50 µg/ml)
with the exception of Bacillus.
2) Cytotoxicity
IC50 = 0.86 µg/ml (Vero cells), 0.23 µg/ml (Raji cells)
3) Acute toxicity (mice i.p.)
LD50 = 100 mg/kg
4) Antitumor activity
11,18-Diacetoxydiazaquinomycin A exhibited antitumor activity
against Meth-A fibrosarcoma (10 mg/kg/day, day 1–4, T/C 141%;
100 mg/kg/day, days 1–4, T/C 175%).
Mode of action (5)
The inhibitory site of diazaquinomycin A was confirmed to be thymidylate synthase. It competitively inhibited bacterial and mammalian thymidylate synthases.
References
1. [250] S. Ōmura et al., J. Antibiot., 35, 1425–1429 (1982)
2. [267] S. Ōmura et al., Tetrahedron Lett., 24, 3643–3646 (1983)
3. T. R. Kelly et al., Tetrahedron Lett., 29, 3545–3546 (1988)
4. [326] S. Ōmura et al., J. Antibiot., 38, 1016–1024 (1985)
5. [327] M. Murata et al., J. Antibiot., 38, 1025–1033 (1985)
6. [412] K. Tsuzuki et al., J. Antibiot., 42, 727–737 (1989)