Total synthesis of the antibiotic sparsomycin, a modified uracil amino acid monoxodithioacetal

Ottenheijm, H. C. J.; Liskamp, Rob M. J.; NISPEN, S. P. J. M. VAN; Boots, H.A.; Tijhuis, M. W.

doi:10.1021/jo00329a027

Cited by 60 publications

(30 citation statements)

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“…Sm and its analogues were synthesized as previously described [6,9]. Drugs were acquired in a freeze dried form and dissolved or suspended in buffered physiological saline before use.…”

Section: Drugsmentioning

confidence: 99%

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In vivo antitumor activity of sparsomycin and its analogues in eight murine tumor models

Żylicz¹,

Wagener²,

Rennes³

et al. 1988

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Sparsomycin (Sm) is a known inhibitor of ribosomal protein synthesis with an attractive anticancer potential. Recently, several analogues of Sm which are more active than the parent drug were selected for further study on the basis of in vitro investigations. Six analogues as well as the parent drug were tested for their antitumor activity in eight in vivo murine tumor models: P388 and L1210 leukemias, RC renal cell carcinoma, B16 melanoma, C38 colon carcinoma, LL Lewis lung carcinoma, C22LR osteosarcoma and M5076 sarcoma. Sm itself appeared to have only borderline activity on L1210 leukemia. The analogues that were most active in vitro showed also the highest in vivo activity. The most sensitive tumors were RC, L1210 and P388. Minimal activity was found on B16 and no activity on C22LR, M5076, C38 and LL. The most active compounds are deshydroxy-Sm, ethyl-deshydroxy-Sm and n-pentyl-Sm. There was a considerable loss of activity when L1210 leukemia was implanted sc while the drugs were administered iv. Only one drug, ethyl-deshydroxy-Sm appeared to be active in this assay. No single most effective compound could be found in this study. The overall activity of Sm and its analogues is moderate. The three analogues which show high activity in three ascitic tumors will be further investigated using human tumor xenograft models.

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“…Sm and its analogues were synthesized as previously described [6,9]. Drugs were acquired in a freeze dried form and dissolved or suspended in buffered physiological saline before use.…”

Section: Drugsmentioning

confidence: 99%

“…The revival of interest in this drug was stimulated by its present accessibility through a flexible total synthesis [6] and by the preparation of more active and less toxic analogues [7,8]. For the review on the total synthesis of Sm and the development of its structural analogues see references [9] and [10].…”

Section: Introductionmentioning

confidence: 99%

In vivo antitumor activity of sparsomycin and its analogues in eight murine tumor models

Żylicz¹,

Wagener²,

Rennes³

et al. 1988

Invest New Drugs

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“…[7][8][9][10] These potentially important biological activities have made 3 an attractive target for a potential antineoplastic compound. 11) Since thê rst synthetic study of sparsomycin in 1976, 12) synthetic studies of sparsomycin, [13][14][15] total synthesis, [16][17][18] biosynthesis, 19,20) and structure-activity relationship studies [21][22][23][24][25][26][27] have been widely reported. There have been many reports on the antitumor, antibacterial, antifungal, and antiviral properties; however, normalization of the phenotype of oncogene-transformed cells by 3 and its analogues has not previously been reported.…”

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Synthesis and Activity of Pyrimidinylpropenamide Antibiotics: The Alkyl Analogues of Sparsomycin

Nakajima

Enomoto

Watanabe

et al. 2003

Bioscience, Biotechnology, and Biochemistry

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“…The structure of sparsomycin was elucidated in 1970 by Wiley and MacKellar (33), while the absolute configuration was deduced by Ottenheijm and coworkers in 1981 (26). Several total syntheses of sparsomycin have been reported previously (14,20,25,26). The biological activity of sparsomycin is the result of its ability to inhibit the peptide bond-forming step of protein biosynthesis by interacting with the large ribosomal subunit in a poorly understood, complex manner (16)(17)(18)30).…”

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confidence: 99%

“…Sparsomycin has also been shown to potentiate the activity of other anticancer agents, such as cisplatin (25). The structure of sparsomycin was elucidated in 1970 by Wiley and MacKellar (33), while the absolute configuration was deduced by Ottenheijm and coworkers in 1981 (26). Several total syntheses of sparsomycin have been reported previously (14,20,25,26).…”

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Purification and preliminary characterization of (E)-3-(2,4-dioxo-6-methyl-5-pyrimidinyl)acrylic acid synthase, an enzyme involved in biosynthesis of the antitumor agent sparsomycin

Parry

Hoyt

1997

J Bacteriol

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Sparsomycin is an antitumor antibiotic produced by Streptomyces sparsogenes. Biosynthetic experiments have previously demonstrated that one component of sparsomycin is derived from L-tryptophan via the intermediacy of (E)-3-(4-oxo-6-methyl-5-pyrimidinyl)acrylic acid and (E)-3-(2,4-dioxo-6-methyl-5-pyrimidinyl)acrylic acid. An enzyme which catalyzes the conversion of (E)-3-(4-oxo-6-methyl-5-pyrimidinyl)acrylic acid to (E)-3-(2,4-dioxo-6-methyl-5-pyrimidinyl)acrylic acid has been purified 740-fold to homogeneity from S. sparsogenes. The molecular mass of the native and denatured enzyme was 87 kDa, indicating that the native enzyme is monomeric. The enzyme required NAD ؉ for activity but lacked rigid substrate specificity, since analogs of both NAD ؉ and 3-(4-oxo-6-methyl-5-pyrimidinyl)acrylic acid could serve as substrates. The enzyme was very weakly inhibited by mycophenolic acid. Monovalent cations were required for activity, with potassium ions being the most effective. The enzyme exhibited sensitivity toward diethylpyrocarbonate and some thiol-directed reagents, and it was irreversibly inhibited by 6-chloropurine. The properties of the enzyme suggest it is mechanistically related to inosine-5-monophosphate dehydrogenase.Sparsomycin (Fig. 1A) is an unusual monooxo-dithioacetalcontaining antibiotic that is produced by Streptomyces sparsogenes var. sparsogenes (3) and Streptomyces cuspidosporus (12). Sparsomycin displays bacteriocidal activity against a wide variety of gram-negative and gram-positive bacteria (27) as well as members of the Archaebacteria (17), and it exhibits potent anticancer activity against a variety of tumors in vivo and against KB human epidermoid carcinoma cells in culture (27). Sparsomycin has also been shown to potentiate the activity of other anticancer agents, such as cisplatin (25). The structure of sparsomycin was elucidated in 1970 by Wiley and MacKellar (33), while the absolute configuration was deduced by Ottenheijm and coworkers in 1981 (26). Several total syntheses of sparsomycin have been reported previously (14,20,25,26). The biological activity of sparsomycin is the result of its ability to inhibit the peptide bond-forming step of protein biosynthesis by interacting with the large ribosomal subunit in a poorly understood, complex manner (16)(17)(18)30). Although the clinical use of sparsomycin is precluded due to drug-related retinopathy, a number of more potent analogs have been prepared which may prove useful in cancer chemotherapy (16). One of the novel components of the sparsomycin molecule is (E)-3-(2,4-dioxo-6-methyl-5-pyrimidinyl)acrylic acid (UCA). Biosynthetic experiments have demonstrated (28) that this compound is derived from L-tryptophan via the intermediacy of (E)-3-(4-oxo-6-methyl-5-pyrimidinyl)acrylic acid (PCA) (Fig. 1A) and that both PCA and UCA are incorporated into sparsomycin. This article describes the first purification and characterization of an enzyme associated with the sparsomycin biosynthetic pathway. This enzyme, UCA synthase, catalyzes the NAD ϩ ...

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Total synthesis of the antibiotic sparsomycin, a modified uracil amino acid monoxodithioacetal

Cited by 60 publications

References 3 publications

In vivo antitumor activity of sparsomycin and its analogues in eight murine tumor models

In vivo antitumor activity of sparsomycin and its analogues in eight murine tumor models

Synthesis and Activity of Pyrimidinylpropenamide Antibiotics: The Alkyl Analogues of Sparsomycin

Purification and preliminary characterization of (E)-3-(2,4-dioxo-6-methyl-5-pyrimidinyl)acrylic acid synthase, an enzyme involved in biosynthesis of the antitumor agent sparsomycin

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