ChemInform Abstract: Structure‐Activity Relationships of Sparsomycin and Its Analogues. Inhibition of Peptide Bond Formation in Cell‐Free Systems and of L1210 and Bacterial Cell Growth.

Broek, L. A. G. M. Van Den; Liskamp, Rob M. J.; Colstee, J. H.; Lelieveld, P.; Remacha, Miguel; Vázquez, David; Ballesta, Juan P. G.; Ottenheijm, H. C. J.

doi:10.1002/chin.198728359

Cited by 3 publications

(8 citation statements)

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“…Fifty percent effective doses of 2.4 and 5.6 ,uM were found for these two compounds, respectively (data not shown), indicating that iodination reduces the activity of phenol-alanine-sparsomycin to about one-half. The iodinated analog was, nevertheless, more active than the original sparsomycin which, in this assay, has a 50% effective dose of 8.5 ,uM (17). Binding experiments indicated that sparsomycin and its derivatives are fully competitive in their interaction with the ribosome (8).…”

Section: Resultsmentioning

confidence: 89%

“…The assay for polyphenylalanine synthesis was performed with 50-pdl samples containing 10 pmol of ribosomes under previously described conditions (17).…”

Section: Methodsmentioning

confidence: 99%

“…The recent synthesis of a number of derivatives having up to 20-fold-higher inhibitory activity than the original drug (16,17) has rekindled interest in sparsomycin as an antitumor antibiotic, and some of these derivatives are currently at the level of clinical testing (19).…”

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confidence: 99%

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Interaction of the antibiotic sparsomycin with the ribosome

Lázaro

San‐Félix

Broek

et al. 1991

Antimicrob Agents Chemother

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Phenol-alanine-sparsomycin, a derivative of sparsomycin carrying a p-hydroxy-benzyl function easily labeled by iodination, has been used to study the interaction of this drug with the ribosome. Our study indicated that the binding of the drug to the ribosome is sensitive to trichloroacetic acid and is equally affected by disintegration of the particle after RNase and protease treatments. The ribosome is not irreversibly inactivated, and the chemical structure of the drug is not affected by interaction with the particle. These data are not compatible with the proposed covalent association of sparsomycin with the ribosome by G. A. Flynn and R. J. Ash (Biochem. Biophys. Res. Commun. 114:1-7, 1983); therefore, the antibiotic must inhibit protein synthesis through a reversible interaction with the ribosome.Sparsomycin is a strong inhibitor of protein synthesis in eucaryotic and procaryotic cells, including highly antibioticresistant organisms such as the archaebacterium Sulfolobus solfataricus (1), suggesting that the drug must interact at a very critical and conserved region of the ribosome. Sparsomycin blocks peptide bond formation by interfering with the interaction of the acceptor tRNA molecule with the A site of the peptidyl transferase center while at the same time strongly stimulating the binding of the donor tRNA to the P site (see Ottenheijm et al. [10] for a review).Interest in the drug as an antitumor agent diminished after a reported sparsomycin-related retinopathy was detected in early clinical studies, although the drug has been used extensively as a tool in studies of ribosome function (10). The recent synthesis of a number of derivatives having up to 20-fold-higher inhibitory activity than the original drug (16, 17) has rekindled interest in sparsomycin as an antitumor antibiotic, and some of these derivatives are currently at the level of clinical testing (19).In this new wave of interest in sparsomycin, a very interesting model has been proposed for the mode of action of the drug; this model implies the occurrence of a chemical reaction involving the sulfoxide moiety of the sparsomycin molecule (4, 5). According to this model, a Pummerer process can be initiated by an imidazole-activated intermediate of the peptide bond-forming reaction, resulting in covalent binding of the drug through its sulfoxide sulfur atom to either the nascent peptide or a ribosomal component.This model is compatible with the analogous stereochemical confirmation of sparsomycin and the 3' aminoacyl adenosine of the aminoacyl-tRNA (4, 5) and provides a plausible explanation for the stimulation of sparsomycin inhibitory activity through preincubation of ribosomes with the drug prior to the initiation of protein synthesis (2). According to the model, this "preincubation effect" would facilitate chemical reaction of the drug at the interaction site. However, experimental evidence supporting the model is based exclusively on the binding of radioactive sparsomycin to ribosomes on sucrose gradients, which does not necessarily deman...

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Section: Resultsmentioning

confidence: 89%

“…The assay for polyphenylalanine synthesis was performed with 50-pdl samples containing 10 pmol of ribosomes under previously described conditions (17).…”

Section: Methodsmentioning

confidence: 99%

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Interaction of the antibiotic sparsomycin with the ribosome

Lázaro

San‐Félix

Broek

et al. 1991

Antimicrob Agents Chemother

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“…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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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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“…Nevertheless, the synthesis of a series of sparsomycin derivatives with higher inhibitory activities (30) has led to a reappraisal of its potential as an anticancer drug (5,7).…”

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confidence: 99%

Characterization of Sparsomycin Resistance in Streptomyces sparsogenes

Lázaro

Sanz

Remacha

et al. 2002

Antimicrob Agents Chemother

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The antitumor antibiotic sparsomycin, produced by Streptomyces sparsogenes, is a universal translation inhibitor that blocks the peptide bond formation in ribosomes from all species. Sparsomycin-resistant strains were selected by transforming the sensitive Streptomyces lividans with an S. sparsogenes library. Resistance was linked to the presence of a plasmid containing an S. sparsogenes 5.9-kbp DNA insert. A restriction analysis of the insert traced down the resistance to a 3.6-kbp DNA fragment, which was sequenced. The analysis of the fragment nucleotide sequence together with the previous restriction data associate the resistance to srd, an open reading frame of 1,800 nucleotides. Ribosomes from S. sparsogenes and the S. lividans-resistant strains are equally sensitive to the inhibitor and bind the drug with similar affinity. Moreover, the drug was not modified by the resistant strains. However, resistant cells accumulated less antibiotic than the sensitive ones. In addition, membrane fractions from the resistant strains showed a higher capacity for binding the drug. The results indicate that resistance in the producer strain is not connected to either ribosome modification or drug inactivation, but it might be related to an alteration in the sparsomycin permeability barrier.

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ChemInform Abstract: Structure‐Activity Relationships of Sparsomycin and Its Analogues. Inhibition of Peptide Bond Formation in Cell‐Free Systems and of L1210 and Bacterial Cell Growth.

Cited by 3 publications

References 1 publication

Interaction of the antibiotic sparsomycin with the ribosome

Interaction of the antibiotic sparsomycin with the ribosome

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

Characterization of Sparsomycin Resistance in Streptomyces sparsogenes

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