Bleomycin: synthesis and structural verification of the tripeptide S and tetrapeptide S moieties

Levin, Mark D.; SUBRAHAMANIAN, K. P.; Katz, Howard E.; Smith, Michael B.; Burlett, Donald J.; Hecht, Sidney M.

doi:10.1021/ja00524a055

Cited by 15 publications

(6 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compound 13 was isolated after partial hydrolysis of bleomycin B2 (Muraoka et al, 1972). The syntheses of tripeptide S (11) and tetrapeptide S (12) were carried out as described (Levin et al, 1980); the preparations of inhibitors 1-5, 7, 9, 10, and 14 are described below.…”

Section: Methodsmentioning

confidence: 99%

Structural basis for the DNA affinity of bleomycins

J¹,

Wd²,

Wa³

et al. 1982

Biochemistry

Self Cite

View full text Add to dashboard Cite

The role of the bithiazole moiety of bleomycin in the interaction of the antibiotic with DNA has been studied by the use of synthetic bithiazole derivatives. The DNA affinity of individual C-terminal (bithiazole) analogues of bleomycin was measured in terms of the ability of these species to block the binding of bleomycin to DNA, as judged by diminution of the DNA degradation that attends bleomycin binding. DNA degradation was monitored both by release of [3H]thymine from radiolabeled PM-2 DNA and by alteration of bleomycin-treated DNA oligomers of defined sequence derived from Escherichia coli plasmid pLJ3. It was found that the affinity of the bithiazole derivatives for DNA depended on the presence of the bithiazole moiety itself but more importantly on the number and spacing of positively charged groups; 2'-(2-aminoethyl)-2,4'-bithiazole-4-[3-[(4-aminobutyl) amino]propyl]carboxamide (14), having three positively charged groups at neutral pH, was a reasonably effective inhibitor of DNA degradation by bleomycin. Consistent with the importance of the spacing of the positively charged groups, tetrapeptide S (12) was found to be significantly less inhibitory toward DNA degradation by bleomycin than tripeptide S, in spite of their equal number of positively charged groups and the greater structural similarity of the former to bleomycin A2. Bleomycin is known to cleave DNA perferentially at certain sequences. It was shown that the inhibitors employed in this study diminished DNA cleavage proportionately at each cleavage site; no alteration was observed in the specificity of cleavage. A number of the bithiazole analogues employed as inhibitors of bleomycin-mediated DNA degradation were also utilized in fluorescence quenching experiments with calf thymus DNA. Consistent with the belief that these species inhibit bleomycin degradation by competitive binding to the DNA substrate, the best inhibitors exhibited the greatest fluorescence quenching upon admixture of DNA.

show abstract

Section: Methodsmentioning

confidence: 99%

Structural basis for the DNA affinity of bleomycins

J¹,

Wd²,

Wa³

et al. 1982

Biochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…[α] 25 D = +12.1° ( c 1.03, H 2 O)) was synthesized according to the reported procedures. , Benzylation of this acid with benzyl alcohol in the presence of anhydrous hydrogen chloride afforded the corresponding benzyl ester ( 8 ) in 89% yield 21c. Threonylbithiazole derivative 9 was synthesized using reported procedures 19a,21a,, (Scheme ). Specifically, 2‘-(2-aminoethyl)-2,4‘-bithiazole-4-[(3-methylthio)propyl]carboxamide ( 14 ) was prepared by the reported method from the corresponding carboxylic acid. 19a,, The coupling of 14 with commercially available ( S )- N α -t -Boc-threonine ( 13 ) via the agency of DCC−HOBt afforded the coupled product N α -t -Boc-threonylbithiazole 15 35 in 68% yield.…”

Section: Resultsmentioning

confidence: 99%

“…Threonylbithiazole derivative 9 was synthesized using reported procedures 19a,21a,, (Scheme ). Specifically, 2‘-(2-aminoethyl)-2,4‘-bithiazole-4-[(3-methylthio)propyl]carboxamide ( 14 ) was prepared by the reported method from the corresponding carboxylic acid. 19a,, The coupling of 14 with commercially available ( S )- N α -t -Boc-threonine ( 13 ) via the agency of DCC−HOBt afforded the coupled product N α -t -Boc-threonylbithiazole 15 35 in 68% yield. Deprotection of 15 with trifluoroacetic acid in the presence of dimethyl sulfide gave threonylbithiazole derivative 9 in 93% yield.…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of Bleomycin Group Antibiotics. Total Syntheses of Bleomycin Demethyl A₂, Bleomycin A₂, and Decarbamoyl Bleomycin Demethyl A₂

Katano

Aoyagi

et al. 1998

J. Am. Chem. Soc.

Self Cite

View full text Add to dashboard Cite

The total syntheses of bleomycin A2 (1) by two routes are described. The final step in the synthesis of bleomycin A2 involves methylation of bleomycin demethyl A2 (2). This bleomycin derivative is of interest mechanistically, and can also provide access to other bleomycins via its known chemical conversion to bleomycinic acid. Accordingly, the synthetic strategy presented represents a particularly versatile approach for the elaboration of a wide variety of BLM congeners. Bleomycin was constructed from five key intermediates, the syntheses of which are described. 1,6-Di-O-acetyl-3,4-di-O-benzyl-2-O-[2,4,6-tri-O-acetyl-3-O-(N-acetylcarbamoyl)-α-d-mannopyranosyl]-β-l-gulopyranose (3) was converted quantitatively to its disaccharide chloride (4), the latter of which was condensed with N α,N im-bis(t-Boc)-(S)-erythro-β-hydroxyhistidine (7) to provide α-O-glycosidated product 16. The subsequent couplings with benzyl valerate 8, threonylbithiazole 9, and N α -t-Boc-pyrimidoblamic acid (10) afforded access to bleomycin demethyl A2 (2) and decarbamoyl bleomycin demethyl A2 (26). Although it was obtained as a byproduct of the synthesis of BLM, the synthesis of decarbamoyl bleomycin demethyl A2 nonetheless constitutes the first report of synthetic access to this BLM congener that is of particular importance from a mechanistic perspective. This BLM can be used to resolve the issue of the participation of the carbamoyl group as a metal ligand in metallobleomycins. Also reported is a new route to bleomycin demethyl A2 that employed an unprotected carbamoyl group throughout the synthesis. In conjunction with the use of the uncharged methylthiopropylamide C-substituent, the latter strategy permitted improved functional group manipulation and thereby afforded intermediates that could be purified with greater facility. Because the synthesis of bleomycin is limited by the efficiency of elaboration of the carbohydrate moiety, a study was carried out to define improved methods for the preparation of this constituent of BLM. Three new routes were explored, and a route involving the intermediacy of disaccharide activated as a glycosyl bromide was found to be particularly efficient and convenient. Also of importance was the finding that activation of carbohydrate intermediates as their glycosyl trichloroacetimidates permitted the requisite couplings to be carried out conveniently and in good yields. Synthetic BLM demethyl A2 was shown to have the same potency as a naturally derived sample in a plasmid DNA relaxation assay. The sequence selectivity of DNA cleavage by synthetic and authentic Fe(II)·BLMs was also shown to be the same. Also established for the first time for any synthetic bleomycin was the actual chemistry of DNA degradation, which is the same as that for naturally derived bleomycins.

show abstract

“…In addition to its medicinal importance, BLM is of great interest because of its unique mechanism of action3 and unusual glycopeptide structure. 4 This communication describes the synthesis of the pyrimidine moiety of bleomycin, including a key pyrimidine intermediate ( 4), pyrimidobleonic acid5•6 (6a), pyrimidoblamic acid (8), and a pyrimidoblamylhistidine equivalent (9), from the starting material ethyl 6-chloro-2-formyl-5-methylpyrimidine-4-carboxylate (1), which is readily accessible by the approach developed in our laboratories.7…”

mentioning

confidence: 99%

“…°C for 24 h. The desired product 4 was obtained in 23% yield along with an elimination product13 upon workup and chromatography on silica gel; Rf values for them were 0.46 and 0.86, respectively (silica gel plates, C6H6-AcOEt, 1:5). The product 4 showed a single spot on TLC, but it was separated cleanly by using high-performance TLC (HPTLC) and found to be a mixture of the two epimers 4a and 4b in about equal amounts (~1 0% yield each).…”

mentioning

confidence: 99%

Synthesis of the pyrimidine moiety of bleomycin

et al. 1980

View full text Add to dashboard Cite

Bleomycin: synthesis and structural verification of the tripeptide S and tetrapeptide S moieties

Cited by 15 publications

References 2 publications

Structural basis for the DNA affinity of bleomycins

Structural basis for the DNA affinity of bleomycins

Total Synthesis of Bleomycin Group Antibiotics. Total Syntheses of Bleomycin Demethyl A₂, Bleomycin A₂, and Decarbamoyl Bleomycin Demethyl A₂

Synthesis of the pyrimidine moiety of bleomycin

Contact Info

Product

Resources

About

Bleomycin: synthesis and structural verification of the tripeptide S and tetrapeptide S moieties

Cited by 15 publications

References 2 publications

Structural basis for the DNA affinity of bleomycins

Structural basis for the DNA affinity of bleomycins

Total Synthesis of Bleomycin Group Antibiotics. Total Syntheses of Bleomycin Demethyl A2, Bleomycin A2, and Decarbamoyl Bleomycin Demethyl A2

Synthesis of the pyrimidine moiety of bleomycin

Contact Info

Product

Resources

About

Total Synthesis of Bleomycin Group Antibiotics. Total Syntheses of Bleomycin Demethyl A₂, Bleomycin A₂, and Decarbamoyl Bleomycin Demethyl A₂