Chemical modification of anthracycline antibiotics. I. Demethoxycarbonylation, 10-epimerization and 4-o-methylation of aclacinomycin A.

Tanaka, Hiroshi; Yoshioka, Takeo; Shimauchi, Yasutaka; Matsuzawa, Yasue; Oki, Taikan; Inui, Taiji

doi:10.7164/antibiotics.33.1323

Cited by 24 publications

(5 citation statements)

References 19 publications

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“…The couplings that remain to the 3.05 resonance (2.4 Hz) and 2.91 resonance (1.1 Hz) are assigned to H10a, H7a and H10e, H7a couplings, respectively. Although these 1,4 long-range couplings are not seen with 7-deoxyaklavinone, the similarity between 7-deoxyaklavinone and 7-deoxydaunomycinone in the C-7 and C-8 coupling and the preference for an axial C-9 hydroxyl regardless of C-10 substitution in the aclacinomycins (Tanaka et al, 1980) suggest similar conformations for 7-deoxydaunomycinone and 7deoxyaklavinone. The proton delivered to the re face of a daunomycinone methide, therefore, should also appear as the pseudoequatorial hydrogen in the proton NMR spectrum.…”

Section: Stereochemistry Of Hydrogen Transfer From Nadh Tomentioning

confidence: 83%

“…This pattern and other NMR data, summarized below, indicate that 7-deoxyaklavinone also adopts the half-chair-like conformation having the C-9 hydroxyl in the pseudoaxial position, as shown in Figure 2. First, the chemical shifts for the C-10 hydrogen and C-10 carbomethoxy methyl group are similar to those of aclacinomycin derivatives (Tanaka et al, 1980) established to have a pseudoaxial placement of the C-10 carbomethoxy group. Decoupling experiments show a nuclear Overhauser effect between the C-10 and C-l 1 methines, and the C-10 methine and C-13 methylene, suggesting an approximately coplanar relationship among these three carbons.…”

Section: Stereochemistry Of Hydrogen Transfer From Nadh Tomentioning

confidence: 90%

See 1 more Smart Citation

Direct enzyme-catalyzed reduction of anthracyclines by reduced nicotinamide adenine dinucleotide

Fisher

Ramakrishnan

Becvar³

1983

Biochemistry

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Section: Stereochemistry Of Hydrogen Transfer From Nadh Tomentioning

confidence: 83%

Section: Stereochemistry Of Hydrogen Transfer From Nadh Tomentioning

confidence: 90%

Direct enzyme-catalyzed reduction of anthracyclines by reduced nicotinamide adenine dinucleotide

Fisher

Ramakrishnan

Becvar³

1983

Biochemistry

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“…6 After the removal of the TMS groups, a trifluoroacetate protecting group at 10-OH of 4-O-methyl-P-rhodomycinone permitted the selective glycosylation at C-7. The TMS protective groups (TMS-C1, pyridine, dichloromethane) were introduced into (J-rhodomycinone 7 5 principally at the secondary hydroxy groups at C-7 and C-10.…”

Section: Resultsmentioning

confidence: 99%

“…6 The reaction of 8 with a large of excess of methyl iodide in the presence of Na 2 CO 3 provides two main products: the 4-O-methyl derivative 10 (43%) as a red compound and the 11-0-methyl derivative 11 (11%) as a yellow compound. The use of Cs 2 CO 3 instead of Na 2 CO 3 considerably reduces the amount of Mel required but only marginally improves the selectivity of the 4-0-methylation step.…”

Section: Resultsmentioning

confidence: 99%

Semisynthetic 4-O-Methyl-ß-Rhodomycins: Synthesis and Structure-Activity Relationships

Kolář¹,

Gerken²,

Kraemer³

et al. 1990

Journal of Carbohydrate Chemistry

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The synthesis of 7-0-a-L-daunosaminyl-4-0-methyl-P-rhodomycinone (3) and the determination of its cytotoxic potency compared to that of the natural 7-<9-cc-L-daunosaminyl-p-rhodomycinone (4) are described. Starting with natural P-rhodomycinone (7), trimethylsilyl protecting groups were attached to the hydroxy groups at position 7 and 10, and the 4-OH group was subsequently methylated (MeVCs 2 CO3), thus providing the 4-0-methyl-7,lO-bis-0-trimethylsilyl-p-rhodomycinone (10). The two TMS groups were then deblocked to give 4-0-methyl-P-rhodomycinone (12). In a 3-stage synthesis 12 was converted into 4-O-methyl-10-d-trifluoroacetyl-B-rhodomycinone (15) to which l,4-bis-O-p-nitrobenzoyl-3-A'-trifluoroacetyl-L-daunosamine 16 was selectively linked to afford the 7-O-a-glycoside 17. The acyl protective groups are removed by treatment with lNNaOHtogive3. 223 Copyright© 1990 by Marcel Dekker, Inc. Downloaded by [McMaster University] at 10:22 22 December 2014 224 KOLAR ET AL.

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“…3) (12,20,23) suggest that this reaction proceeds by hydrolysis of the C 10 OC 15 bond, but similarity with the Pseudomonas esterase (29) indicates possible hydrolysis of the methyl group. It is possible that RdmC catalyzes both reactions, as decarboxylation of aklavinone carboxylic acid is known to occur spontaneously in dimethylformamide (33,35). The conserved active-serine sequence GXSXG (4) is present around Ser-102, in addition to a conserved putative active-site histidine at 276.…”

mentioning

confidence: 99%

Nucleotide sequences and expression of genes from Streptomyces purpurascens that cause the production of new anthracyclines in Streptomyces galilaeus

Niemi

Mäntsälä

1995

J Bacteriol

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Six open reading frames, rdmA to rdmF, in a 6,077-bp segment of Streptomyces purpurascens DNA which caused the production of hybrid anthracyclines were identified. The minimal fragment that produced anthracyclines modified at the 10th position contained rdmB to rdmD; rdmE is the gene for aklavinone-11-hydroxylase. RdmC is similar to a putative open reading frame in the daunorubicin biosynthetic cluster of Streptomyces peucetius and is likely to participate in the removal of the side chain at the 10th position.Anthracyclines are a group of substances that contain the 7,8,9,10-tetrahydro-5,12-naphthacene quinone structure (31); they are usually antibiotics produced by actinomycetes or their synthetic analogs. Some of them are important pharmaceutical agents which are used in cancer therapy. The anthracycline chromophore, aglycone, is synthesized by the polyketide pathway in producing organisms (6). The polyketide synthases of several streptomycetes have been found to have a high degree of conservation (17,18), which has enabled the biosynthetic genes of additional polyketide antibiotics to be cloned (22).Hybrid antibiotics are molecules which combine structural features of two or more antibiotics that are not normally produced by the same organism and are often produced by transferring genes from one antibiotic producer to another strain that produces a structurally related antibiotic by recombinant DNA techniques (14, 16).Previously, Niemi et al. (25,27) described hybridizing a segment of Streptomyces purpurascens DNA near the locus with an actI (polyketide synthase) probe from Streptomyces coelicolor (22), which caused the production of glycosides of several modified aglycones ( Fig. 1) in Streptomyces galilaeus, a producer of aklavinone glycosides. The genes that caused hybrid production were located on a 6.1-kb BamHI-Sau3AI fragment, EB3 (including 9 bp from the polylinker of EMBL4 [8] with an EcoRI site).We have sequenced this fragment and expressed the aglycone-modifying enzyme activities it encodes by using a strong, constitutive promoter. Expression and sequence data indicate interesting similarities with daunorubicin and doxorubicin biosynthesis in Streptomyces peucetius.Sequence analysis. A random subcloning strategy was used (28). M13mp18 (37) clones were sequenced with Taq polymerase (Promega Corporation, Madison, Wis.); with most clones, 7-deazaguanidine nucleotide mixes were used. Clone preselection by single-nucleotide tracking (26), clone inversion, and subcloning of selected restriction fragments were also used to completely sequence both strands of DNA. Assembly and analysis of the nucleotide sequence were performed with the Genetics Computer Group package (10). ATG and GTG start codons (30) were accepted, and the codon usage table for CODONPREFERENCE was prepared by using previously published data (36).On the basis of codon bias (1), six presumed protein-coding open reading frames (ORFs), rdmA to rdmF, were observed (Fig. 2).The beginning of rdmA is uncertain because although an apparent ribosom...

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Chemical modification of anthracycline antibiotics. I. Demethoxycarbonylation, 10-epimerization and 4-o-methylation of aclacinomycin A.

Cited by 24 publications

References 19 publications

Direct enzyme-catalyzed reduction of anthracyclines by reduced nicotinamide adenine dinucleotide

Direct enzyme-catalyzed reduction of anthracyclines by reduced nicotinamide adenine dinucleotide

Semisynthetic 4-O-Methyl-ß-Rhodomycins: Synthesis and Structure-Activity Relationships

Nucleotide sequences and expression of genes from Streptomyces purpurascens that cause the production of new anthracyclines in Streptomyces galilaeus

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