Mazethramycin, a new member of anthramycin group antibiotics.

Kunimoto, Setsuko; Masuda, Tohru; Kanbayashi, Nobuo; Hamada, Masa; Naganawa, Hiroshi; Miyamoto, Masashi; Takeuchi, Tomio; Umezawa, Hamao

doi:10.7164/antibiotics.33.665

Cited by 26 publications

(18 citation statements)

References 2 publications

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“…The methoxy derivative of porothramycin was named porothramycin B, while the carbinolamine form was named porothramycin A . In most cases, the carbinolamine form is considered the parent compound, such as in mazethramycin, sibiromycin, and anthramycin . However, adding to this confusion, in other cases the imine form is considered, such as in sibanomicin and neothramycin .…”

Section: Isolation and Characterization Of Naturally Produced Pyrrolomentioning

confidence: 99%

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Gerratana

2010

Medicinal Research Reviews

118

143

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Pyrrolobenzodiazepines (PBDs) are sequence selective DNA alkylating agents with remarkable antineoplastic activity. They are either naturally produced by actinomycetes or synthetically produced. The remarkable broad spectrum of activities of the naturally produced PBDs encouraged the synthesis of several PBDs, including dimeric and hybrid PBDs yielding to an improvement in the DNA binding sequence specificity and in the potency of this class of compounds. However, limitation in the chemical synthesis prevented the testing of one of the most potent PBDs, sibiromycin, a naturally produced glycosylated PBDs. Only recently the biosynthetic gene clusters for PBDs have been identified opening the doors to the production of glycosylated PBDs by mutasynthesis and biosynthetic engineering. The present review describes the recent studies on the biosynthesis of naturally produced pyrrolobenzodiazepines. In addition, it provides an overview on the isolation and characterization of naturally produced PBDs, on the chemical synthesis of PBDs, on the mechanism of DNA alkylation, and on the DNA binding affinity and cytotoxic properties of both naturally produced and synthetic pyrrolobenzodiazepines.

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Section: Isolation and Characterization Of Naturally Produced Pyrrolomentioning

confidence: 99%

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Gerratana

2010

Medicinal Research Reviews

118

143

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“…Combination of above two fragments III and IV allowed us to propose l,10,ll,lla-tetrahydro-9, 1 l -dimethoxy-5JfiT-pyrrolo [2, l -c][l ,4]benzodiazepine-5-one-2-Ar,Ar-dimethylacrylamide for the structure of II. As analyzed in Table 3, lla (5) configuration is estimated for II. The spectral difference between I and II indicated that I has a free hydroxyl group at C-ll.…”

Section: Structure Determinationmentioning

confidence: 99%

Porothramycin, a new antibiotic of the anthramycin group: Production, isolation, structure and biological activity.

Tsunakawa¹,

Kamei²,

Konishi³

et al. 1988

J. Antibiot.

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A newantitumor antibiotic porothramycin wasproduced by a newstrain of Streptomyces albus1^. The antibiotic was isolated in two active forms, the natural free hydroxyl form (porothramycin A) or the crystalline methyl ether form (porothramycin B) depending upon the isolation process used. Structural studies established that porothramycin is a newmember of the pyrrolo [l ,4] In the course of a screening program for newantitumor antibiotics, a strain of actinomycete (K731-1 13) classified as Streptomyces albus was found to produce a novel antitumor antibiotic, which wasdesignated as porothramycin. The antibiotic was recovered from the fermentation broth by using organic solvent or Diaion HP-20 and purified by column chromatographies. Whenmethanol was used in the isolation or purification process, the antibiotic was obtained as the crystalline methyl ether form (porothramycin B). While the natural hydroxyl form of the antibiotic (porothramycin A) was recovered by the procedure without using methanol. Both porothramycins A and B were active against Gram-positive bacteria and anaerobes but inactive against Gram-negative bacteria and fungi. They exhibited strong antitumor activity against P388 and L1210 leukemia and B16 melanoma in mice. This paper reports the discovery, production, isolation, structure determination and biological activity of porothramycins A and B.Production A well grown agar slant of S. albus, K731-113, was used to inoculate a vegetative medium consisting of soluble starch 2%, beet molasses 1 %, fish meal 1 % and CaCO3 0.5 %, the pH being adjusted to 7.0 before sterilization. The vegetative mediumwas incubated at 28°C for 3 days on a rotary shaker (250 rpm) and 5 ml of the growth was transferred into 500-ml Erlenmeyer flasks containing 100 ml each of the fermentation mediumhaving the same composition as the vegetative medium. The fermentation was carried out at 28°C for 7 to 8 days on a rotary shaker. The antibiotic activity in the fermentation broth was determined by the paper-disc agar diffusion method using Bacillus subtilis M45(Rec~mutant) and Bacteroides fragilis as the test organisms. After 7 days cultivation, the antibiotic activity reached a maximumpotency of 60~100 jug/ml.Porothramycin was originally called as BMY-28121 or BU-2916T.

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“…Seven natural PBDs with a 3C APD moiety in their nal structures have been described, including anthramycin, 42 sibiromycin, 43 usabamycin A, 40 mazethramycin, 44 porothramycin, 45 sibanomicin 46 and one C11-oxo derivative oxoanthramycin (originally inappropriately named limazepine H). 36 Another six PBDs incorporate a 2C APD moiety: tomaymycin and oxotomaymycin, 47 prothracarcin (also named limazepine F), 48 oxoprothracarcin, 35 limazepine C 49 and boseongazepine A.…”

Section: Pyrrolo[21-c][14]benzodiazepines (Pbds)mentioning

confidence: 99%

Biosynthesis and incorporation of an alkylproline-derivative (APD) precursor into complex natural products

et al. 2018

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Covering: up to 2017This review covers the biosynthetic and evolutionary aspects of lincosamide antibiotics, antitumour pyrrolobenzodiazepines (PBDs) and the quorum-sensing molecule hormaomycin. These structurally and functionally diverse groups of complex natural products all incorporate rarely occurring 4-alkyl-l-proline derivatives (APDs) biosynthesized from l-tyrosine through an unusual specialized pathway catalysed by a common set of six proteins named Apd1-Apd6. We give an overview of APD formation, which involves unusual enzyme activities, and its incorporation, which is based either on nonribosomal peptide synthetase (PBDs, hormaomycin) or a unique hybrid ergothioneine-dependent condensation system followed by mycothiol-dependent sulphur atom incorporation (lincosamides). Furthermore, within the public databases, we identified 36 novel unannotated biosynthetic gene clusters that putatively encode the biosynthesis of APD compounds. Their products presumably include novel PBDs, but also novel classes of APD compounds, indicating an unprecedented potential for the diversity enhancement of these functionally versatile complex metabolites. In addition, phylogenetic analysis of known and novel gene clusters for the biosynthesis of APD compounds allowed us to infer novel evolutionary hypotheses: Apd3 methyltransferase originates from a duplication event in a hormaomycin biosynthetic gene cluster ancestor, while putative Apd5 isomerase is evolutionarily linked to PhzF protein from the biosynthesis of phenazines. Lastly, we summarize the achievements in preparing hybrid APD compounds by directing their biosynthesis, and we propose that the number of nature-like APD compounds could by multiplied by replacing l-proline residues in various groups of complex metabolites with APD, i.e. by imitating the natural process that occurs with lincosamides and PBDs, in which the replacement of l-proline for APD has proved to be an evolutionary successful concept.

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Mazethramycin, a new member of anthramycin group antibiotics.

Cited by 26 publications

References 2 publications

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Porothramycin, a new antibiotic of the anthramycin group: Production, isolation, structure and biological activity.

Biosynthesis and incorporation of an alkylproline-derivative (APD) precursor into complex natural products

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