Structure of tomaymycin, a DNA binding antitumor antibiotic.

Arora, S. K.

doi:10.7164/antibiotics.34.462

Cited by 23 publications

(24 citation statements)

References 6 publications

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“…The relevant torsion angles are listed in Table 2. A similar conformation pattern is observed in related compounds, for example, anthramycin methyl ester (Mostad, Rcmming & Storm, 1978;Arora, 1979) and tomaymycin (Arora, 1981). The overall twist, defined as the dihedral angle between the leastsquares plane of the aromatic ring and the planar part of the pyrrolo ring, is 17.0 (6) ° for the more occupied and 33.7 (6) ° for the less occupied alternatives, and is intermediate between the values for tomaymycin, 9.0 (1) °, and anthramycin methyl ester, 45.0 (1) °.…”

Section: Commentsupporting

confidence: 71%

(11R,11aS-trans)-11-Ethylthio-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one

Kubicki¹,

Szkaradzinska²,

Codding³

1997

Acta Crystallogr C

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Section: Commentsupporting

confidence: 71%

(11R,11aS-trans)-11-Ethylthio-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one

Kubicki¹,

Szkaradzinska²,

Codding³

1997

Acta Crystallogr C

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“…I refer to the references of Table for detailed conditions and structural characterization of the naturally produced PBDs. The crystal structure of anthramycin, and tomaymycin were pivotal, not only to confirm the structure of these compounds but also, more importantly, to assign the S ‐stereochemistry of C11a, which gives the characteristic right‐handed twist of the PBD scaffold. The assignment of the structure of sibiromycin was not as straightforward.…”

Section: Isolation and Characterization Of Naturally Produced Pyrrolomentioning

confidence: 94%

“…). The right‐handed twists of free anthramycin and tomaymycin are 35.4°, and 9.1°, respectively. The right‐handed twist increases by few degrees once anthramycin is bound to the DNA .…”

Section: Dna Alkylating Properties Of Pyrrolobenzodiazepinesmentioning

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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“…Purine-purine steps exhibit low helical twist angles (Yanagi et al, 1991). The normals between the fiveand six-membered rings of tomaymycin make a 90 angle (Arora, 1981) in comparison to a 35.4°a ngle between normals in anthramycin (Mostad et al, 1978;Arora, 1979). For anthramycin, the small helical twist provided by purine-purine steps is always more important than the room provided by A-T base pairs adjacent to the binding site, even though the acrylamide tail in anthramycin is longer than the ethylidene tail in tomaymycin.…”

Section: Discussionmentioning

confidence: 99%

Time-resolved fluorescence studies of tomaymycin bonding to synthetic DNAs

Barkley

Chen

Walczak

et al. 1996

Biophysical Journal

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Tomaymycin reacts covalently with guanine in the DNA minor groove, exhibiting considerable specificity for the flanking bases. The sequence dependence of tomaymycin bonding to DNA was investigated in synthetic DNA oligomers and polymers. The maximum extent of bonding to DNA is greater for homopurine and natural DNA sequences than for alternating purine-pyrimidine sequences. Saturation of DNA with tomaymycin has little effect on the melting temperature in the absence of unbound drug. Fluorescence lifetimes were measured for DNA adducts at seven of the ten unique trinucleotide bonding sites. Most of the adducts had two fluorescence lifetimes, representing two of the four possible binding modes. The lifetimes cluster around 2-3 ns and 5-7 ns; the longer lifetime is the major component for most bonding sites. The two lifetime classes were assigned to R and S diastereomeric adducts by comparison with previous NMR results for oligomer adducts. The lifetime difference between binding modes is interpreted in terms of an anomeric effect on the excited-state proton transfer reaction that quenches tomaymycin fluorescence. Bonding kinetics of polymer adducts were monitored by fluorescence lifetime measurements. Rates of adduct formation vary by two orders of magnitude with poly(dA-dG).poly(dC-dT), reacting the fastest at 4 x 10(-2) M-1 s-1. The sequence specificity of tomaymycin is discussed in light of these findings and other reports in the literature.

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Structure of tomaymycin, a DNA binding antitumor antibiotic.

Cited by 23 publications

References 6 publications

(11R,11aS-trans)-11-Ethylthio-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one

(11R,11aS-trans)-11-Ethylthio-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Time-resolved fluorescence studies of tomaymycin bonding to synthetic DNAs

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