The Structures of Tomaymycin and Oxotomaymycin

Kariyone, Kazuo; Yazawa, Hisatoyo; Kohsaka, Masanobu

doi:10.1248/cpb.19.2289

Cited by 57 publications

(41 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The PBD series were developed as minor-groove binding covalent molecules. PBDs are antitumor antibiotics derived from Streptomyces species and include anthramycin and tomaymycin (12,13). PBDs interact within the minor groove of DNA by binding covalently to the C2-amino position of a guanine residue.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of DNA binding of the NF-Y transcription factor by the pyrrolobenzodiazepine-polyamide conjugate GWL-78

Kotecha

Kluza

Wells

et al. 2008

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Many genes involved in cell cycle control have promoters that bind the heterotrimeric transcription factor NF-Y. Several minor-groove binding drugs have been shown to block interactions of transcription factors with cognate DNA-binding sequences. We showed previously that noncovalent minor-groove binding agents block interactions of NF-Y with the promoter of topoisomerase IIA (topo IIA). In this study, we investigated the ability of GWL-78, a pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugate, to inhibit the binding of NF-Y to DNA. Electrophoretic mobility shift assays showed that GWL-78 could displace NF-Y bound to several CCAAT motifs within promoters of genes involved in cell cycle progression. DNase I footprinting of the topo IIA promoter confirmed binding of GWL-78 to AT-rich sequences corresponding to the preferred binding site of NF-Y. Incubation with GWL-78 resulted in displacement of NF-Y binding to DNA. Chromatin immunoprecipitation assays on the topo IIA promoter showed that GWL-78 was able to enter the nucleus and interact with specific DNA sequences. Treatment of NIH3T3 cells with GWL-78 resulted in a block of cell cycle progression, which did not involve activation of p53. Thus, agents such as GWL-78 may be useful in modulating transcription and blocking cellular proliferation.

show abstract

Section: Introductionmentioning

confidence: 99%

Inhibition of DNA binding of the NF-Y transcription factor by the pyrrolobenzodiazepine-polyamide conjugate GWL-78

Kotecha

Kluza

Wells

et al. 2008

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…After evaporation, the residue was purified by column chromatography on silica gel. The eluates of n-hexane -isopropylether (iPE) (7: 3) were evaporated and the residue was recrystallized from n-hexane -iPE (1: 1) to give 9E (5.9 g, 58 %), mp 95-96°C: IR (Nujol) 1755, 1695 cm-1: NMR (90°C, DMSO-d6) 6 (Z)-N-t-Butoxycarbonyl-4-ethylidene-L-proline Diphenylmethyl Ester (9Z) To a suspension of potassium t-butoxide (20.4 g) in dry THE (720 ml) were added 85) (51.4 g) and ethyltriphenylphosphonium bromide (67.6 g) under a nitrogen atmosphere. The mixture was refluxed for 45 minutes with stirring and evaporated in vacuo.…”

Section: Methodsmentioning

confidence: 99%

“…6) In this paper we will describe the total syntheses of E-(IE) and Z-tomaymycins (1Z) and their antibacterial activity. by the method of STAAB'7) gave the corresponding aldehyde (5) in 76 % yield.…”

Section: Tomaymycin1mentioning

confidence: 99%

“…by the method of STAAB'7) gave the corresponding aldehyde (5) in 76 % yield. Hydrogenation of 5 in the presence of 10 % Pd-carbon gave a pyrrolo(1,4)benzodiazepine derivative (6) in 89 % yield. However, attempted oxidation of 6 by a number of methods did not produce the desired ketone (7), because 6 was unstable under acidic or basic conditions.…”

Section: Tomaymycin1mentioning

confidence: 99%

See 1 more Smart Citation

Studies on tomaymycin. II total syntheses of the antitumor antibiotics, E-and Z-tomaymycins.

Tozuka

Takasugi

Takaya³

1983

J. Antibiot.

View full text Add to dashboard Cite

The total syntheses of naturally occurring E-tomaymycin (1E) and its olefinic geometrical isomer, Z-tomaymycin (1Z) are described. The Z-isomer was found to have the same antibacterial activity as E-isomer (IE).Tomaymycin1) is an antitumor antibiotic possessing the pyrrolo(1,4)benzodiazepine skeleton, such as anthramycin2), neothramycin3), and sibiromycin4). In a previous paper5), we reported the structural determination of tomaymycin on the basis of NMR spectra. The structure of naturally occurring Etomaymycin (1E) was determined as (11R, I1aS)-(E)-2-ethylidene-2,3,5,10,11,11 a-hexahydro-8-hydroxy-7,11-dimethoxy-5 -oxo-1 H-pyrrolo(2,1-c)-(1,4)benzodiazepine, although its plane structural t formula has been determined by the chemical degradation method.6) In this paper we will describe the total syntheses of E-(IE) and Z-tomaymycins (1Z) and their antibacterial activity. by the method of STAAB'7) gave the corresponding aldehyde (5) in 76 % yield. Hydrogenation of 5 in the presence of 10 % Pd-carbon gave a pyrrolo(1,4)benzodiazepine derivative (6) in 89 % yield. However, attempted oxidation of 6 by a number of methods did not produce the desired ketone (7), because 6 was unstable under acidic or basic conditions. Therefore, the introduction of the ethylidene group into the pyrrole ring by the WITTIG reaction must be done before cyclization to a pyrrolo(1,4)benzodiazepine derivative. In a previous paper5) the WITTIG reaction of N-t-butoxycarbonyl-4-oxo-L-proline diphenylmethyl ester (8) according to the modified procedure reported by BETHELL et al.8) gave a mixture of the corresponding 4E-and 4Z-ethylidene derivatives (9E, 9Z), which were separated by repeated column chromatography on silica gel.

show abstract

“…The antibiotic has ant|tumor and antiprotozoal activity. Tomaymycin was first isolated by Arima, Kohsaka, Tamura, Imanaka & Sakai (1972) and the structure was reported by Kariyone, Yazawa & Kohsaka (1971). Sibiromycin was isolated and partially characterized by Gause, Preobrazhenskaya, Ivanitskaya & Sveshnikova (1969), but the complete structure was determined by Mesentsev, Kuljaeva & Rubasheva (1974).…”

Section: Introductionmentioning

confidence: 99%

Structural investigations of mode of action of drugs. II. Molecular structure of anthramycin methyl ether monohydrate

Arora¹

1979

Acta Crystallogr Sect B

View full text Add to dashboard Cite

The crystal and molecular structure of CxTHt9N304. H20, an ant|tumor agent, has been determined using X-ray diffraction. The space group is orthorhombic, P2~ 2 ~ 21. The cell dimensions, measured on a diffractometer, are a = 7.984 (1), b = 13.495 (3), c = 16.200 (3) A, and Z = 4. The structure was solved by direct methods and refined by anisotropic least squares to an R index of 0.050. The 1,4-diazepine ring has a boat conformation while the five-membered pyrrole ring is a flattened envelope. The stereochemistry at C(12) and C (13) is trans. There are one intramolecular and five intermolecular hydrogen bonds. One interesting feature is the involvement of the methoxy O atom in hydrogen bonding. A Kendrewmodels study indicates that the anthramycin molecule is most probably covalently bound at C(11) to DNA through N(2) of guanine in the wide groove and also O(1) of the anthramycin molecule may be involved in hydrogen bonding to sugar O atoms.

show abstract

The Structures of Tomaymycin and Oxotomaymycin

Cited by 57 publications

References 0 publications

Inhibition of DNA binding of the NF-Y transcription factor by the pyrrolobenzodiazepine-polyamide conjugate GWL-78

Inhibition of DNA binding of the NF-Y transcription factor by the pyrrolobenzodiazepine-polyamide conjugate GWL-78

Studies on tomaymycin. II total syntheses of the antitumor antibiotics, E-and Z-tomaymycins.

Structural investigations of mode of action of drugs. II. Molecular structure of anthramycin methyl ether monohydrate

Contact Info

Product

Resources

About