Antitumour imidazotetrazines. Part 31. The synthesis of isotopically labelled temozolomide and a multinuclear (1H, 13C, 15N) magnetic resonance investigation of temozolomide and mitozolomide

Wheelhouse, Richard T.; Wilman, D. E. V.; Thomson, W.; Stevens, Malcolm F. G.

doi:10.1039/p19950000249

Cited by 24 publications

(30 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This value is very close to previously reported 1 J(N,H) coupling constants. 2 The value of these 15 N chemical shift assignments is evident in the analysis of the 15 N NMR spectrum of 3-(carbamoylmethyl)-4-imino-1,2,3-benzotriazine (3). In an independent study, 5 a series of 1-aryl-3-carbamoylmethyltriazenes, ArN N-NH-CH 2 CONH 2 , were prepared and characterized.…”

Section: Spectroscopy Techniquesmentioning

confidence: 98%

See 1 more Smart Citation

A ¹⁵N NMR investigation of a series of benzotriazinones and related antitumour heterocycles

Vaughan¹,

Wilman²,

Wheelhouse³

et al. 2002

Magnetic Reson in Chemistry

Self Cite

View full text Add to dashboard Cite

A series of 3-substituted 1,2,3-benzotriazin-4-ones, 1 and 2, were synthesized by standard methods and the 15 N NMR spectra were recorded. All spectra were obtained using the natural abundance of the nitrogen-15 isotope. The chemical shifts appear in the normal range for N-1, N-2 and N-3 of the triazine ring, and also correlate with the chemical shifts in the spectra of the imidazolotriazinone, 4, and the imidazolotetrazinone, 5. Significantly, the spectra of 1a, 2 and 4, recorded with full NOE, show inversion of the singlet assigned to N-3, demonstrating that these compounds exist in the tautomeric form shown. The structure of the 4-iminobenzotriazinone (3) was confirmed by this 15 N NMR analysis. The spectrum shows a signal for the NH-bearing imino-nitrogen atom, which is an inverted singlet in the NOE spectrum, whereas the signal from the N-3 atom of 3 is not inverted in the NOE spectrum.

show abstract

Section: Spectroscopy Techniquesmentioning

confidence: 98%

“…1 A previous study 2 reported a multinuclear NMR study of temozolomide and the related drug mitozolomide. The …”

Section: Introductionmentioning

confidence: 98%

A ¹⁵N NMR investigation of a series of benzotriazinones and related antitumour heterocycles

Vaughan¹,

Wilman²,

Wheelhouse³

et al. 2002

Magnetic Reson in Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although use of these reaction solvents results in clinical grade material, reaction times are very slow due to the insolubility of diazo-IC, typically taking several weeks to reach completion [20]. More recent synthetic protocols generally employ DMSO as the reaction solvent, giving rise to much faster reaction times [26,43]. Attempts using a range of imidazolonium and phosphonium ionic liquids failed to improve on the rate, yield or purity of the DMSO reaction [44].…”

Section: Synthesis Of Temozolomide and The Imidazotetrazine Corementioning

confidence: 99%

The Medicinal Chemistry of Imidazotetrazine Prodrugs

Moody

Wheelhouse

2014

Pharmaceuticals

View full text Add to dashboard Cite

Temozolomide (TMZ) is the standard first line treatment for malignant glioma, reaching “blockbuster” status in 2010, yet it remains the only drug in its class. The main constraints on the clinical effectiveness of TMZ therapy are its requirement for active DNA mismatch repair (MMR) proteins for activity, and inherent resistance through O6-methyl guanine-DNA methyl transferase (MGMT) activity. Moreover, acquired resistance, due to MMR mutation, results in aggressive TMZ-resistant tumour regrowth following good initial responses. Much of the attraction in TMZ as a drug lies in its PK/PD properties: it is acid stable and has 100% oral bioavailability; it also has excellent distribution properties, crosses the blood-brain barrier, and there is direct evidence of tumour localisation. This review seeks to unravel some of the mysteries of the imidazotetrazine class of compounds to which TMZ belongs. In addition to an overview of different synthetic strategies, we explore the somewhat unusual chemical reactivity of the imidazotetrazines, probing their mechanisms of reaction, examining which attributes are required for an active drug molecule and reviewing the use of this combined knowledge towards the development of new and improved anti-cancer agents.

show abstract

“…Moreover, DPU has been extensively studied for application as synthetic intermediates especially for the production of carbamates and isocyanates [9][10][11][12][13][14][15][16][17][18][19][20][21][22], whose importance both in industrial and academic fields is well known. Traditionally, aromatic isocyanates and carbamates are prepared on a commercial scale from aromatic nitro compounds, which are first catalytically hydrogenated to the corresponding amine.…”

Section: Introductionmentioning

confidence: 99%

Phosgene-free synthesis of 1,3-diphenylurea via catalyzed reductive carbonylation of nitrobenzene

Vavasori

Ronchin

2012

Pure and Applied Chemistry

View full text Add to dashboard Cite

1,3-Diphenylurea (DPU) has been proposed as a synthetic intermediate for phosgene-free synthesis of methyl N-phenylcarbamate and phenyl isocyanate, which are easily obtained from the urea by reaction with methanol. Such an alternative route to synthesis of carbamates and isocyanates necessitates an improved phosgene-free synthesis of the corresponding urea. In this work, it is reported that Pd(II)-diphosphine catalyzed reductive carbonylation of nitrobenzene in acetic acid (AcOH)-methanol proceeds in high yield and selectivity as a one-step synthesis of DPU. We have found that the catalytic activity and selectivity of this process depends on solvent composition and on the bite angle of the diphosphine ligands. Under optimum reaction conditions, yields in excess of 90 molar % and near-quantitative selectivity can be achieved.

show abstract

Antitumour imidazotetrazines. Part 31. The synthesis of isotopically labelled temozolomide and a multinuclear (1H, 13C, 15N) magnetic resonance investigation of temozolomide and mitozolomide

Cited by 24 publications

References 11 publications

A ¹⁵N NMR investigation of a series of benzotriazinones and related antitumour heterocycles

A ¹⁵N NMR investigation of a series of benzotriazinones and related antitumour heterocycles

The Medicinal Chemistry of Imidazotetrazine Prodrugs

Phosgene-free synthesis of 1,3-diphenylurea via catalyzed reductive carbonylation of nitrobenzene

Contact Info

Product

Resources

About

Antitumour imidazotetrazines. Part 31. The synthesis of isotopically labelled temozolomide and a multinuclear (1H, 13C, 15N) magnetic resonance investigation of temozolomide and mitozolomide

Cited by 24 publications

References 11 publications

A 15N NMR investigation of a series of benzotriazinones and related antitumour heterocycles

A 15N NMR investigation of a series of benzotriazinones and related antitumour heterocycles

The Medicinal Chemistry of Imidazotetrazine Prodrugs

Phosgene-free synthesis of 1,3-diphenylurea via catalyzed reductive carbonylation of nitrobenzene

Contact Info

Product

Resources

About

A ¹⁵N NMR investigation of a series of benzotriazinones and related antitumour heterocycles

A ¹⁵N NMR investigation of a series of benzotriazinones and related antitumour heterocycles