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Decomposition of 1-(azidophenyl)-4,6-diamino-1,3,5-triazines 11-13 and their 4-amino-6-(azidoanilino) 1,3,5-triazine isomers 31-33 in trifluoromethanesulphonic acid at 0° led to the introduction of the triflate group (OSO 2 CF 3 ) into the aryl group. This method can be employed to introduce a bulky substituent into the hindered position ortho to the triazinyl substituent. Dimroth rearrangement of 1-(aryl)-4,6-diamino-1,3,5-triazines is best effected in refluxing ethanolic pyridine

Decomposition of 1-(azidophenyl)-4,6-diamino-1,3,5-triazines 11-13 and their 4-amino-6-(azidoanilino) 1,3,5-triazine isomers 31-33 in trifluoromethanesulphonic acid at 0° led to the introduction of the triflate group (OSO 2 CF 3 ) into the aryl group. This method can be employed to introduce a bulky substituent into the hindered position ortho to the triazinyl substituent. Dimroth rearrangement of 1-(aryl)-4,6-diamino-1,3,5-triazines is best effected in refluxing ethanolic pyridine

The growth-inhibitory activities of an extensive series of quaternized quino[4,3,2- kl]acridinium salts against tumor cell lines in vitro have been measured and their biological properties interpreted in the light of differential binding to different DNA isoforms. Selectivity for quadruplex DNA binding and stabilization by compounds were explored through an array of methods: UV absorption and fluorescence emission spectroscopy, surface plasmon resonance, and competition dialysis. Quadruplex DNA interaction was further characterized through FRET and DNA polymerase arrest assays. Telomerase inhibition, inferred from the TRAP assay, is attributed to quadruplex stabilization, supported by the strong correlation (R(2) = 0.81) across the series between quadruplex DNA binding affinity and TRAP inhibition potency. Growth inhibition potency in the NCI60 human tumor cell line panel is more marked in compounds with greater DNA duplex binding affinity (R(2) = 0.82). Quantification of relative quadruplex and duplex binding affinity constants puts some of these ligands among the most selective quadruplex DNA interactive agents reported to date.

The preparation of 3-(2-chlorethyl)-4-oxo-3H-imidazo[5,1-d]-1,2,3,5- tetrazine-8-carboxylic acid, a key derivative of mitozolomide in our exploration of the structure-activity relationships of this class of antitumor agents, is described. The facile conversion to the 8-carbonyl chloride gave a derivative that reacted preferentially with nucleophiles at the 8-position rather than at the reactive 4-oxo group, allowing the preparation of a wide range of ester, thioester, amide (including an amide derived from an amino acid), hydroxamic acid, hydrazide and sulfoximide, azide and diazoacetyl derivatives. The in vivo activity is presented of a range of these compounds against TLX5 lymphoma and L1210 leukemia cell lines.

An objective observer tracking the literature relevant to the science of cancer treatment might conclude that all the important questions are now being engendered by advances in molecular biology. Whereas, in the last three decades, mathematicians, physicists and engineers led mankind in an exploration of the solar system, it will, so the molecular biologists argue, be a biology-driven space programme — one targeted at the innermost recesses of the cell itself — which will finally unravel the mysteries of the malignant state. However, even if the new biological revolution generates leaders with the vision of an Einstein or the imagination of an Arthur C. Clarke, it is unlikely that the power of molecular biology alone will give sufficient insights into how the disease might be cured even if it is fully understood.

A. Varnavas and colleagues (16) have synthesized 1,3-di (4-carboxyphenyl) triazene (I), which is a diaryltriazene analogue of the antimetastatic agent DM-COOK (II).

The apparent solubility of ABPP in aqueous solutions suitable for intravenous use was increased by cosolvent systems.The solubility of ABPP was determined as a function of pH and concentration of NaOH, NaCl, Na2CO3 and co-solvents. Partition coefficient of ABPP in Octanol/water systems were also determined at various pH values. Solubility data and spectrophotemetric methods were used to determine the pKa values. The solubility of the compound increased at lower and higher pHs with increasing NaOH and Na2CO3 concentrations and increasing PEG 400, Propylene glycol, dimethylformamide and dimethylacetamide concentrations but decreased with the introduction of NaCl to the solution. The apparent partition coefficient of ABPP showed similar but reversed dependence to the pH of the buffer system.From these results, suitable formulations for use as parenteral solutions are proposed. The increase in the apparent aqueous solubility of ABPP in such formulations my increase up to 800-fold, depending upon the pH and so...

The mass spectra of monocyclic 1,2,4-triazines and 1,2,4-triazines fused to a pyrazole ring through a bridgehead nitrogen have been investigated: fragmentation pathways were elucidated by the use of metastable ions and high resolution mass measurements. The spectra of the monocyclic 1,2,4-triazines indicate that loss of nitrogen from the molecular ions is a relatively unimportant feature. The decomposition modes of the bicyclic pyrazolo[3,2-c]-as-triazines are sensitive to the nature of the substituent in the triazine ring.

The mass spectra of twenty-one s-triazines have been interpreted. An unusual feature noted in the spectra of some of the compounds is transfer of a hydrogen atom of a side chain to a nitrogen atom of the s-triazine ring; two such shifts are suggested as a rationale for the unusual loss of nitrogen from a hydrazide derivative. The fragmentation of triamino- and some diamino- derivatives indicates that imino tautomers play a significant role. The spectra of aryldiamino s-triazines suggest that the site of a substituent in the aryl ring is important in some cases in directing the decomposition; some transitions have been rationalised on the basis of the juxtaposition of the substituent in relation to a nitrogen atom of the heterocyclic ring.

CCRG 81010 is one of the most potently active experimental antitumour agents which has been tested against murine tumours in vivo and it accomplishes the cure of animals bearing most of the ascitic or solid tumours (1–3). The rationale for its synthesis and screening arose from long term interests in the chemistry and pharmacology of molecules which contain triazene (N-N-N) linkages (4,5) and in the pharmacology of the nitrosoureas (6). Figure 1 shows the structure of CCRG 81010 together with that of the clinically useful antitumour triazene DTIC and a generalised formula for the chloroethylnitrosoureas. Structural similarities are apparent and indeed these similarities have been shown to extend to the broad spectrum of antitumour activity demonstrated by CCRG 81010 and to its mechanism of action, both of which will be outlined here.

Although the history of the development of 5- (3, 3-dimethyl-triazen-l-yl) imidazole-4-carboxamide (DTIC; NSC 45388) has been fully documented (1–5) a definitive account of the mode of action of the drug has yet to appear. There are almost as many theories purporting to explain the mode of action of DTIC as there are chemists and biochemists who, ensnared by the apparent deceptive simplicity of the molecule, have responded to the challenge but abjectly failed in the task of unravelling its perverse secrets.

A series of 1,2,3-benzotriazin-4(3H)-ones carrying 3-(4,6-diamino-s-triazin-2-ylphenyl) substituents has been prepared by diazotisation of appropriately substituted o-aminobenzamides, or by cyclisation of o-methoxycarbonyl-phenyltriazenes in ethanol containing 2% piperidine. Cyclisation of 1-p-(4,6-diamino-s-triazin-2-yl)phenyl-3-o-cyanophenyltriazene in ethanol–piperidine affords 3-p-(4,6-diamino-s-triazin-2-yl)phenyl-3,4-dihydro-4-imino-1,2,3-benzotriazine, which in 2N-hydrochloric acid rearranges to the isomeric substituted 4-anilino-1,2,3-benzotriazine. 4-p-Cyanoanilino-1,2,3-benzotriazine decomposes in alcohols containing 1% potassium hydroxide to give ethers; the scope of this reaction has been investigated.