Joan E. McCormick

Nitrosoureas from chemist to physician: classification and recent approaches to drug design.

Molecular design of chemotherapeutic nitrosoureas is reviewed in the light of a chemical classification of N-(2-chloroethyl)-N-nitrosoureas (CNUs), particularly those recently introduced and earlier compounds tested in the clinic. Of the six categories, three are rather arbitrarily based on physicochemical properties: the original, lipid-soluble drugs, water-soluble sugar derivatives, and amides of intermediate character. Others deal with more complex drug designs incorporating antimetabolites (5-fluorouracil), steroids, redox delivery systems, or hypoxia-selective 2-nitroimidazoles. Current attempts to modify the standard 2-chloroethyl group, with implications for interstrand cross-linking of DNA, are considered. Two unfortunate factors influencing the choice of drugs for clinical trial have been prejudice from the physician and commercial interests. The latter requires no further comment, but a strong plea is made for recognition of the CNU group as one of comparatively few valuable tools for rational drug design requiring appropriate pharmacokinetic evaluation, rather than as a somewhat boring hallmark of repetitive chemists.

The reaction of the periodate-oxidation products of 1,4-anhydroerythritol and of some related pyrrolidine glycols with thiosemicarbazides

Abstract Simple analogues of the dialdehyde formed by periodate oxidation of benzyl β- L -arabinopyranoside have been prepared. Oxydiacetaldehyde may be condensed with one or two moles of substituted thiosemicarbazides, whereas N -aryliminodiacetaldehydes give only bis(thiosemicarbazones). The oxidation of N -arylpyrrolidine-3,4-diols with one equivalent of periodate is straightforward if electron-attracting aromatic substituents are present, but, otherwise, some cleavage of NC bonds in the pyrrolidine ring can be demonstrated. The crystalline hemialdal, 2,6-dihydroxy-4-phenylmorpholine, was isolated. The rates of conversion of some α-functionally-substituted thiosemicarbazones into glyoxal derivatives have been compared.

Nucleoside analogues. Part 12. The anomalous 19F NMR spectrum of B.3996, a molecular combination of 5-fluorouracil and N-(2-chloroethyl)-N-nitrosourea and synthesis of its N′-nitroso isomer and related compounds

In an attempt to explain the two signals in the 19F NMR spectrum of the 5-fluorouracil (5-FU)/N(2-chloroethyl)-N-nitrosourea (CNU) molecular combination B.3996, we synthesised the isomeric N(2-Chloroethyl)-N′-nitrosourea (isoCNU) by an unequivocal route involving N-nitrosation of an aryl carbamate bearing the appropriate pyrimidine-containing N-substituent. In the event, this isoCNU was not responsible for the second peak in the 19F NMR spectrum, but itself showed two peaks. The 1H NMR spectra at 300 MHz of these sulphides and the two corresponding N′-isomers and the two methoxy CNU analogues confirmed that a combination of methylthio/N3-substitution is necessary for the duplication pattern. In the compounds which show this behaviour, it is suggested that the Z and E isomers (around the N–NO system) equilibrate at a rate slower than the NMR time scale. This may have implications for the mechanism of biological action of 8.3996.

Nucleoside analogues. Part 10. Synthesis of three unusual 5-fluorouracil seco-nucleosides incorporating N-(2-chloroethyl)-N-nitrosourea residues

Seco-nucleosides in which 5-fluorouracil (5-FU) is attached at N3 cannot be synthesised when the heteroatom is O by the methods effective when it is S. An N-phthaloyl representative of this class has now been made from a suitably protected pyrimidine and converted into the corresponding N-(2-chloroethyl)-N-nitrosourea (CNU), a molecular combination of anti-tumour drugs of great interest for comparison with other closely related structures. Further, the successful manipulation of the carboxy group in the standard synthetic scheme has led to the preparation of the first molecular combination incorporating this function. Thirdly, hydrazinolysis of phthalimido-CNUs has made possible the construction of complex drugs with both CNU and MNU (N-methyl-N-nitrosourea) moieties, thus achieving regiospecific location of two N-nitroso groups in molecules with four dissimilar urea NHs. All these drugs are undergoing anti-tumour evaluation, the effect of the CNU-MNU combinations on a repair enzyme of DNA metabolism being of additional significance.

Nucleoside analogues. Part 2. Further molecular combinations of (5-substituted) uracil and N-(2-chloroethyl)-N-nitrosourea residues as anticancer agents

To assess the contribution of 5-fluorouracil (5-FU) to the antitumour activity observed in B.3829 (1), the original molecular combination of 5-FU and N-(2-chloroethyl)-N-nitrosourea residues, the antimetabolite has been replaced by thymine and by uracil. The pyrimidine 5-substitutent influenced the ratio of N1:N3 seco-nucleosides formed at the outset of the synthesis, and later the production of bicyclic bases by intramolecular addition across the 5,6-double bond. To provide drugs from which 5-FU would be cleaved more readily than from B.3829, first the antimetabolite has been attached at a different point (N3 instead of N1) although the intermediates proved more difficult to crystallise; and secondly, the methylthio group attached to the ‘anomeric’ carbon has been replaced by methylsulphinyl and by alkoxy. Investigation of alternative synthetic sequences confirmed that alkoxy groups had to be incorporated at an early stage, and, since they were sensitive to HBr, base-catalysed isomerisation of the bicyclic bases was necessary, best yields being obtained with the trifluoroacetyl derivatives. N3-Substituted uracil derivatives with alkoxy groups could be prepared, but not the 5-fluoro analogues.

Thio-sugars. Part 1. 4-Thiotetrose derivatives via Pummerer rearrangement

A number of 4-thiotetrose derivatives have been prepared by Pummerer rearrangement of esters of thiolan-3,4-diol 1-oxides. This synthesis illustrates the key step in a general scheme for the elaboration of glycosides and nucleosides containing sulphur in the sugar ring. In using non-sugar starting materials, it differs from other methods of obtaining these compounds. Several esters have been studied, and the protecting and directing properties of the phenylboronate function were found especially useful. The stereochemistry of the Pummerer rearrangement products is discussed, and the bicyclic phenylboronate and carbonate systems are compared. Many of the reactions are of great preparative value. The S-oxidation and rearrangement steps can be repeated, giving symmetrical bicyclic derivatives of tartaraldehyde. (Diacetoxyiodo)benzene or t-butyl perbenzoate converts esters of thiolan-3,4-diol directly into α-acyloxy-compounds, but in poor yield.

Thio-sugars. Part 3. 4-Thiotetrofuranose nucleosides

Nucleosides have been prepared for biological testing with 6-substituted purines, theophylline, and 5-substituted uracils as bases and 4-thio-DL-erythrofuranose and 4-thio-DL-threofuranose as sugars. 1-O-Acetyl-4-thioerythrofuranose 2,3-phenylboronate has again proved a valuable synthetic intermediate, yielding under mild conditions the purine nucleoside esters in the presence of toluene-p-sulphonic acid and the pyrimidine compounds from the silylated bases with tin(IV) chloride. The corresponding 2,3-dibenzoates of both sugars were also used, but in all cases the uracil N3-nucleosides were obtained.

Thio-sugars. Part 2. Glycosides from acid-catalysed reactions of 1-O-acetyl-2,3-di-O-acyl-4-thiotetrofuranoses

Alcohols and thiols in presence of toluene-p-sulphonic acid readily displace the 1-O-acetyl group from the title compounds, now available by Pummerer rearrangement of the appropriate sulphoxides, thus providing a very convenient synthesis of these thio-sugar glycosides. Glycosyl bromides can also be prepared. The advantages of the phenylboronate function described in Part 1 are further illustrated. O-Glycosides are formed with a high degree of stereoselectivity, S-glycosides are not. Toluene-ω-thiols with electron-repelling substituents react normally, but the corresponding alcohols are acetylated rather than glycosylated. A disaccharide (glycosyl glycoside) has been prepared. Other esters give lower yields of glycosides than the phenylboronates. The reactions with hydrazides of the substituted 3-heteraglutaraldehydes from periodate oxidation of some of these glycosides and related nucleosides were compared with earlier examples.