Pyrimidines, antitumour

Most drugs in the pyrimidine series fall into four categories the barbiturates, the sulfonamides, the antimicrobials and the antitumour agents. In addition there are innumerable pyrimidines with diverse biological activities, some of which are in use. 

Pyrimidine, 4-fluoro-2-isopropyl-synthesis, 3, 140 Pyrimidine, 4-fluoro-2-methoxy-synthesis, 3, 140 Pyrimidine, 4-fluoro-2-methyl-NMR, 3, 63 Pyrimidine, halo-aleoholysis, 3, 100 aminolysis, 3, 99 as antitumour agents, 3, 152 bipyrimidines from, 3, 103 Buseh biaryl synthesis, 3, 103 hydrolysis, 3, 101... 

An excellent antineoplastic potency against the murine neoplasm Sarcoma 180 has been observed with arylsulphonylhydrazones derived from pyridazine-3-carboxaldehyde 2-oxide (85) [298]. These compounds were prepared in the U.S.A. in order to investigate the effect of the incorporation of an additional nitrogen atom into antitumour active pyridine 1-oxide congeners. Interestingly, the pyridazine-derived compounds (85, R = H, Me, MeO) proved to be superior to the corresponding pyridine derivatives, whereas the analogous pyrimidine-4-carboxaldehyde 3-oxide derivatives were found to be devoid of activity. 

Clinically, this pyrimidine was found to produce prohibitive gastrointestinal and vascular toxic reactions at intravenous doses from 0.3 to 10 mg/kg and total doses of 1.25 to 126 mg/kg for periods up to 60 days. It is not considered to be an agent with significant antitumour effect [333]. 

Much interest has been shown in pyrimidines having unsaturated substituents because of the in vitro antitumour and antiviral activity of such compounds. Routes to 5-ethynyluracil (168)... 

Alloxan 29 is formed in organisms by the oxidative degradation of uric acid (see p 414). Willardiin 30 is a nonproteinogenic a-amino acid with a uracil structure which is present in the seeds of some types of acacia. A few pyrimidine antibiotics, especially those isolated from streptomyces, possess potent antitumour properties, e.g. the structurally complex bleomycins 31. The commercial product is a mixture of various bleomycins, main components being bleomycins A2 (55-70%) and B2 (25-32%). 

Fluorination using DAST was employed in the synthesis of the 2 -deoxy-2 -fluoro-P-D-arabinofuranoside of 6-chloropurine (64), and a number of pyrimidine nucleosides with a 2 -deoxy-2 -fluoro-p-L-arabinofuranose unit have been prepared using base-sugar coupling procedures the thymine compound 65 (l-FMAU) had particular potency against The synthesis and antitumour activity of 2, 2 -difluoro-deoxycytidine (gemcyta-bine) has been reviewed by workers at Eli Lilly. ... 

A further very well-defined cationic series with antitumour activity is the triamine series c/5-[PtCl(NH3)2(py)], where py is a substituted pyridine ligand, purine or pyrimidine [120]. Unlike the sulfoxide complexes, mechanistic studies indicate that the pyridine ligand is not lost upon reaction with DNA and thus there is the possibility that these complexes... 

The platinum—pyrimidine blues, derived from cisplatin, are an interesting class of complexes with antitumour activity. They were first discovered as a result of studies on the interaction of c/ [PtCl2(NH3)2] and its aquated products with pyrimidines. The identification of DNA as the target for platinum attack naturally led to a systematic study of the reactions of the complex with nucleic acid constituents. The observation that with polyuridine no immediate reaction took place but that a blue color slowly developed in solution, from which a blue solid could be isolated, led to the preparation of a series of complexes containing substituted uracils and thymines. 

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