Antitumour agent

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... 

Anticancer agents — see Antibiotics, Antitumour agents Anticonvulsant drugs, 3 (1963) 261 ... 

Platinum antitumour agents, 24 (1987) 129 Platelet aggregration, inhibitors of,... 

The starting point of this article is the discovery by Rosenberg and his collaborators of the activity of certain platinum compounds as antitumour agents (7). Here we wish to introduce the chemistry of these agents, which will be relatively familiar to inorganic chemists, but not to chemists and biochemists of other disciplines. At the same time we wish the inorganic chemist to see the relevance of the chemistry to biological fields. 

The most potent antitumour agent isovanilic isomer la has been synthesized in 11 steps starting from isovanillin 271 (Scheme 49) <2001BML2205>. 

Various pyridazine-A-oxides (including cinnoline A-oxides) have been prepared as potential antitumour agents in Japan [276-278]. Among several 4-nitro-pyridazine 1-oxides tested for activity against rat ascites hepatoma AH-13, 3,6-dimethoxy-4-nitropyridazine 1-oxide (74) has been found to be the most potent compound a minimal effective dose of 5 mg/kg has been estimated [276], Also pyridazine A-oxides of type (75) bearing a bis(2-chloroethyl)ami-nomethyl side-chain at C-6 have been reported to be effective (0.5-5 mg/kg, i.p.) against AH-13 in rats [278]. Both types of compound (74), (75, R = H, Br), however, have been shown to be inactive against mouse lymphoid leukaemia L-1210. 

J. I. Brodfuehrer, T. J. Wilke, G. Powis, Pharmacokinetics and Metabolism of the Antitumour Agent Sulphamic Acid 1,7-Heptanediyl Ester (Sulphamic Acid Diester) in the Mouse and Ebagle Dog , Cancer Chemother. Pharmacol. 1988, 22, 120-129. 

Taxol (Paclitaxel) 137, a natural product derived from the bark of the Pacific yew, Taxus brevifolia [213-215], and the hemisynthetic analogue Docetaxel (Taxotere) 138, two recent and promising antitumour agents, have been the matter of extensive in vivo and in vitro animal metabolic studies. The major metabolites of taxol excreted in rat bile [216] were identified as a C-4 hydroxylated derivative on the phenyl group of the acyl side chain at C-13 (139), another aromatic hydroxylation product at the mefa-position on the benzoate group at C-2 (140) and a C-13 deacylated metabolite (baccatin III, 142) the structure of six minor metabolites could not be determined. The major human liver microsomal metabolite, apparently different from those formed in rat [217], has been identified as the 6a-hydroxytaxol (141) [218, 219]. A very similar metabolic pattern was... 

A similar approach to a DCL of bivalent ligands linked by flexible disulfide spacers was taken by Daiueli and coworkers [24]. Their library consisted of the antitumour agents thiocolchicine and podophyllotoxin, derivatized to form disulfide-linker homo- and heterodimers (Scheme 2.5). The components could be effectively exchanged in the presence of catalytic thiol in orgaiuc solvents. 

H. Ouadid-Ahidouch, and J. M. Garcia Fernandez, Synthesis of N-, S-, and C-glycoside castanosper-mine analogues with selective neutral a-glucosidase inhibitory activity as antitumour agents, Chem. Commun., 46 (2010) 5328-5330. 

Rosenberg B, VanCamp L, Trosko J, Mansour VH. Platinum compounds a new class of potent antitumour agent. Nature 1969 222 385-386. 

As part of the total synthesis of the triterpene (+)-a-onocerin, one of the first total syntheses in which RuO played a key role, a diphenylethyleneacetoxyketone was oxidised to the corresponding acetoxyketoacid by RuO /aq. Na(10yacetone. Aromatic ring oxidation was also involved (cf. 3.3.1 below) [219]. An oxidative cyclisation of a 1,5-diene to a diol by RuCl3/Na(10 )/wet SiO /THF formed part of the synthesis of the antitumour agent cw-solamin [220]. 

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