Synthesis of 5'-thymidinyl bis(1-aziridinyl)phosphinates as antineoplastic agents

Hsiao, L. Y.; Bardos, Thomas J.

doi:10.1021/jm00139a024

Cited by 5 publications

(2 citation statements)

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“…NMR (CDCl3)/5% DMSO-d6) 1.42 (s, 12 H, aziridine CH3), 2.18 (d, 4 H, aziridine CH2, JpH = 14 Hz), 3.83 (br, 2 , 5'-H), 4.03 (br, 1 , 4'-H), 4.18 (br, 2 H, 3'-and 2'-H), 6.18 (br, 2 , 1'-and C6-H), 7.83 (d, 1 H, C6-H). Anal.…”

Section: Methodsmentioning

confidence: 99%

“…In our first attempt to achieve this, we coupled the phosphoraziridine moiety through an ester linkage to the S'-position of 3'-acetylthymidine; the resulting compound showed only moderate antitumor effects in vivo against L-1210 and P-388 leukemias in mice, but it was unexpectedly a potent inhibitor of horse serum cholinesterase. 7 This could be attributed to rapid hydrolysis of the phosphor-ester linkage; therefore, it was decided that the use of carbamate and amide linkages would be explored in the syntheses of new nucleoside phosphoraziridines. These are the subjects of the present paper.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of new nucleoside phosphoraziridines as potential site-directed antineoplastic agents

Breiner¹,

Rose²,

Dunn³

et al. 1990

J. Med. Chem.

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With the aim of increasing the selectivity of the 2,2-dimethylphosphoraziridine type antitumor agents toward the intracellular site of DNA synthesis, a series of new compounds was synthesized in which the reactive bis(2,2-dimethyl-1-aziridinyl)phosphinyl (2,2-DMAP) group was linked through a carbamate or amide linkage to thymidine or cytosine nucleoside moieties. The 3'- and 5'-(2,2-DMAP)carbamates of thymidine (1 and 2) were found to be highly unstable, therefore the corresponding O-acetyl derivatives 5 and 6 were prepared by reacting 5'- and 3'-acetylthymidine, respectively, with dichloroisocyanatophosphine oxide followed by the addition of 2,2-dimethylaziridine and triethylamine. The 3'- and 5'-(2,2-DMAP)amides of thymidine 14 and 15 were prepared by reacting the appropriate thymidinylamines with bis(2,2-dimethyl-1-aziridinyl)phosphinyl chloride (17). The N4-(2,2-DMAP)amides of cytidine, 2'-deoxycytidine, and cytosine arabinoside (18, 19, and 20, respectively) were prepared by reacting the hydrochlorides of the O-peracetylated cytosine nucleosides with triethylamine and POCl3 and, subsequently, with 2,2-dimethylaziridine and triethylamine, to give the corresponding N4-(2,2-DMAP)cytosine nucleoside peracetates 21, 22, and 23, respectively, which were then deacetylated by aminolysis. However, the peacetate intermediates were found to be more stable and, probably for the same reason, also more active against P388 leukemia in mice than the deacetylated products. Particularly, 22 and 23 showed sufficient activity in this in vivo assay system to warrant further evaluation. The relationships between the antitumor activities, the chemical alkylating activities, and the cholinesterase inhibitory activities of these agents are discussed.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%