Synthesis and chemotherapeutic effects of ethyl bis-(2, 2-dimethyl)-ethylenamido phosphate. A preliminary report

Chmielewicz, Z. F.; Bardos, Thomas J.; Munson, Albert E.; Babbitt, H.; Ambrus, Julian L.

doi:10.1002/jps.2600560929

Cited by 8 publications

(3 citation statements)

References 3 publications

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“…Following addition the resulting mixture was stirred in a cold room (4 °C) overnight (17 h) and then filtered to remove Et^N-HCl. The filtrate was evaporated to a white foam and chromatographed on a silica gel column pretreated with 1 % Et3N in methylene chloride, eluting with a gradient of 0-10% methanol in methylene chloride to afford 0.80 g (89%) of 5 as a white foam: mp 78-81 °C; NMR (CDC13) 1.45 (s, 12 H, aziridine CH3), 1.92 (s, 3 H, C5-CH3), 2.13 (s, 3 H, acetyl), 2.35 (d, 4 H, aziridine CH2, Jpx = 14 Hz), ca. 2.2 (m, 2 H, 2'-H), 4.35 (br, 3 H, 5'-H, and 4'-H), 5.27 (m, 1 H, 3'-H), 7.3 (s, 1 H, C6-H).…”

Section: Methodsmentioning

confidence: 99%

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%

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

Breiner¹,

Rose²,

Dunn³

et al. 1990

J. Med. Chem.

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“…These results suggest continuing interest in the clinical study of this agent. In the meantime, several other compounds containing the 2,2-dimethylaziridine moiety were synthesized and found to be effective against a spectrum of transplanted tumors in rodents (21)(22)(23)(24)(25)(26). Two of these agents, ethyl bis(2,2-dimethyl-l-aziridinyl)phosphinate (11) (23,24) and tris(2,2-dimethyl-l-aziridinyl)phosphine oxide (111) (25), which showed particularly potent activities against leukemia L-1210 in mice, passed through the preclinical pharmacology stage (24) and are presently undergoing preliminary evaluation against solid tumors in man.…”

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confidence: 99%

Reactions of 2,2-dimethylaziridine-type Alkylating Agents in Biological Systems I: Colorimetric Estimation and Stability in Physiological Media

Lalka

Bardos

1973

Journal of Pharmaceutical Sciences

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“…The dried (MgS04) ether yielded la as a green powder upon evaporation. (11) Mouse and chick screening were performed according to the standard profile described in T. S. Osdene, P. D. Russell, and L. Rane, ibid., 10,431 (1967). ( 12) Melting points were determined in a Mel-Temp apparatus and are uncalibrated.…”

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confidence: 99%

Synthesis and antimalarial activity of 4-aminobenzo[g-1,5]naphthyridines

Heindel¹,

Fine²

1970

J. Med. Chem.

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p-CH3C()NHCMfi CH:, p-CH3C()NHC6H4 215 dec" C17Hlg04N3S2 12 p-nh,c,h4 CM, p-NH2C"H4 224 dec" C13Hi302N3S2 13Pharmacology.-All the compounds were screened against Plasmodium gallinaceum in mosquitoes (Aedes aegypti). All the compounds except 5, 15, and 17 were screened against P. berghei in mice. Compounds 12 and 15 were also screened against P. gallinaceum in chicks. Compound 12 showed slight activity in the mouse test. At a dose level of 320 mg/kg, the mean survival time of the treated mice was 11.6 days and at a dose level of 640 mg /kg, it was 12.8 days. The mean survival time of the control mice wras 6.1 days. Compound 1 was assayed for antifolie acid activity in a bacterial system. It gave questionable activity wúth Streptococcus fecalis, but was inactive with Lactobacillus casei and Pediococcus cerevisiac. None of the other compounds showed any significant activity. All of the tests were carried out by contractors of the Walter Reed Army Institute of Research.

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Synthesis and chemotherapeutic effects of ethyl bis-(2, 2-dimethyl)-ethylenamido phosphate. A preliminary report

Cited by 8 publications

References 3 publications

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

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

Reactions of 2,2-dimethylaziridine-type Alkylating Agents in Biological Systems I: Colorimetric Estimation and Stability in Physiological Media

Synthesis and antimalarial activity of 4-aminobenzo[g-1,5]naphthyridines

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