Synthesis of bis(aziridinyl)phosphinyl-N-hydroxyurethane derivatives as antineoplastic agents

Yy, Hsiao; Tj, Bardos; Gl, Wampler; Regelson, William

doi:10.1021/jm00236a019

Cited by 13 publications

(15 citation statements)

References 7 publications

(18 reference statements)

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“…Column chromatography (silica gel, elution with 0-5% MeOH gradient in CH2C12) yielded 8 as a white, solid foam. Crystallization from ethanol/water afforded 2.9 g (81%) of H, SiCH3), 0.89 (s, 9 H, C(CH3)3), 1.92 (s, 3 H, C5-CH3), 2.39 (t, 2 H, 2'-H), 2.96 (br s, 1 H, 4'-H), 3.92 (br s, 3 H, 5'-and 3'-H), 4.50 (br s, 1 , 5'-OH), 6.18 (t, 1 H, l'-H), 7.43 (s, 1 H, C6-H), 9.32 (br s, 1 H, N3-H). Anal.…”

Section: Methodsmentioning

confidence: 99%

“…The filtrate was evaporated to dryness and then placed under high vacuum to give 4 as a white solid foam: NMR (CDC13) 0.16 (s, 6 H, CH3), 0.94 (s, 9 H, CH3), 1.45 (s, 12 H, aziridine CH3), 2.1 (s, 3 H, C5-CH3), ca. 2.25 (m, 2 H, 2'-H), 2.40 (d, 4 H, aziridine CH2, JPH = 14 Hz), 3.95 (s, 3 H, 5'-H and 4'-H), 4.10 (s, 1 , 3'-H), 6.01 (d, 1 H, carbamate N-H), 7.65 (s, 1 H, C6-H), 9.85 (br, 1 H, N3-H). Improved Synthesis of 3'-0-(p-Methoxytrityl)thymidine (12).…”

Section: Methodsmentioning

confidence: 99%

“…3'-0-Acetyl-5'-0-[[bis(2,2-dimethyl-l-aziridinyl)phosphinyl]carbamoyl]thymidine (6). The preparation of this compound from 3'-O-acetylthymid ine18 was analogous to that of its isomer 5, except that the final product was crystallized from chloroform/hexane to give 0.380 g (70%) of 6 as white plates: mp 141-143 °C; NMR (CDC13) 1.43 (s, 12 H, aziridine CH3), 1.82 (s, 3 H, C5-CH3), 2.1 (s, 3 H, acetyl), 2.30 (d, 4 H, aziridine CH2, JPli = 14 Hz), 2.2 (m, 2 H, 2'-H), 4.23 (br s, 1 H, 3'-H), 4.38 (br s, 2 H, 5'-H), 5.33 (br, 1 H, 4'-H), 6.43 (t, 1 H, l'-H), 7.43 (s, 1 H, C6-H), 8.45 (br d, 1 H, carbamate N-H), 10.58 (br, 1 H, N3-H).…”

Section: Methodsmentioning

confidence: 99%

“…The isomeric CDFi mice per dosage tested. 6 Average weight change of mice. "Highest dose level evaluated.…”

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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The isomeric CDFi mice per dosage tested. 6 Average weight change of mice. "Highest dose level evaluated.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Breiner¹,

Rose²,

Dunn³

et al. 1990

J. Med. Chem.

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“…59 O-Benzyl-N-hydrourethane 157 is used as the starting material and reacts with phosphorus oxychloride to give the corresponding compound 158 by P−N bond formation. Subsequent reaction with 2,2-dimethylaziridine gives O-benzyl-N-phosphinyl derivative 159 (Scheme 54).…”

Section: Phosphorus N-substituted Hydroxamic Acid Derivativesmentioning

confidence: 99%

Phosphorus substituted hydroxylamine and hydroxamic acid derivatives: synthesis and reactivity

Alonso¹,

Santos²,

Vicario³

et al. 2011

Arkivoc

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Dedicated to Prof. Julio Alvarez-Builla on the occasion of his 65 th anniversary AbstractThis review summarizes several reports concerning the synthesis and synthetic applications of hydroxylamines derived from phosphines, phosphine oxides and phosphonates, and phosphorus substituted hydroxamic acid derivatives. The first section outlines the synthesis and reactivity of phosphorus O-substituted and N-substituted hydroxylamines as well as several transformations of phosphorus substituted hydroxylamines including: rearrangement, hydrolysis, reduction and oxidation reactions. The second part of the review covers the synthesis and reactivity of phosphorus O-, N-, and C-substituted hydroxamic acid derivatives.

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Aziridines

Deyrup¹

1983

Chemistry of Heterocyclic Compounds: A Series of Monographs

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Synthesis of bis(aziridinyl)phosphinyl-N-hydroxyurethane derivatives as antineoplastic agents

Abstract: Several new "dual antagonists" were synthesized in which the 2,2-dimethyl (or ring C unsubstituted) aziridine phosphinyl function is linked to N-hydroxyurethane rather than the urethane moiety. Three of the new compounds showed very high activities against leukemia L1210 in mice.

Cited by 13 publications

References 7 publications

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

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

Phosphorus substituted hydroxylamine and hydroxamic acid derivatives: synthesis and reactivity

Aziridines

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