Synthesis and properties of bis(2,2-dimethylaziridinyl)phosphinic amides: a series of new antineoplastic agents

Abstract

In continuation of efforts to improve the antitumor selectivity of the 2,2-dimethylaziridine class of alkylating agents, a series of N-substituted bis(2,2-dimethyl-1-aziridinyl)phosphinic amides has been synthesized and evaluated. All of these compounds (3-15) were tested in vivo against leukemia P-388 in mice, where most of them caused significant increase of survival time at nontoxic dose levels. Some of the most active compounds were also tested against leukemia L1210, B16 melanoma, and colon 26 carcinoma; in the latter tests, the parent unsubstituted amide 3 appeared to show the highest antitumor activity. Since the dose-limiting toxicity of the clinically tested prototypes of this class of anticancer agents AB-132 (1) and AB-163 (2) had been found to be CNS toxicity attributable mainly to the inhibition of cholinesterase, the compounds were tested in vitro against the cholinesterases from horse serum, electric eel, and bovine erythrocytes, as well as in vivo for the inhibition of the cholinesterase present in the whole blood of mice. In all of these assays, the various members of the present series showed a wide range of anticholinesterase activities, ranging from almost zero (for 3) to even higher potency than that of the prototype 2. A similarly wide range of stability was observed toward hydrolytic ring opening of the 2,2-dimethylaziridine moieties. Several of the compounds, particularly 3, deserve further study.

Molecular basis for bleomycin amplification: conformational and stereoelectronic effects in unfused amplifiers

“…Methods of Synthesis of Compounds 1-4 and 10-16 in the spectra of 8 and 9 permitted the unambiguous structural assignments for the two isomers. Biphenyl amino ethers [13][14][15] were prepared in the alkylation reaction of the respective phenylphenols 23-25 with 2-(dimethylamino)ethyl chloride. In the preparation of compound 16, 4,4,-dimethyl-2,2'-bipyridine (26) was brominated with IV-bromosuccinimide, and the resultant monobromo derivative 27 was reacted with sodium 2-(dimethylamino)ethoxide.…”

“…Intercalation of an aromatic compound with DNA induces upfield shifts in the proton NMR spectra of both the intercalating molecule and DNA imino protons, as well as a downfield shift of the DNA 31P signal. 13 Nonintercalative binding modes induce much smaller effects in the spectra of the bound molecule and the DNA. Reasonable line widths in the NMR spectra are obtained for samples with sonicated DNA.…”

Relationship between properties of a series of anilines and their transformation by bacteria

“…Anilines are ubiquitous in the environment. They are used in the manufacture of pesticides, dyes, and pharmaceuticals (2,12,16,17). They are also common metabolites of the microbial transformation of nitroaromatic compounds, such as explosives and dinitroaniline herbicides (8,13,20,30).…”

Metal-Free Synthesis of N-Aryl-Substituted Azacycles from Cyclic Ethers Using POCl3

“…1-(4-Nitrophenyl)pyrrolidine (3g). 9 It is obtained as a yellow solid (0.162 g, 84% yield); mp 167−169 °C; 1 H NMR (400 MHz, CDCl 3 ): δ 8.13 (d, J = 9.2 Hz, 2H), 6.49 (d, J = 9.2 Hz, 2H), 3.37−3.29 (m, 4H), 2.15−2.05 (m, 4H); 13 C NMR (100 MHz, CDCl 3 ): δ 151.9, 136.6, 126.3 (2C), 110.4 (2C), 47.9 (2C), 25 1-(3-Chlorophenyl)pyrrolidine (3h). 9 It is obtained as colorless oil (0.165 g, 91% yield); 1 H NMR (400 MHz, CDCl 3 ): δ 7.14 (t, J = 8.0 Hz, 1H), 6.64 (dd, J = 7.6, 1.2 Hz, 1H), 6.55 (t, J = 2.0 Hz, 1H), 6.45 (dd, J = 8.4, 2.0 Hz, 1H), 3.32−3.25 (m, 4H), 2.07−2.00 (m, 4H); 13 C NMR (100 MHz, CDCl 3 ): δ 148.8, 134.9, 130.0, 115.1, 111.4, 109.8, 47.6 (2C), 25.4 (2C); HRMS (ESI) m/z: (M + H) + calcd for C 10 H 13 ClN, 182.0737; found, 182.0736.…”

“…24 It is obtained as a white solid (0.197 g, 83% yield); mp 49−51 °C; 1 H NMR (400 MHz, CDCl 3 ): δ 7.25−7.15 (m, 4H), 6.67 (s, 2H), 6.55 (s, 1H), 4.43 (s, 2H), 3.57 (t, J = 5.6 Hz, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.35 (s, 6H); 13 Phenylphosphoramidic Dichloride (6). 25 To a 20 mL vial containing a stirring mixture of aniline (1a) (0.093 g, 1.00 mmol) and DBU (0.304 g, 2.00 mmol) in xylene (3 mL) was added dropwise POCl 3 (0.230 g, 1.50 mmol) at room temperature. The mixture was then stirred at 90 °C for 30 min, quenched with saturated ammonium chloride, and extracted with CH 2 Cl 2 (2 × 10 mL).…”