Aziridinyl Groups Research Articles

N‐Heterocyclic Carbene‐Catalyzed Activation of 3‐Membered Rings: Cyclopropanes, Epoxides, Azirines and Aziridines

AbstractThe activations of carbonyl compounds bearing cyclopropyl, epoxyl, azirine and aziridinyl groups by N‐heterocyclic carbene (NHC) organic catalysts are reviewed. The reactions are introduced and discussed from 3 aspects according to the activation modes involved in these transformations. A brief summary on the achievements and the remaining challenges in NHC‐catalyzed activation of cyclopropanes and their analogues is given at the end of this minireview. Our own perspectives on the future development within this highly active research field are also provided.

Probing the binding of thioTEPA to human serum albumin using spectroscopic and molecular simulation approaches

The present work is devoted to probing the molecular interaction of N,N′,N″-triethylenethiophosphoramide (thioTEPA) with human serum albumin (HSA) using UV-visible and fluorescence spectroscopies. Further, molecular dynamics and molecular docking simulations were used to investigate the binding site of thioTEPA. The outcomes of the spectroscopic observations and also the Stern−Volmer and van’t Hoff equations were employed to determine the binding thermodynamic parameters. It was found out that the interaction of thioTEPA with HSA is enthalpy driven through a quenching mechanism that is both static and dynamic at domain I of HSA. No significant changes in the local and overall secondary structure, polarity, and hydrophobicity of HSA were observed. The low values of binding free energies and binding constants are evidence for necessary high dosage of thioTEPA in chemotherapies. These results may be attributed to the spherical geometry and steric hindrance of the free vibrating aziridinyl groups of thioTEPA.

Antiplasmodial activity of quinones: Roles of aziridinyl substituents and the inhibition of Plasmodium falciparum glutathione reductase

Although quinones have been the subject of great interest as possible antimalarial agents, the mechanism of their antimalarial activity is poorly understood. Flavoenzyme electrontransferase-catalyzed redox cycling of quinones, and their inhibition of the antioxidant flavoenzyme glutathione reductase (GR, EC 1.8.1.7) have been proposed as possible mechanisms. Here, we have examined the activity of a number of quinones, including the novel antitumor agent RH1, against the malaria parasite Plasmodium falciparum strain FcB1 in vitro, their single-electron reduction rates by P. falciparum ferredoxin:NADP + reductase ( PfFNR, EC 1.18.1.2), and their ability to inhibit P. falciparum GR . The multiparameter statistical analysis of our data implies, that the antiplasmodial activity of fully-substituted quinones ( n = 15) is relatively independent from their one-electron reduction potential ( E 7 1 ). The presence of aziridinyl groups in quinone ring increased their antiplasmodial activity. Since aziridinyl-substituted quinones do not possess enhanced redox cycling activity towards PfFNR, we propose that they could act as as DNA-alkylating agents after their net two-electron reduction into aziridinyl-hydroquinones. We found that under the partial anaerobiosis, i.e., at the oxygen concentration below 40–50 μM, this reaction may be carried out by single-electron transferring flavoenzymes present in P. falciparum, like PfFNR. Another parameter increasing the antiplasmodial activity of fully-substituted quinones is an increase in their potency as P. falciparum GR inhibitors, which was revealed using multiparameter regression analysis. To our knowledge, this is the first quantitative demonstration of a link between the antiplasmodial activity of compounds and GR inhibition.

Chromosome-breaking capacity of tepa and analogues in Vicia faba and Chinese hamster cells

The insect chemosterilant tris(l-aziridinyl)phosphine oxide, tepa, with three aziridinyl groups, six tepa analogues with two aziridinyl groups and carbon chains of varying length, one monoaziridinyl analogue of tepa, and hempa with no aziridinyl group have been tested for chromosome-breaking ability in root tips of Vicia faba and in cell cultures of Chinese hamster. The difunctional analogues proved to be as active as tepa in both materials; the monofunctional analogue was less effective and hempa produced no effect. The hamster cells proved to be 23 times more sensitive than the bean roots to the chromosome-breaking effect of tepa. In the hamster cells the chromatid break was the most frequent type of aberration. Incomplete chromosomal aberrations were more numerous in the hamster cells than in the root tips. Combined treatments with tepa and [3H]-thymidine were performed to determine the sensitivity of the various phases of the mitotic cycle to the chromosome-breaking effect in the two materials. Treatment with tepa induced only chromatid-type aberrations. Chromosomal aberrations at the first mitosis (T1) were observed only in cells treated with tepa while in the DNA synthesis (S) and pre-synthetic (G1) periods, but not in the post-synthetic (G2) period. In the second mitosis (T2), G2 cells which were visibly undamaged at T1 mitosis, contained chromatid-type aberrations. The frequency of aberrations observed in T2 mitosis was higher than in T1 mitosis. Thus, although tepa produces lesions in chromosomes independently of cell phase at the time of treatment, these lesions apparently require a period of DNA synthesis before they are converted to chromatid aberrations observable in the following mitosis.

Aqueous-based polyurethane with dual-functional curing agent

Aqueous-based polyurethane (PU) with a carboxyl pendent group was prepared from a conventional PU prepolymer process. Its carboxyl group served as the ionic center for stabilizing the aqueous PU dispersion and as the curing site for post-curing reaction. A curing agent was synthesized from the substitution reaction of phosphorus oxychloride or phenylphosphonic dichloride by aziridine. Each compound consisted of two aziridinyl groups and the phosphorus composition. Its aziridinyl group reacted with a PU carboxyl group and its phosphorus content was introduced to this PU curing system simultaneously. Those compounds served as both curing agent and flame retardant for the PU curing system. The physical and mechanical properties of the resulting PU were improved corresponding to the curing dosage. The thermal properties and the flame inhibition behaviors of those post-cured PUs were evaluated by measurements using thermogravimetric analysis, dynamic mechanical thermal analysis, a limiting oxygen index, and a cone calorimeter.

Flame retardation improvement of aqueous-based polyurethane with aziridinyl phosphazene curing system

Aziridinyl phosphazene (NPAZ) was introduced to aqueous-based polyurethane (PU) as a flame retardant and a postcuring agent, mainly because of the presence of phosphorus compositions, as well as the reactive aziridinyl groups on NPAZ. This dual-function NPAZ was prepared from the substitution reaction of hexachlorocyclotriphosphazene with aziridine. Aqueous-based PU was treated with NPAZ and its curing reaction took place upon drying. The performance properties of this NPAZ cured PU (NPAZ-PU) were improved and better than those of the original PU. The phosphorus composition from NPAZ was evenly distributed on this NPAZ-PU film, which was identified by the phosphorus mapping on the energy dispersion spectrum. The physical and mechanical properties of NPAZ-PU were evaluated by the measurements of the gel content, water uptake, ethanol swelling, and tensile stress. The thermal properties of NPAZ-PU were investigated by thermogravimetric analysis (TGA), TG analyzer-interfaced FTIR, and dynamic mechanical thermal analysis. Furthermore, its combustion behaviors were demonstrated with the data of a cone calorimeter measurement. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 79: 662–673, 2001

Thermal and combustion behaviors of aqueous-based polyurethane system with phosphorus and nitrogen containing curing agent

Carboxyl group containing aqueous-based polyurethane (PU) is prepared by a conventional method. PU carboxyl group is the reactive site toward an aziridinyl containing post-curing agent for PU curing system. Two compounds are prepared from the substitutions of phosphorus oxychloride with aziridine (TAP) or then with N, N-diethylamine (DDP), respectively. TAP or DDP consists of three or two aziridinyl groups and also contains stable phosphorus-nitrogen bonds. It serves as a post-curing agent and a reactive flame retardant for the aqueous-based PU simultaneously. The mechanical and the physical properties of post-cured PU are modified corresponding to the curing dosage. The thermal stability of the resulted PU is improved and confirmed by thermogravimetric analyzer and dynamic mechanical thermal analyzer. Furthermore, the combustion behaviors of final PU are evaluated by the measurements of limiting oxygen index and cone calorimeter.

Synthesis and cytotoxic activity of aziridinyl-1,4-naphthoquinones and naphthazarins

Several derivatives of 1,4-naphthoquinone and naphthazarin, bearing one or two aziridinyl groups were synthesized, and their cytotoxic activity was evaluated on HeLa S 3 cells in tissue culture. Three of these compounds were found to be active ( ED 50 < 0.1 μg/ml). Compounds bearing two aziridinyl substituents were less active than their corresponding monoaziridinyl-substituted derivatives. Methylaziridinyl-substituted compounds were less active than their corresponding aziridinyl-substituted compounds.

Isomer-dependent cytostatic activity of bis(1-aziridinyl)cyclophosphazenes

A number of recently synthesized mono- and bis(1-aziridinyl) derivatives of the inorganic ring systems (NPCl2)3 and (NPCl2)4 was tested for their cytostatic activity in vitro (L1210 and L5178Y cells) and in vivo (intraperitoneal leukemia L1210 in CDF1 mice). Generally, the nongeminal bis(1-aziridinyl) isomers (either trans or cis) appear to be potent tumor growth inhibitors in contrast to their geminally substituted and mono(1-aziridinyl)-substituted analogues. A relationship between the biological activity and the number of alkylating centers (i.e., P atoms carrying one or two aziridinyl groups) is proposed.

The stability of carboquone in aqueous solution. II. Kinetics and mechanisms of degradation of 2,5-bis(1-aziridinyl)-3,6-dimethyl-1,4-benzoquinone and 2,5-bis-(1-aziridinyl)-3,6-diisopropyl-1,4-benzoquinone in aqueous solution.

The kinetics and mechanisms of the degradation of 2, 5-bis (1-aziridinyl)-3, 6-dimethyl-1, 4-benzoquinone (MEB) and 2, 5-bis (1-aziridinyl)-3, 6-diisopropyl-1, 4-benzoquinone (IPEB) were investigated and compared with those of 2, 5-bis (1-aziridinyl)-1, 4-benzoquinone (EB) investigated previously. The degradation of MEB and IPEB follows pseudo first-order kinetics in the same way as that of EB. The pH-rate profiles showed slopes of -1 on the acidic side and +1 on the basic side, as did that of EB. Thus, the degradation of MEB and IPEB is subject to specific acid-base catalysis. The apparent activation energies for MEB degradation at pH 4 and pH 11 were 16 and 24 kcal/mol, and those for IPEB degradation were 17 and 23 kcal/mol, respectively. In basic aqueous solution, MEB and IPEB are degraded to dihydroxybenzoquinones with monohydroxy-mono (1-aziridinyl) benzoquinones as intermediates in the same way as EB. On the other hand, in acidic aqueous solution, (2-hydroxyethylamino) benzoquinones are produced from MEB and IPEB, as in the case of EB, but they are further degraded to hydroxybenzoquinones. This was not practically observed in the case of EB. This phenomenon can be explained as follows : the alkyl groups at the 3 and 6 positions of benzoquinone increase the relative hydrolysis rate of 2-hydroxyethylamino groups derived from the hydrolytic cleavage of aziridine rings at the 2 and 5 positions of benzoquinone, making it comparable to the ring cleavage rate of aziridinyl groups.

Structures of inorganic rings as antitumor agents. I. Structure of the two allotropic varieties of 1,3,3,5,5-penta(1-aziridinyl)-1λ6,2,4,6,3,5-thiatriazadiphosphorine 1-oxide, (NPaz2)2-(NSOaz)

The two allotropic varieties of the title compound N3P2SO(NC2H4) 5 have been studied; they are respectively named SOaz(I) and SOaz(II). SOaz(I) crystallizes in the orthorhombic system, space group P2~2~2~, with a - 8.972 (1), b = 23.547 (2), c = 8.028 (1) A, and Z = 4, V = 1696 A 3, d m = 1.40 (5), d x = 1.419 Mg m -3,/t(Mo Ka) = 0.39 mm -~, m.p. = 357 K. SOaz(II) is monoclinic, P2~/c, with a -- 15.614(4), b -- 14.151(6), c = 16.310(6) A, fl = 114.7 (1) °, and Z = 8, V = 3274 A 3, d m = 1.45 (5), d x = 1.471 Mg m -3,/~(Mo Kct) = 0.41 mm -l, m.p. = 376 K. Both structures have been determined using direct methods and refined to conventional R factors of 0.051 [SOaz(I)] and 0.035 [SOaz(II)] for 1492 and 2242 reflections respectively. SOaz(I) contains one type of N3PzSO(NC2H4) 5 molecule, and SOaz(II) two types, A and B; these three different types of molecule exhibit drastic changes in their conformation. This last fact is explained by the possible rotation around the (P-N) and (S-N) bonds which link the aziridinyl groups to the six-membered ring N3P2S.

Notizen: Cyclophosphazenes as Novel Antitumour Agents: Geometry of the Hexaziridinocyclotriphosphazene, N3P3Az6, from an X-ray Investigation of the Benzene Clathrate

Abstract Hexaziridinocyclotriphosphazene forms a 2:1 clathrate with benzene. The benzene makes a sandwich between the two phosphazene molecules with the planes of the rings parallel. The geminal aziridinyl groups have a most unusual eclipsed conformation.

Introduction of Selenium into Organophosphorus Compounds Containing the Aziridinyl and Stable Nitroxyl Groups

Introduction of Selenium into Organophosphorus Compounds Containing the Aziridinyl and Stable Nitroxyl Groups

42—PERMANENT-PRESS EFFECTS IN WOOL. PART XIII: DELAYED-CURE CROSS-LINKING

Experiments are described in which cross-linking agents containing N-hydroxymethyl, N-methoxymethyl, or aziridinyl groups were tested for their effectiveness in stabilizing set in chlorinated wool by a delayed-cure procedure that involved the application of the cross-linking agent and sodium bisulphite to fabric, followed by setting and curing. Premature cross-linking, leading to unstable set, occurred with all the reagents tested except hexamethoxymethylmelamine.

Structure-activity relationship in analogs of tapa and hempa.

Two series of compounds related to tepa and hempa were tested on male house flies, Musca domestica L. The 1st series consisted of bis (1-aziridinyl) alkylaminophosphine oxides, the 2nd series of tepa-hempa intermediates. The sterilizing effect and toxicity of the compounds in both series were determined. In the 1st series, the sterilizing effect decreased with increasing length of the carbon chain in the alkyl group, except for the isopropyl compound which was a more effective chemosterilant than the ethyl compound. In the 2nd series, the progressive replacement of the aziridinyl groups with dimethylamino groups led to a steady decrease in the sterilizing effect. The toxicity of compounds in either series showed no definite trend and was entirely unrelated to sterilizing Effect. A safety factor was defined and calculated for each compound.

Fate of Tepa Uniformly Labeled with C14 in Male House Flies23

Tepa uniformly labeled with C14 with a specific activity of 12 mc/mmole was used to study the metabolism and mechanism of sterilization in male house flies, Musca fomestica L. A wet-combustinon method was developed for C14-labeled compounds which gave quantitative recovery and reproducible results. The injection of C14-labeled tepa was adjusted to about 1 µg per male fly. Total recovery of radioactivity from treated flies and their excreta was almost quantitative; radioactivity in respiratory CO2 was only 0.75% of the injected dose during the first 12 hours. When male flies were allowed normal activities after an injection of about 1 µg of C14-labeled tepa, 50% of the dose was retained in the fly 5 hours after treatment. Radioactivity was present in treated flies as tepa or aziridinyl metabolites; radioactive metabolites in the excreta did not contain aziridinyl groups. Radiometric and colorimetric determinations indicated that treated flies retained about 9 and 5%, respectively, of the injected dose over prolonged periods. Radioactivity was transferred to female flies by copulation with treated males. Because this radioactivity was found within the female body and not on its surface, we concluded that the transfer was by copulation rather than by body contact. However, no detectable radioactivity was found in the sperm or the seminal fluid present in the spermathecae of inseminated females. An electron microscopic scrutiny of house fly sperm failed to reveal any structural changes brought about by the chemosterilant.

Some Structure-Activity Relationships Among Aziridinyl Antifertility Agents in Screw-Worm Flies12

Candidate chemosterilants with 1, 2, or more molecular aziridinyl groups were screened topically and orally against adult screw-worm flies, Cochliomyia homitlivorax (Coquerel). Sexual sterility of the flies and number of unsubstituted functional groups were largely unrelated. However, more compounds with 3 or more substituted groups (56%) were active topically than with fewer substituted groups (14%), but they were equal to unsubstituted polyfunctional compounds (53%). Otherwise, about twice as many compounds with unsubstituted aziridinyl carbon atoms were effective as those that were substituted. Toxicity was independent of number of functional groups, irrespective of substitution. In general, more compounds were potent chemosterilants (90%) and nontoxic (38%) when administered multiple orally than topically (44% and 20%, respectively). Sterility, after oral administration, resulted from cumulative action of all monofunctional and half of all other aziridinyl compounds.

Studies on Ethyleneimine Derivatives. III

The applications of ethyleneimine derivatives to dyestuffs were investigated, and useful reactive dyestuffs were synthesized. Introducing aziridinyl groups into dyestuff molecules makes generally the dyestuff insoluble in water. In dyeing, textile fabrics are padded in the dyestuff suspension and then heat-treated. The fastness of the dyestuff is appreciably improved and the color is not changed. Copper phthalocyanine dye was chlorosulfonated and then reacted with ethyleneimine to give di- and tetra-substituted compounds. The tetra-aziridinyl compound is insoluble in water.The di-aziridinyl compound, however, was made soluble in water by changing the remaining two sulf ochloride groups into sodium sulf ovate groups. The dyestuff thus modified has partially the properties of acid dye, and can uniformly dye not only cotton but wool, nylon and polyacry lonitrile fabrics in the usual method of dyeing. The color of the dye was very bright blue and the fastness was the highest.

Studies on Ethyleneimine Derivatives. II

Reactions of ethleneimine with various aldehydes and acid chlorides were investigated. The reaction products retain the reactive aziridinyl groups in their molecules, and can react with cellulose.Diaziridinyl phenyl methane obtained by the reaction of ethyleneimine with benzaldehyde and N-stearoyl ethyleneimine obtained by the reaction of ethyleneimine with stearoyl chloride were investigated to use as the finishing agents of viscose rayon fibers.It was found that the physical properties of the fibers treated with these agents in solution are hardly affected by the treatments, but the dyeability is considerably improved. The fibers are dyeable almost alike wool.It is considered that only the surface of the fibers are modified chemically in the treatment with the finishing agents.Viscose rayon fibers which are mixed-spun with small amounts of diaziridinyl, phenyl methane were produced, but the physical properties of the rayon fibers were not found to be so good.Compounds produced by the reactions of ethyleneimine with furfural, glyoxal and glutaryl dialdehyde were so unstable that they could not be used in the finishing of the cellulose fibers.