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PubMedDate not supplied

Copolymers of ethylene imine and N-(2-hydroxyethyl)-ethylene imine as tools to study effects of polymer structure on physicochemical and biological properties of DNA complexes.

A series of five poly[(ethylene imine)-co-N-(2-hydroxyethyl-ethylene imine)] copolymers with similar molecular weights and different degrees of branching was established to study structure-function relationship with regard to physicochemical and biological properties as gene delivery systems. Copolymers were synthesized by acid-catalyzed ring-opening copolymerization of aziridine and N-(2-hydroxyethyl)-aziridine in aqueous solution and characterized by GPC-MALLS, (1)H- and (13)C NMR, IR, potentiometric titration, and ion exchange chromatography. Complexation of DNA was determined by agarose gel electrophoresis, and complex sizes were quantitated by PCS. Cytotoxicity of the copolymers in fibroblasts was assessed by MTT-assay, LDH-assay, and hemolysis. The transfection efficiency was determined using the reporter plasmid pGL3 in 3T3 mouse fibroblasts. The copolymers obtained by solution polymerization had relatively low molecular weights of about 2000 Da, and the degree of branching increased with increasing ethylene imine ratio. The pK(a) as well as the buffer capacity increased proportional to the number of primary and secondary amines. Higher branched polymers showed stronger complexation and condensation of DNA, formed smaller polymer/DNA complexes, and induced the expression of plasmids to a higher extent than less branched polymers. In vitro cytotoxic effects and the hemolysis of erythrocytes decreased with decreased branching. Our results indicate that the basicity and degree of protonation of the polymers depending on their amount of primary and secondary amines seem to be important factors both for their transfection efficiency and for their cytotoxicity in gene transfer.

3T3 Cells↗
PubMed1981

Reductive metabolism and alkylating activity of mitomycin C induced by rat liver microsomes.

Mitomycin C, an antitumor antibiotic, is rapidly metabolized in the presence of rat liver microsomes. NADPH and anaerobic conditions are required for the process. The products isolated after reexposure to air are 2,7-diaminomitosene derivatives. Specifically, in the presence of inorganic phosphate, 1,2-cis- and -trans-2,7-diaminomitosene 1-phosphates, 1,2-cis- and -trans-2,7-diamino-1-hydroxymitosenes, and 2,7-diaminomitosene are formed. The last substance is a new mitomycin C derivative, and proof for its structure is presented. Mytomycin C has been previously postulated to be an alklating agent requiring reduction for activity (Iyer, V. N., & Szybalski, W. (1964) Science (Washington, D.C.) 145, 55]. The 1-phosphates above represent the first chemically characterized bioreductive alkylation products of the drug. 5'-Uridylic acid is alkylated analogously under these conditions, to give cis- and trans-2,7-diaminomitosene 1-(5'-uridylate), while the phosphodiester UpU and uridine itself are inert. Hydrogen gas/PtO2 gives the same results as microsomes/NADPH. The formation of the observed compounds indicates that enzymatic (or chemical) reduction of the quinone system of mitomycin C induces ring opening of the aziridine function, generating a reactive center at the C1 position as previously postulated by others (ibid.). The second alkylating center, also postulated, is not evident, however, under the conditions tested, indicating that the aziridine is the primary bioreductive alkylation function of mitomycin C. Identification of the products and mechanism of the microsomal anaerobic metabolism of mitomycin C are significant in view of the reported toxicity of the drug to anaerobic cancer cells.

Alkylation↗
PubMed2002

The ene reactions of nitroso compounds involve polarized diradical intermediates.

The ene reactions of nitroso compounds were studied with B3LYP/6-31G* geometry optimizations and energy calculations, along with single point energy evaluations using CASPT2/6-31G** and UCCSD(T)/6-311+G* methods. Reactions of HNO with propene and of MeNO and p-NO2C6H4NO with propene or substituted alkenes were also studied. The reaction mechanism is stepwise and involves a polarized diradical intermediate. The electronic structure of this intermediate is between that of a closed shell polar species and that of a pure diradical, and it is stabilized by polar solvents. A weak C-N bonding interaction combined with a CH-O hydrogen bond leads to heightened barriers to rotation about formally single bonds compared to conventional diradicals. Consequently, rotation is slower than hydrogen abstraction and cyclization to form an aziridine N-oxide. This aziridine N-oxide does not lead to ene products without subsequent ring opening but provides a mechanism for the RNO moiety to translate from one end of the alkene to the other. B3LYP calculations are also able to reproduce kinetic isotope effects and regioselectivity.

Journal Article↗
PubMed2004

A surprising dipolar cycloaddition provides ready access to aminoglycosides.

This contribution describes the results of a new research effort in our laboratory aimed at the synthesis of novel aminoglycosides and amino-C-glycosides. Despite the importance of such compounds, and the previous development of some methodological solutions, this remains an important area of research. Notable features of our approach, which is distinct from and complementary to previous efforts, are the following: (1) Reliance on a surprising and unprecedented formation of glycal triazolines via an inverse electron demand dipolar cycloaddition of glucal. We believe this desirable transformation has not previously been discovered because of the unusual selection of substrates and solvent required. (2) Very mild reaction conditions. An initial thermal cycloaddition is carried out in an inert solvent, the triazoline generated is photochemically converted to a reactive aziridine, and the crude aziridine undergoes ring opening at room temperature in the presence of a nucleophile and a mild Lewis acid catalyst. (3) Formation of products lacking an N-acyl group, allowing ready synthesis of novel glucosamine derivatives.

Aminoglycosides↗
PubMed2003

The surprising nitrogen-analogue chemistry of the methyltrioxorhenium-catalyzed olefin epoxidation.

Density functional theory calculations at the B3LYP level have been carried out to investigate the mechanism of the reaction of ethylene with [Re(O)2(O-NH)Me], a formal hydroxylamine derivative of the industrial epoxidation catalyst methyltrioxorhenium(VII) (MTO). A variety of reaction pathways has been considered, including the concerted heteroatom-transfer mechanism postulated by Sharpless and the stepwise mechanism via a five-membered "organometallacycle" postulated by Mimoun. Ethylene has been found not to coordinate directly at the metal. The calculations reveal similar activation free enthalpies for the concerted nitrene-transfer event (aziridination) and for the formation of an organometallic rhena-2,3-oxazolidine via [2+2] addition of ethylene across the Re-N bond of the metallaoxaziridine moiety. The fragmentation of the organometallacycle is faster than its formation and gives ethylideneazane rather than aziridine. An additional pathway has a lower activation free enthalpy and leads to a rhena-3,2-oxazolidine. The formation of this organometallacycle proceeds via an intermediate ring-opening product, [Re(O)2(eta1-O-NH)Me], which undergoes [3+2] cycloaddition across the C=C bond of ethylene. Analysis of its electronic structure reveals that the eta1 species should be considered a metalla-analogue nitrosonium ylide rather than a metalla-analogue imine oxide. Fragmentation of the rhena-3,2-oxazolidine liberates acetaldehyde. The discovery of favorable pathways leading to organometallacycles upon reaction of C=C bonds with [Re(O)2(O-NH)Me] stands in sharp contrast to the strong preference of the concerted mechanism in the olefin epoxidation with rhenium peroxo complexes. The calculations show the multiple mechanisms to be distinguishable by four different products, calling for further experimental studies. The successful search for the five-membered organometallacycles parallels the computational prediction of four-membered organometallacycles derived from d0 metal oxo complexes (Deubel, D. V.; Frenking, G. Acc. Chem. Res. 2003, 36, 645) and the indirect observation of metalla-2-oxetanes in recent gas-phase experiments (Chen, X.; Zhang, X.; Chen, P. Angew. Chem., Int. Ed. 2003, 42, 3798).

Journal Article↗
PubMed2005

Use of the intramolecular Heck reaction for forming congested quaternary carbon stereocenters. Stereocontrolled total synthesis of (+/-)-gelsemine.

Intramolecular Heck reactions of alpha,beta-unsaturated 2-haloanilides derived from azatricyclo[4.4.0.0(2,8)]decanone 5 efficiently install the congested spirooxindole functionality of gelsemine. Depending upon the Heck reaction conditions and the nature of the beta-substituent, either products having the natural or unnatural configuration of the spirooxindole group are formed predominantly. Efforts to elaborate the hydropyran ring of gelsemine from the endo-oriented nitrile substituent of pentacyclic Heck product 18 were unsuccessful. Important steps in the ultimately successful route to (+/-)-gelsemine (1) are as follows: (a) intramolecular Heck reaction of tricyclic beta-methoxy alpha,beta-unsaturated 2-iodoanilide 68 in the presence of silver phosphate to form pentacyclic product 69 having the unnatural configuration of the spirooxindole fragment, (b) formation of hexacyclic aziridine 80 from the reaction of cyanide with intermediate 79 containing an N-methoxycarbonyl-beta-bromoethylamine fragment, (c) introduction of C17 by ring-opening of the aziridinium ion derived from aziridine 80, and (d) base-promoted skeletal rearrangement of pentacyclic equatorial alcohol 82 to form the oxacyclic ring and invert the spirooxindole functional group to provide hexacyclic gelsemine precursor 83.

Alkaloids↗
PubMed2006

Surface-mediated NH and N addition to styrene on Ag(110).

In this paper, we report the investigation of the reaction of adsorbed NH and N with styrene on Ag(110) using temperature-programmed reaction spectroscopy. Using O2 and NH3 as the starting reagents, NH and N species were deposited on a Ag surface. The reaction of styrene on NH- and N-covered Ag surface appears to yield 2-phenylaziridine and benzonitrile, with additional products HCN and NH3. The formation of aziridine, the nitrogenous analogue of styrene epoxide, is proposed to be due to the cycloaddition of adsorbed NH to the carbon-carbon double bond. These results suggest that Ag-based heterogeneous catalysts may be useful for the aziridination of olefins.

Journal Article↗
PubMed2006

Synthesis and reactivity of azapalladacyclobutanes.

N-Sulfonyl aziridines undergo oxidative addition to palladium(0) complexes generated in situ from mixtures of Pd2(dba)3 and 1,10-phenanthroline. The resulting azapalladacyclobutane complexes undergo intramolecular carbopalladation in the presence of copper(I) iodide to afford azapalladabicyclo[3.2.1]octanes. A deuterium-labeling experiment indicates that the oxidative addition proceeds via SN2-type attack of palladium(0) on the less-hindered carbon of the aziridine ring and that alkene insertion occurs in a syn fashion. The azapalladabicyclo[3.2.1]octane complexes undergo oxidative palladium-carbon bond functionalization in the presence of copper(II) bromide.

Journal Article↗
PubMed1981

Development of new mitomycin C and porfiromycin analogues.

New mitomycin C and porfiromycin analogues were prepared by treating mitomycin A and N-methylmitomycin A with a variety of amines, including aziridines, allylamines, propargylamines, chloroalkylamines, hydroxyalkylamines, glycine derivatives, aralkylamines, and heterocyclic amines. All analogues were evaluated against P-388 murine leukemia and selected ones were examined for their leukopenic properties. Certain analogues were found to be superior to mitomycin C in potency, efficacy, and therapeutic ratio in the P-388 assay. The most active substituents at the mitosane 7 position included aziridine, 2-methylaziridine, propargylamine, furfurylamine, methyl glycinate, and 3-aminopyridine. Mitomycin A and the 7-aziridino, 7-(2-methylaziridino), and 3-aminopyridine analogues were less leukopenic than mitomycin C. Certain other analogues, including propargylamino and methyl glycinate, were highly leukopenic. The three compounds tested against B-16 melanoma in mice were significantly more effective than mitomycin C in this assay. Previously established structure--activity relationships were found inadequate to account for all of the new data.

Animals↗
PubMed1990

Structural, conformational, and theoretical binding studies of antitumor antibiotic porfiromycin (N-methylmitomycin C), a covalent binder of DNA, by X-ray, NMR, and molecular mechanics.

X-ray, NMR, and molecular mechanics studies on antitumor antibiotic porfiromycin (C16H20N4O5), a covalent binder of DNA, have been carried out to study the structure, conformation, and theoretical interactions with DNA. The crystal structure was solved by direct methods and refined to an R value of 0.052. The configurations at C(9), C(9a), C(1), and C(2) are S, R, S, and S, except for the orientation of the aziridine ring and (carbamoyloxy)methyl side chain. The five-membered ring attached to the aziridine ring adopts an envelope conformation. The solution conformation is similar to that observed in the solid state except for the (carbamoyloxy)methyl side chain. Monovalent and cross-linked models of the drug bound to DNA have been energetically refined by using molecular mechanics. The results indicate that, in the case of monocovalent binding, the drug clearly prefers a d(CpG) sequence rather than a d(GpC) sequence. In the case of the cross-linked model there is no clear-cut preference of d(CpG) over d(GpC), indicating that the binding preference of the drug may be kinetic rather than thermodynamic.

Antibiotics, Antineoplastic↗
PubMed1984

In the search for new anticancer drugs. 9. Synthesis and anticancer activity of spin-labeled analogues of N,N:N',N':N",N"-Tri-1,2-ethanediylphosphoric triamide and N,N:N',N':N",N"-tri-1,2-ethanediylphosphorothioic triamide.

A number of N,N:N',N':N",N"-tri-1,2- ethanediylphosphoric triamide (TEPA) and N,N:N',N':N",N"-tri-1,2- ethanediylphosphorothioic triamide (thio-TEPA) derivatives containing either two aziridine moieties (1a) or two (2-chloroethyl)amino functions (1b) and either a 2,2,6,6-tetramethylpiperidine, 1-oxy-2,2,6,6-tetramethylpiperidine or 1-hydroxy-2,2,6,6-tetramethylpiperidine component were synthesized and tested against lymphocytic leukemia P388 in mice. In a structure-activity comparison it was found that at optimum dose all compounds containing the nitroxyl radical were more active than the corresponding hydroxylamine derivatives. The open-chain compounds (1b) were less active than the corresponding aziridine ring compounds (1a). The replacement of the X = bridge in 1a with the X = N(CH3) group resulted in lowering of the anticancer activity.

Animals↗
PubMed1997

2-Cyclopropylindoloquinones and their analogues as bioreductively activated antitumor agents: structure-activity in vitro and efficacy in vivo.

A series of 2-cycloalkyl- and 2-alkyl-3-(hydroxymethyl)-1-methylindoloquinones and corresponding carbamates have been synthesized and substituted in the 5-position with a variety of substituted and unsubstituted aziridines. Cytotoxicity against hypoxic cells in vitro was dependent upon the presence of a 5-aziridinyl or a substituted aziridinyl substituent for 3-hydroxymethyl analogues. The activity of 5-methoxy derivatives was dependent upon the presence of a 3-(carbamoyloxy)methyl substituent. Increasing the steric bulk at the 2-position reduced the compounds' effectiveness against hypoxic cells. A 2-cyclopropyl substituent was up to 2 orders of magnitude more effective than a 2-isopropyl substituent, suggesting possible radical ring-opening reactions contributing to toxicity. Nonfused 2-cyclopropylmitosenes were more effective than related fused cyclopropamitosenes reported previously. The reduction potentials of the quinone/semiquinone one-electron couples were in the range -286 to -380 mV. The semiquinone radicals reacted with oxygen with rate constants 2-8 x 10(8) dm3 mol-1 s-1. The involvement of the two-electron reduced hydroquinone in the mediation of cytotoxicity is implicated. The most effective compounds in vitro were the 2-cyclopropyl and 5-(2-methylaziridinyl) derivatives, and of these, 5-(aziridin-1-yl)-2-cyclopropyl-3-(hydroxymethyl)-1-methylindole-4 ,7-dione (21) and 3-(hydroxymethyl)-5-(2-methylaziridin-1-yl)-1,2-dimethylindole+ ++-4,7-dione (54) were evaluated in vivo. Both compounds showed antitumor activity both as single agents and in combination with radiation, with some substantial improvements over EO9 (3) at maximum tolerated doses and as single agents against the RIF-1 tumor model and comparable efficacy in the KHT tumor model.

Animals↗
PubMed2005

Synthesis of 6,19-sulfamidate bridged pregnanes.

Conformationally restrained substituted pregnane-20-one derivatives were obtained by an intramolecular nitrene addition onto a C-5/C-6 double bond involving a tethered C-19 sulfamoyl moiety. The resulting aziridine underwent regioselective nucleophilic ring opening at C-5 at room temperature with cyanide, fluoride, and acetate. In the isolated case of acetate, a reversal of regioselectivity was observed at higher temperatures, a result attributed to a rearrangement process involving aziridine ring opening at the C-5 position and subsequent migration of the acetyl moiety to C-6.

Bridged-Ring Compounds↗
PubMed2006

Regio- and stereoselective synthesis of aziridino epoxides from cyclic dienes.

Two different routes for the regio- and stereoselective synthesis of aziridino epoxides from cyclic dienes have been explored. The first strategy involves regiospecific aziridination of cyclic diene derivatives and subsequent epoxidation with m-CPBA to yield cis-aziridino epoxides as major products. The second strategy utilizes regiospecific epoxidation of cyclic diene derivatives followed by Sharpless aziridination to provide exclusively trans-aziridino epoxides. Synthesis of both enantiomers of cis-aziridino epoxides from (R)-(-)- and (S)-(+)-carvones are also reported.

Journal Article↗
PubMed1996

A Direct Route to C-Vinylaziridines: Reaction of N-Sufonylimines with Allylic Ylides under Phase-Transfer Conditions or with Preformed Ylides at Low Temperature.

Allylic sulfonium salts 3, 5, 7, 11, 12, 13, and arsonium salt 14 react with aromatic, heteroaromatic, and alpha,beta-unsaturated N-sulfonylimines under solid-liquid phase-transfer conditions in the presence of KOH at room temperature to produce, respectively, vinyl-, (beta-phenylvinyl)-, and [beta-(trimethylsilyl)vinyl]aziridines in excellent yields within several minutes. In some cases, pyrroline compound 9 is obtained as a minor product. This aziridination reaction has also been carried out with preformed ylides, generated from sulfonium salts 3, 7, arsonium salt 14, and telluronium salts 15, 16 with a base in THF at -78 degrees C. In most examples, quantitative yields were achieved. However, the trans/cis selectivity of the reaction was not high in either case. A semistable allylic sulfonium ylide, i.e., dimethylsulfonium 3-(trimethylsilyl)allylide, was found to not undergo an expected [2,3]-sigma-rearrangement and so can also be used in this reaction.

Journal Article↗
PubMed1997

A New Synthesis of 2-Methyleneaziridines.

A new synthetic route leading to 2-methyleneaziridines has been developed by base-induced 1,2-dehydrobromination of 2-(bromomethyl)aziridines. Several base-solvent pairs did not lead to 2-methyleneaziridines. Only potassium tert-butoxide in tetrahydrofuran afforded 2-methyleneaziridines in competition with the substitution products, i.e. 2-(tert-butoxymethyl)aziridines. Various attempted functionalizations of 1-(arylmethyl)-2-methyleneaziridines failed, but they proved to be excellent substrates for the synthesis of beta-lactam derivatives, i.e. 1-(arylmethyl)-2-iminoazetidines, through ring expansion with azides carrying electron-withdrawing substituents.

Journal Article↗
PubMed1998

Isophosphoramide Mustard and Its Mechanism of Bisalkylation.

To investigate the mechanism(s) of bisalkylation by isophosphoramide mustard (IPM), IPM-beta,beta,beta',beta'-d(4) was synthesized and the products of its reaction with thiosulfate (at pD 7.0) were analyzed by NMR. By both (1)H and (13)C NMR, the distribution of deuterium in the products was consistent with bisalkylation through sequential aziridinyl intermediates [(NCH(2)CD(2)S):(NCD(2)CH(2)S) = 53:47]. Under the given reaction conditions, label scrambling as a result of thiosulfate acting as a leaving group was ruled out through control experiments. The data gave a calculated kinetic isotope effect of 0.97 per deuterium. For the initial aziridine species formed from IPM, ab initio quantum chemical calculations gave a hybridization value of sp(2.4)(-)(2.5) for each of the C-H bonds of the reaction centers, and this correlated with the observed inverse isotope effect. Other structure and bond order data were also determined for this aziridine intermediate and related compounds.

Journal Article↗