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PubMed1990

Dual-function 2-nitroimidazoles as hypoxic cell radiosensitizers and bioreductive cytotoxins: in vivo evaluation in KHT murine sarcomas.

The efficacies of a series of potential prodrugs of RSU-1069 and its alkyl-aziridine analogues were assessed. These 1-(2-haloethylamino)-3-(2-nitro-1-imidazolyl)-2-propanol compounds were designed to cyclize in vivo to generate 2-nitro-imidazoles with aziridine (RSU-1069) or alkyl-substituted aziridine (RSU-1164, RB-7040, or RSU-1150) functions. Maximum tolerated single, intraperitoneal doses (MTD) were determined in C3H/He mice bearing subcutaneous KHT sarcomas, and a drug dose-response relationship for radiosensitization was established for each compound administered at the optimum time (45-60 min) before local irradiation of tumors with a 10-Gy dose of X-rays. The potentials of the compounds as bioreductive cytotoxins were studied by administering them immediately after irradiation. Tumor cell survival was measured 18-24 h after treatment in an in vitro soft agar clonogenic assay. Results of toxicity, radiosensitization, and bioreductive cytotoxicity assays for each of the prodrugs (RB-6171, RB-6172, RB-6173, RB-6174, and RB-6175) of the alkyl-substituted aziridines were entirely consistent with complete conversion to their respective target compounds. For example, RB-6171 (the prodrug form of RSU-1164) was only about four times less efficient than RSU-1069 as a radiosensitizer and bioreductive cytotoxin but had an MTD 7.5 times higher. In contrast, prodrugs of RSU-1069 (RB-6144 and RB-6145) were two- to threefold less toxic than their expected product. RB-6144 was a poor radiosensitizer and bioreductive agent compared with RSU-1069 and was similar to RB-6170, a nonalkylating nitroimidazole. This is consistent with the observation that there is limited conversion of RB-6144 to RSU-1069 in vitro. However, radiosensitization and bioreductive cytotoxicity produced by RB-6145 were only slightly less than the effects produced by RSU-1069; thus a therapeutic gain was achieved with RB-6145 in a murine tumor model.

Animals↗

PubMed1987

Mechanism of action of some bioreducible 2-nitroimidazoles: comparison of in vitro cytotoxicity and ability to induce DNA strand breakage.

The interaction of a series of nitroimidazole-aziridine radiosensitisers, as parent or radiation-reduced species, with plasmid DNA in aqueous solution at pH7 results in strand breakage. The efficiency of strand breakage substantially increases on reduction of the nitroimidazole analogues. The rate of production of strand breaks decreases on interaction with both parent and reduced nitroimidazole analogues as the aziridine moiety is deactivated through alkyl-substitution. These variations in efficiency are reflected in changes in the toxicity towards both oxic and hypoxic cells and in the decrease in toxicity with progressive substitution of the aziridine moiety. The stabilities of these nitroimidazoles in aqueous solution at pH7 have also been determined. However, these stabilities do not parallel the variations in the alkylating efficiency of DNA by the aziridine moiety. These results have been discussed in terms of the relative reactivities of the nitroimidazoles with plasmid DNA and their ability to act as cytotoxic agents, especially following bioreduction and how the findings may relate to the radiosensitising properties of these agents.

Antineoplastic Agents↗

PubMed1985

Mechanism for the reductive activation of diaziquone.

In order to understand the redox properties of diaziquone (AZQ) and the reductive alkylation role of its one-electron reduced free radical anion AZQ- in biological systems, we investigated the electrochemical and structural properties of AZQ and its reduced species by cyclic voltammetry, controlled potential electrolysis, optical absorbance spectroscopy and 1H NMR. This study was carried out in aqueous media as well as in Me2SO. In aqueous media AZQ can be reduced by 2 electrons to the dianion AZQ2- which is oxidized back to AZQ- and AZQ. In Me2SO, 1 - e- reduction or oxidation steps are possible. This allowed the characterization of AZQ and its 1 or 2 - e- reduced species by UV-visible absorbance spectroscopy. The redox properties of the aziridine rings were observed by cycle voltammetry. Using 1H NMR, it was possible to follow the structural dependence of AZQ on the nature of the medium. Protonation of the aziridine rings at low pH may facilitate the opening of the ring leading to the carbonium ion, the required species for alkylation. Cyclic voltammetry data indicate that reduction of the quinone facilitates the aziridine ring opening.

Antineoplastic Agents↗

PubMed2002

Enhanced antitumor activity of irofulven in combination with thiotepa or mitomycin C.

PURPOSE: Irofulven (6-hydroxymethylacylfulvene, MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a toxin present in the Omphalotus mushroom. Irofulven has demonstrated activity against a broad range of solid tumors in both xenograft models and human trials. The potential application of administering irofulven in combination with aziridine-containing chemotherapeutic agents was evaluated in this study. METHODS: Human lung carcinoma MV522 cells and BALB/c athymic mice bearing the human lung carcinoma MV522 xenograft were used to evaluate the activity of irofulven in combination with aziridine-containing drugs. RESULTS: Irofulven in combination with either thiotepa or mitomycin C demonstrated a strong synergistic (supraadditive) activity both in vitro and in vivo, that exceeded results obtained with monotherapy at the same or higher doses of these agents. The majority of xenograft-bearing animals that received subtoxic doses of irofulven, and either thiotepa or mitomycin C, demonstrated a complete cure. In contrast, there was no detectable synergistic activity between irofulven and other aziridine-containing drugs, including AZQ and thiotepa metabolites such as TEPA or AZD. CONCLUSIONS: These results indicate that the therapeutic activity of irofulven is enhanced when combined with mitomycin C or thiotepa, and further evaluation of these combinations is therefore warranted.

Animals↗

PubMed1990

Inactivation of viral antigens for vaccine preparation with particular reference to the application of binary ethylenimine.

Viral antigens for human and veterinary vaccines are still inactivated with formaldehyde. This is not an ideal inactivant and the problems of formaldehyde inactivation of vaccines are discussed. Vaccines inactivated with aziridines are superior in safety and antigenicity. Aziridines inactivate viruses in a first-order reaction and the inactivation rate and endpoint can be determined. The preparation and application of the aziridine compound binary ethylenimine (BEI) and the necessary conditions for and controls of the inactivation process are described and discussed. A computer program has been written for assistance in the use of BEI for controlled inactivation of viral antigens.

Animals↗

PubMed1985

Electron spin resonance of electrochemically generated free radicals from diaziquone and its derivatives.

The one-electron electrochemical reduction of diaziquone (AZQ) and 12 analogs is analyzed using ESR spectroscopy and cyclic voltammetry. The hyperfine coupling constants arising from the interaction of the unpaired electron with the aziridine nitrogen nuclei fall within 1.20 and 2.26 G. Smaller couplings are observed arising from the protons and nitrogens in the carboethoxyamino groups. The in vitro activity of AZQ and its analogs is examined. Methyl groups in the aziridine rings increase the activity of some analogs. In the absence of aziridines, a chloroquinone compound with only carboethoxyamino groups was surprisingly active. This compound has a more positive cathodic peak than diaziquone.

Animals↗

PubMed1983

Free radicals in quinone containing antitumor agents. The nature of the diaziquone (3,6,-diaziridinyl-2,5-bis(carboethoxyamino)-1,4-benzoquinone) free radical.

The enzymatically generated free radical of the antitumor agent diaziquone is analyzed with the help of two analogs where either the aziridine rings (RQ14) or the carboethoxyamino groups (RQ2) were substituted by chlorine atoms. The hyperfine couplings observed in the diaziquone free radical are due to the nitrogens in the aziridine group. Unresolved coupling and hindered rotation contribute to line broadening. We find that diaziquone free radicals are more stable than RQ14 but less stable than RQ2 free radicals. The reason for this is that the carboethoxyamino groups make the aromatic ring unstable, while the aziridines contribute to its stability. The free radical observed in diaziquone is in all probability that of the parent compound and not that of an intermediate metabolite.

Antineoplastic Agents↗

PubMed1984

Pharmacology of the mixed-function radio- and chemosensitizers CB 1954 and RSU 1069.

We have studied the pharmacokinetics and metabolism in mice of CB 1954 and RSU 1069. Containing both nitro and alkylating (aziridine) substituents, these are lead compounds in the mixed-function analogue series, which show particular promise for sensitizer development. Both compounds are degraded extensively, via pathways including nitro reduction, aziridine ring hydrolysis and aziridine ring removal RSU 1069 (plasma t1/2 22 min) was eliminated more rapidly than CB 1954 (blood t1/2 84 min), and the AUC was three times less. Tissue/plasma ratios tended to be rather lower than those for simple nitroimidazoles of intermediate lipophilicity, which are usually close to 100%. With CB 1954, for example, tumor/plasma and brain/plasma ratios were 58 and 37% respectively, whereas with RSU 1069 the values were 29 and 26%. Nevertheless, tumor concentrations were consistent with potent sensitization. There is, however, scope for pharmacokinetic fine-tuning to modify tissue penetration as appropriate.

Animals↗

PubMed2005

Pyridinium salt photochemistry in a concise route for synthesis of the trehazolin aminocyclitol, trehazolamine.

[reaction: see text] A strategy for the concise synthesis of trehazolamine, the aminocyclitol core of the potent trehalase inhibitor trehazolin, has been developed. The methodology takes advantage of photocyclization reaction of 1-methoxyethoxymethyl-3-pivaloxymethylpyridinium perchlorate to generate a bicyclic-aziridine intermediate, which is transformed under aziridine ring opening conditions to the key intermediate, 3,5-diacetoxy-3-pivaloxymethyl-4-(N-acetylamino)cyclopentene. In addition, the strategy is used in an enantio-divergent sequence for preparation of the natural (+)-trehazolamine and its unnatural (-)-enantiomer. In this route, the chiral auxiliary containing 1-(tetracetyl-alpha-D-glucosyl)-3-pivaloxymethylpyridinium perchlorate undergoes photocyclization to generate separable, diastereomeric bicyclic-aziridines, which are then independently transformed to enantiomeric 3,5-diacetoxy-3-pivaloxymethyl-4-(N-acetylamino)cyclopentenes.

Aziridines↗

PubMedDate not supplied

Diaziquone-glutathione conjugates: characterization and mechanisms of formation.

The antitumor agent diaziquone (AZQ) reacts with reduced glutathione (GSH) in aqueous solutions and under aerobic conditions to give rise to the glutathionyl and hydroxyl free radicals, as well as the AZQ semiquinone. Under anaerobic conditions, the only radical observed was the glutathionyl radical. These radicals are quickly abrogated when superoxide dismutase and catalase are coincubated. Separately, superoxide dismutase favors the formation of thiyl radicals while catalase favors the formation of hydroxyl radicals and AZQ semiquinone. The metal chelator diethylenetriaminepentaacetic acid favors the production of hydroxyl radicals and AZQ semiquinone. The reaction of AZQ with GSH at pH 7.2 and 5.5 results in a variety of conjugates. These conjugates include addition of glutathione to both aziridines, displacement of the aziridines by GSH, and a combination of both. The majority of the conjugates are formed by nucleophilic attack of GSH to the AZQ aziridines or by 1,4-Michael addition to the AZQ quinone or a combination of both. There may be a small free radical component in conjugate formation, but the majority of the free radicals observed are from redox reactions that involve the oxidation of glutathione and the reduction and autoxidation of AZQ to produce oxygen radicals and hydrogen peroxide, a process that is enhanced by trace metal ions.

Antineoplastic Agents↗

PubMed1991

DNA adducts of the antitumor agent diaziquone.

We have studied adduct formation of the antineoplastic agent diaziquone (AZQ; NSC 182986) with DNA and nucleotides in vitro. The aziridine moieties of AZQ can be expected to interact covalently with DNA which, in turn, presumably elicits the antitumor activity. We analyzed AZQ-DNA adducts by a modified 32P-postlabeling assay involving purification of the nuclease P1-enriched labeled adducts by high-salt C18 reversed-phase thin-layer chromatography and separation of the eluted adducts on a polyethyleneimine-cellulose layer using non-urea salt solutions. Modification of calf thymus DNA with AZQ produced two major (22% and 40%) and at least eight minor adducts. At equal concentrations of AZQ and DNA (1 micrograms/microliters each), peak binding was observed in about 2 h [1926 +/- 378 (SD) fmol/micrograms of DNA] with the binding levels remaining practically unchanged through 4 h. However, incubation for 24 h resulted in over 40% decline, indicating adduct instability. AZQ was found to be highly reactive in vitro as evidenced by its substantial binding (49 +/- 14 fmol/micrograms of DNA) even at a DNA:AZQ ratio of 100:1. When incubated with mononucleotides, AZQ reacted extensively with adenine, guanine, and cytosine but only slightly with thymine. Cochromatography of the modified DNA and nucleotides revealed that one of the major adducts and several minor adducts were guanine derived. The aziridine rings of AZQ were found to be the main reactive sites as its monoaminoalcohol derivative showed as much DNA reactivity as did the parent compound, but no activity was observed when both aziridine groups were hydrolyzed to diaminoalcohols. The improved 32P-postlabeling assay seems capable of detecting relatively polar adducts such as those formed with AZQ at a level of one adduct/10(9) nucleotides.

Animals↗

PubMed1990

Structural studies of immunomodulators. Part 2: Crystal structure and conformation of azimexon (BM 12.531) an immunostimulant and an anti-tumor drug.

Azimexon [2-cyanaziridinyl-2-carbamoyl-aziridinyl-1-propane] is a derivative of 2-cyanaziridine. Azimexon is an immunostimulant which shows therapeutic effects in tumor models and experimental infections in mice in vitro, enhances T lymphocyte transformation in vitro and increases phagocytosis of latex particles by mouse peritoneal cells. In cancer patients it increases blood active T rosettes, increases T4/T8 ratio and is used in the treatment of melanomas. The crystal structure analysis of azimexon has been undertaken to study the conformation of the molecule in the solid state as a first step in the investigation of a possible structure-function relationship of immunomodulators. Crystals of azimexon are triclinic, space group P1, with a = 6.342(2), b = 6.804(1), c = 13.106(2) A, alpha = 75.17(1), beta = 89.17(2), gamma = 83.26(2) degrees, V = 542.8 A3, Z = 2, D0 = 1.18 g cm-3 and Dc = 1.189 g cm-3. The structure was solved using CAD-4 data by multisolution techniques and refined to a final R value of 0.057. There are two independent molecules in the asymmetric unit with very different conformations relating the two aziridine rings in the molecule. The mean lengths of C-N and C-C in the aziridine rings are 1.461 and 1.494 A and the configuration of the ring nitrogen is pyramidal. The mean C-C-N and C-N-C bond angles in the ring are 59.2 and 60.6 degrees respectively. The two molecules, which differ significantly in the relative orientation of their aziridine rings, are linked by hydrogen bonding involving the amino group of one molecule as the donor and the cyano nitrogen and carbamoyl oxygen of the other molecule as the acceptor. There are a number of C-H...O and C-H...N interactions in the structure. The mode of action of azimexon is unknown. It has been suggested that azimexon may alkylate DNA. The knowledge of the three-dimensional structure should facilitate distance geometry calculations that would determine which modes of crosslinking would be possible. The end-to-end distances between the two ends of the molecule is 9.0 A which is of the same order as the intrastrand distances in the DNA double helix. The present structural work of azimexon strongly indicates that azimexon crosslinks with DNA using its two reactive groups at its ends. Further study is necessary in order to determine which modes of crosslinking would be possible.

Adjuvants, Immunologic↗

PubMed1986

Reductive activation of diaziquone and possible involvement of free radicals and the hydroquinone dianion.

To analyze the mode of action of diaziquone [AZQ] on DNA, we examined the activity of two AZQ analogues and N,N',N"-triethylenethiophosphoramide on three forms [supercoiled (Form I), open circular (Form II), and linear (Form III)] of PM-2 DNA. The AZQ analogues contained chlorine atoms which substituted either the carbethoxyamino groups or the aziridine groups of the parent compound. N,N',N"-triethylenethiophosphoramide is a triaziridine compound containing pentavalent phosphorus instead of a quinone group. We found that only when reduced with sodium borohydride did AZQ change the topology of the three forms of PM-2 DNA by introducing mainly single strand breaks. The AZQ analogue containing only aziridines (RQ2) was active in both its oxidized and its reduced forms, while the analogue containing only the carbethoxyamino groups (RQ14) or N,N',N"-triethylenethiophosphoramide were not active in either form. Under similar experimental conditions, Adriamycin alone altered the electrophoretic mobility of PM-2 DNA, while borohydride reduced Adriamycin did not. By using electron spin resonance spectroscopy, we showed that dihydrodiaziquone (AZQH2) oxidizes to the semiquinone in the presence of oxygen. Although AZQH2 was active against DNA, it was not active against cellular DNA synthesis as measured by [3H]thymidine incorporation into exponentially growing HEp-2 cells. However, AZQ alone prevented [3H]thymidine incorporation into HEp-2 cells. We found that HEp-2 cells have the ability to reduce AZQ to its free radical anion, but AZQH2 does not autoxidize to the free radical in the presence of cells. The reductive ability of HEp-2 cells may be responsible in part for preventing the oxidation of AZQH2 to the free radical. We found that under our conditions (1-h incubations) the aziridines are essential for the activity of aziridinyl quinones against PM-2 DNA and that in the case of AZQ the hydroquinone is also required.

Aziridines↗

PubMed2000

A Hyperbranched Poly(ethyleneimine) Grown on Surfaces.

Aminosilylated substrate was treated with aziridines in order to prepare hyperbranched polymers on solid supports such as silicon wafer and fused silica. It is observed that the primary amine on the substrate is good enough to initiate the ring-opening polymerization of aziridine. Measuring the thickness of the film and the absolute density of the primary amine functionality shows that a very highly branched poly(ethyleneimine) is formed upon the reaction. The surface density of the primary amine functional group (-NH(2)) on the very top surface increased dramatically (from 3.5 amines/nm(2) to 66 amines/nm(2)). A protected aziridine, benzyl 1-aziridinecarboxylate, was employed for the stepwise growth of the film. Two step-processes, chain growth and deprotection, were successful in growing the molecular layer, and a linear chain was formed without branching. Copyright 2000 Academic Press.

Journal Article↗

PubMed1988

Pharmacokinetics and metabolism of the mixed-function hypoxic cell sensitizer prototype RSU 1069 in mice.

RSU 1069 is a leading compound in the class of mixed-function hypoxic cell sensitizers. Possessing an alkylating aziridine function as well as a nitro group, it represents an important prototype molecule for new sensitizer development. Using a novel HPLC assay for RSU 1069 and its metabolites with a cyanopropyl column, we studied the detailed pharmacokinetics and metabolism of this drug in mice. An i.v. dose of 100 mg kg-1 produced peak plasma concentrations of about 100 micrograms ml-1. Absorption was rapid after i.p. injection but peak plasma concentrations were some three- to fourfold lower, giving an i.p. bioavailability of 55%. The elimination t1/2 was route-dependent; e.g. after 50 mg kg-1 the t1/2 was 37.2 and 22.4 min for the i.v. and i.p. routes respectively (P less than 0.001). There was also an indication of dose-dependent kinetics, with a 37% increase in elimination t1/2 when the i.p. dose was doubled from 50 to 100 mg kg-1. Oral bioavailability was low. The volume of distribution was 0.65-1.31 ml g-1 at 50 mg kg-1, but tissue penetration was limited. Brain/plasma ratios ranged from 9.3% to 66.8%, while the mean steady-state tumour/plasma ratio was 28.4%, a value considerably less than the 80%-100% ratios occurring with the neutral 2-nitroimidazole misonidazole. About 18% and 8% of a dose were excreted as the parent drug and the ring-opened hydrolysis product (RSU 1137) in the 8 h urine, indicating the likelihood of extensive metabolism via aziridine-ring removal and nitroreduction. RSU 1137 was also detected in mouse plasma and tissues and, in contrast to the aziridine ring-intact parent compound, gave tumour/plasma ratios of 100%. These studies should provide a pharmacokinetic basis for the evaluation and development of improved mixed-function sensitizers.

Animals↗

PubMed1993

William L. McGuire Memorial Symposium. Estrogen receptors: ligand discrimination and antiestrogen action.

We have used affinity labeling, site-directed mutagenesis and regional chemical mutagenesis in order to determine regions of the estrogen receptor (ER) important in hormone binding, ligand discrimination between estrogens and antiestrogens, and transcriptional activation. Affinity labelling studies with the antiestrogen, tamoxifen aziridine and the estrogen, ketononestrol aziridine have identified cysteine 530 in the ER hormone binding domain as the primary site of labeling. In the absence of a cysteine at 530 (i.e. Cys530A1a mutant), C381 becomes the site of estrogen-compatible tamoxifen aziridine labeling. Hence these two residues, although far apart in the primary linear sequence of the ER protein, must be close in the three-dimensional structure of the protein, in the ER ligand binding pocket, so that the ligand can reach either site. Site-directed and region-specific chemical mutagenesis have identified a region around C530 important in discrimination between estrogens and antiestrogens, and other mutants have allowed identification of residues important in hormone-dependent transcriptional activation. Some transcriptionally inactive ER mutants also function as potent dominant negative ERs, suppressing the activity of wild-type ERs at low concentrations. These studies are beginning to provide a more detailed picture of the ER hormone binding domain and amino acids important in ligand binding and discrimination between different categories of agonist and antagonist ligands. Such information will be important in the design of maximally effective antiestrogens. In addition, since there is now substantial evidence for a mixture of wild-type and variant ERs in breast cancers, our studies should provide insight about the bioactivities of these variant receptors and their roles in modulating the activity of wild type ER, and should lead to a better understanding of the possible role of variant receptors in altered response or resistance to antiestrogen and endocrine therapy in breast cancer.

Amino Acid Sequence↗

PubMed1986

Studies on the toxicity of RSU-1069.

RSU-1069 combines an aziridine function with a 2-nitroimidazole and has been reported to exhibit extraordinary radiosensitization both in vitro and in vivo. Such sensitization appears to be at variance with the electron affinity of the compound. In addition, recent experiments suggest that the compound is highly toxic to hypoxic tumor cells in vivo. On the assumption that the observed radiosensitizing ability may be a manifestation of toxicity and because of the high in vivo toxicity, we have investigated aerobic and hypoxic toxicity, both in wild type CHO cells and in mutants sensitive to a variety of DNA damaging agents. With wild type cells under aerobic conditions, the compound is approximately 50 times as toxic as misonidazole and under hypoxic conditions, approximately 250 times as toxic. The ratio of hypoxic to aerobic toxicity is approximately 80 times. Under aerobic conditions, repair-deficient mutants are 10 times as sensitive to RSU-1069 as wild type cells and approximately 100 times as sensitive under hypoxic conditions. The ratio of hypoxic to aerobic toxicity for the mutant cells is approximately 900. Based on these observations, we suggest that under aerobic conditions the aziridine function is primarily responsible for toxicity, whereas, under hypoxic conditions, the aziridine moiety combined with a reduced 2-nitroimidazole moiety produces a bifunctional agent.

Aerobiosis↗

PubMed1992

Pharmacologic/pharmacokinetic evaluation of emesis induced by analogs of RSU 1069 and its control by antiemetic agents.

RB 6145, the ring-opened analog of RSU 1069, and PD 130908, the desoxy ring-opened analog of RSU 1069, were compared to RSU 1069 for their emetic potential in dogs. When RB 6145 and PD 130908 were administered intravenously at doses ranging from 20% to 50% of the mouse equivalent maximum tolerated dose (MTD), both analogs were less emetic than RSU 1069 on a molar basis. Furthermore, the 5HT3 antagonist ondansetron prevented emesis at doses as high as 75% of the MTD. The reactivity, and hence the emetic liability of these compounds, is thought to be mediated by formation of the corresponding aziridine intermediate. In mouse plasma, both analogs rapidly converted to two products, the reactive aziridine and a stable oxiazolidinone species formed upon reaction with bicarbonate in the blood. A positive correlation exists between the amounts of aziridine formed by these analogs and their emetic potential.

Animals↗