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PubMed1984

Reactions of ethyleneimine with guanosine and deoxyguanosine.

Ethyleneimine was reacted with guanosine in aqueous medium and the products were purified by Sephadex G-10 and high-performance liquid chromatography (HPLC). Two products were identified by UV-spectroscopy: imidazole-ring opened 7-alkylguanosine and 1-alkylguanosine, accounting for 80% and 14% of all adduct radioactivity, respectively. When the incubation with ethyleneimine and guanosine or deoxyguanosine was carried out at pH 6.0 for 1 h intact 7-alkylation products were detected. The half-life of imidazole ring opening of 7-alkylguanosine was 11, 5 and 2.8 min at pH-values 7.0, 7.7 and 8.0, respectively, as measured fluorometrically at 25 degrees C. The respective half-life of alkylated deoxyguanosine was 21 min at pH 7.7. The half-life of depurination of alkylated deoxyguanosine was 42 min at pH 6.0 and 25 degrees C.

Aziridines↗
PubMed1987

The chemical reduction of diaziquone: products and free radical intermediates.

Sodium borohydride reduced diaziquone (AZQ) can cause cross-links between DNA molecules, between DNA and proteins and cause single- and double-strand DNA breaks. In order to understand these effects better, we investigated the reduction of diaziquone by borohydride, and looked at reaction products. We found that a major product was formed during the oxidation of the colorless 2-electron reduced AZQ, and that this product was a monoaziridinyl quinone. We interpret this result to mean that both the leaving aziridine as well as the remaining one can alkylate. This mode of alkylation does not explain cross-links which may occur by a different mechanism requiring simultaneous opening of the aziridine rings. Most of the antitumor activity of borohydride reduced AZQ is probably exerted during the oxidation of the 2-electron reduced AZQ (AZQH2).

Antineoplastic Agents↗
PubMed1987

Aziridine biotransformation by microsomes and lethality to hepatocytes isolated from rat.

To clarify the relationship of aziridine biotransformation to their cytotoxic activities, the metabolism of optical isomers of typical cytotoxic and non-cytotoxic aziridines was studied in isolated hepatocytes, rat liver microsomes, mitochondria and L-1210 mouse leukemia cells. Cytotoxic 1-methyl-2-beta-naphthylaziridine (NAZ) gave nitrosomethane as one of the bioactivation products in isolated hepatocytes and simultaneously induced a marked decrease in cellular ATP followed by cell lethality. NAZ itself did not directly affect the respiratory function of mitochondria in isolated hepatocytes or in buffer solution, however, it inhibited the mitochondrial activity in the presence of microsomes in the buffer solution. Nitroso-t-butane or nitrosomethane dimer, used as a substitute for extremely labile nitrosomethane, strongly inhibited the respiration of mitochondria. On the other hand, optical isomers of 2-aziridinecarboxylic acid (AZC) which did not give nitrosomethane in isolated hepatocytes or microsomes also did not show cytotoxicity. Thus, the cytotoxicity of NAZ seems to be induced by bioactivation via cellular oxidases with the nitrosomethane generated being a major toxic component. This may occur with most of the cytotoxic aziridine derivatives.

Adenosine Triphosphate↗
PubMed1989

DNA alkylation and formation of DNA interstrand cross-links by potential antitumour 2,5-bis(1-aziridinyl)-1,4-benzoquinones.

A series of 3,6-substituted 2,5-bis(1-aziridinyl)-1,4-benzoquinone derivatives was shown to alkylate calf thymus DNA and to form DNA interstrand cross-links. Alkylation and cross-link formation were enhanced after electrochemical reduction of the compounds and increased with lower pH in the pH range from 4.5 to 8.0. Reduction especially shifts the pH at which cross-linking and alkylation occurs to higher values, which are more physiologically relevant. This shift is probably caused by the increase in pKa value of the aziridine ring after reduction of the quinone moiety. The inactivation of single-stranded bacteriophage M13mp19 DNA to form phages in an E. coli host, by the 3,6-unsubstituted parent compound 2,5-bis(1-aziridinyl)-1,4-benzoquinone (TW13) was dependent upon reduction and pH in a similar way as was alkylation. The compound in our series with the least bulky, 3,6-substituents, TW13, caused a high amount of cross-link formation. Compounds with methyl-substituted aziridine rings showed low cross-linking ability. Our results support the concept that the protonated reduced compound is the reactive species that alkylates DNA, and that steric factors play an important role in the reactivity towards DNA. A correlation is observed between the ability to induce DNA interstrand cross-links and inactivation of M13mp19 bacteriophage DNA. Cross-link formation was also demonstrated in E. coli K12 cells, where the compounds are reduced endogenously by bacterial reductases.

Alkylation↗
PubMed1990

Covalent binding studies on the 14C-labeled antitumor compound 2,5-bis(1-aziridinyl)-1,4-benzoquinone. Involvement of semiquinone radical in binding to DNA, and binding to proteins and bacterial macromolecules in situ.

2,5-Bis(1-aziridinyl)-1,4-benzoquinone (BABQ) is a compound from which several antitumour drugs are derived, such as Trenimone, Carboquone and Diaziquone (AZQ). The mechanism of DNA binding of BABQ was studied using 14C-labeled BABQ and is in agreement with reduction of the quinone moiety and protonation of the aziridine ring, followed by ring opening and alkylation. The one-electron reduced (semiquinone) form of BABQ alkylates DNA more efficiently than two-electron reduced or non reduced BABQ. Covalent binding to polynucleotides did not unambiguously reveal preference for binding to specific DNA bases. Attempts to elucidate further the molecular structure of DNA adducts by isolation of modified nucleosides from enzymatic digests of reacted DNA failed because of instability of the DNA adducts. The mechanism of covalent binding to protein (bovine serum albumin, BSA) appeared to be completely different from that of covalent binding to DNA. Binding of BABQ to BSA was not enhanced by reduction of the compound and was pH dependent in a way that is opposite to that of DNA alkylation. Glutathione inhibits binding of BABQ to BSA and forms adducts with BABQ in a similar pH dependence as the protein binding. The aziridine group therefore does not seem to be involved in the alkylation of BSA. Incubation of intact E. coli cells, which endogenously reduce BABQ, resulted in binding to both DNA and RNA, but also appreciable protein binding was observed.

Alkylation↗
PubMed1980

Fertility regulation in male rats and hamsters with alkylating agents.

A single intratesticular injection of TEPA or Thio-TEPA induced a period of infertility lasting 1-2 months. Restoration of fertility was characterized by a reduction of the litter size resulting from the first inpregnation post-treatment. There was no evidence of tissue pathogenesis 6-12 months after treatment.

Animals↗
PubMed1977

The interaction of 1-(2(diarylmethoxy)ethyl)aziridines with histamine receptors in the longitudinal muscle strip of the guinea pig ileum.

The time course of the onset and decline of histamine antagonism by 1-(2-(diarylmethoxy)ethyl)aziridines, compounds which could be expected to have H1-receptor alkylating properties, was investigated on the longitudinal muscle strip of the guinea pig ileum. Experiments were performed with normal preparations and with muscle strips pretreated with a prostaglandin synthesis inhibitor in order to prevent spontaneous rise of muscle tone. In contrast to the previously reported observation that antihistaminic potency decreased with prolongation of the preincubation time, histamine antagonism by the aziridine compounds remained at a constant level for more than 60 min in the presence of indomethacin. This indicated that the aziridines are not hydrolyzed either directly in solution or after interaction with the tissue since the supposed hydrolysis product had a significantly lower antihistaminic activity. A comparison between 1-(2-diphenylmethoxy)ethyl)aziridine and diphenhydramine showed the former compound to have a slightly more rapid onset and a considerably more rapid decline of histamine receptor blockade. It was concluded that 1-(2-(diarylmethoxy)ethyl)aziridines did not alkylate the histamine H1-receptor in the longitudinal muscle layer of the guinea pig ileum.

Animals↗
PubMed1986

Acute in vivo exposure to ethylcholine aziridinium (AF64A) depresses the secretion of quanta from motor nerve terminals.

Quantal release of acetylcholine was evaluated for soleus nerve-muscle preparations removed from mice treated with the cholinergic neurotoxin AF64A. Treatment with two and three times the LD50 (i.p.) of AF64A caused a marked reduction of the frequency of miniature end-plate potentials (mepps) and the amplitude of end-plate potentials (epps). Since the amplitude of mepps was not altered, the reduction of epps was not due to reduction in the number of molecules of acetylcholine (ACh) per quantum or the end-plate sensitivity to ACh, but to a reduction of the number of quanta released in response to a nerve action potential. While this effect was not reversed when preparations were washed for 3 h, exposure to the potassium channel blocker, 3,4-diaminopyridine returned the mean quantal content of epps to normal. These data further support a presynaptic site of action for AF64A, and suggest that it may acutely disrupt the ionic processes underlying transmitter release.

Acetylcholine↗
PubMed1986

Septohippocampal neurons after intraventricular AF64A administration in rats: an electrophysiological study.

The putative cholinergic neurotoxin, ethylcholine aziridinium ion (AF64A), was injected bilaterally into the cerebral ventricles of male rats. The properties of the medial septum-nucleus of the diagonal band of Broca's area (MS-nDBB) neurons were studied 4 to 6 or 19 to 23 days following injections. The spontaneous activity of those neurons was higher in the injected animals, but their responses to glutamate and cholinergic agonists were not modified. The proportion of orthodromic responses elicited by fimbria-fornix stimulation in MS-nDBB neurons was unchanged. In contrast, the proportion of septohippocampal neurons (SHNs) identified by the antidromic stimulation of the fimbria-fornix was smaller in pretreated animals and their mean antidromic latency was shorter. These results suggest that intracerebroventricular administration of the neurotoxin AF64A is followed by changes in the properties of MS-nDBB neurons and specifically by the disappearance of a subpopulation of SHNs.

Animals↗
PubMed1983

Liposome-mediated labeling of adrenocorticotropin fragments parallels their biological activity.

To test our hypothesis that specific interactions of ACTH peptides with model lipid membranes reflect the biological importance of similar interactions on target cells, we investigated the liposome-mediated labeling of ACTH fragments with the extremely hydrophobic photolabel, 3-trifluoromethyl-3-(m-[125I]iodophenyl)diazirine. Correlations were found between the labeling rates and the agonistic and antagonistic potencies of the peptides for in vitro steroidogenesis and inhibition of a synaptosomal protein kinase. A model for the cross-reactivity between ACTH and opioid peptides is discussed.

Adrenal Cortex Hormones↗
PubMed1984

Hydrophobic labeling of the membrane binding domain of acetylcholinesterase from Torpedo marmorata.

Membrane-bound acetylcholinesterase (AChE) from the electric organ of Torpedo marmorata was labeled with the hydrophobic photoactivatable reagent 3-trifluoromethyl-3-(m-[125I]iodophenyl) diazirine ( [125I]TID). Labeling with [125I]TID was restricted to the membranous polypeptide segment of AChE as shown upon conversion of the amphiphilic form to the hydrophilic one by limited digestion with proteinase K. The labeled membranous segment, which has an Mr of approx. 3000 was isolated by gel filtration on Sephadex LH-60 in ethanol/formic acid.

Acetylcholinesterase↗
PubMed1989

GTP interacts through its ribose and phosphate moieties with different subunits of the eukaryotic initiation factor eIF-2.

We have previously shown that a GTP derivative bearing p-azidoaniline at the gamma-phosphate group specifically labels the gamma-subunit of eukaryotic initiation factor eIF-2. In the present study a new GTP derivative carrying the photoreactive group at the ribose moiety of GTP was applied for affinity labeling of eIF-2 in different initiation complexes. Using this GTP analogue the beta-subunit of eIF-2 was found to be specifically labeled in all complexes investigated. It is concluded that GTP interacts with both the beta- and gamma-subunit of eIF-2: the guanosine moiety is in contact with the beta-subunit and the gamma-phosphate group with the gamma-subunit.

Affinity Labels↗
PubMed1991

Diazipine, a novel photoaffinity probe for dihydropyridine receptors of calcium channels.

A new 1,4-dihydropyridine photoaffinity ligand, [3H]diazipine, has been assessed by binding and photolabeling, and compared with a currently used [3H]azidopine. [3H]Diazipine reversibly binds to skeletal muscle Ca2+ channels with a similar affinity to [3H]azidopine, but [3H]diazipine labels the channel two times more efficiently and no release of the incorported amount is observed after dithiothreitol treatment.

Affinity Labels↗
PubMed1985

Hydrophobic photolabelling of sarcoplasmic reticulum with [125I]TID.

[125I]TID, a small photoreactive lipophylic reagent, was used to label intrinsic proteins of rabbit and rat sarcoplasmic reticulum membranes. A 160,000 glycoprotein, the Ca2+-ATPase and polypeptides of mol. wt 53-55,000, 30,000, 20,000 and 6000 dalton were labelled suggesting that these proteins are integral membrane components.

Animals↗