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PubMed2002

The apurinic/apyrimidinic endonuclease activity of Ape1/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress.

Alkylating agents are standard components of adjuvant chemotherapy for gliomas. We provide evidence here that Ape1/Ref-1, the major mammalian apurinic/apyrimidinic endonuclease (Ap endo), contributes to alkylating agent resistance in human glioma cells by incising DNA at abasic sites. We show that antisense oligonucleotides directed against Ape1/Ref-1 in SNB19, a human glioma cell line lacking O(6)-methylguanine-DNA-methyltransferase, mediate both reduction in Ape1/Ref-1 protein and Ap endo activity and concurrent reduction in resistance to methyl methanesulfonate and the clinical alkylators temozolomide and 1,3-(2-chloroethyl)-1-nitrosourea. An accompanying increase in the level of abasic sites indicates that the DNA repair activity of Ape1/Ref-1 contributes to resistance. Conversely, we also show that exposure of SNB19 cells to HOCl, a generator of reactive oxygen species (ROS), results in elevated Ape1/Ref-1 protein and Ap endo activity, enhanced alkylator resistance, and reduced levels of abasic sites. Given current evidence that heightened oxidative stress prevails within brain tumors, the finding that ROS increase resistance to clinical alkylators in glioma cells may have significance for the response of gliomas to alkylating agent-based chemotherapy. Our results may also be relevant to the design of therapeutic regimens using concurrent ionizing radiation (a generator of ROS) and alkylating agent-based chemotherapy.

Antineoplastic Agents, Alkylating↗
PubMed1992

Differential responsiveness of human neutrophils to the autocrine actions of 1-O-alkyl-homologs and 1-acyl analogs of platelet-activating factor.

The phlogistic actions of six molecular species of platelet-activating factor (PAF) (1-O-alkyl-PAF homologs, 16:0-, 18:0- and 18:1-alkyl-PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (AGEPC) and their respective 1-acyl-PAF analog counterparts, 16:0-, 18:0- and 18:1-acyl-PAF, 1-acyl-2-acetyl-sn-glycero-3-phosphocholine (AGPC)) were assessed relative to five human neutrophilic polymorphonuclear leukocyte (PMN) functional responses: 1) lysosomal enzyme secretion; 2) specific desensitization to 16:0-AGEPC-induced lysosomal enzyme secretion; 3) O2- production; 4) chemotaxis; and 5) priming for enhanced O2- production. With respect to inducing lysozyme secretion, 18:0-AGEPC was 30- and 75-fold less potent than 16:0-AGEPC and 18:1-AGEPC, respectively, and was 25- and 40-fold less potent for inducing beta-glucuronidase secretion. 18:0-AGEPC was also 10-fold less active than 18:1- and 16:0-AGEPC for inducing O2- production. Thus, the rank order of potency of the alkyl-PAF homologs for inducing both lysosomal enzyme secretion and O2- production was 18:1- greater than or equal to 16:0- much greater than 18:0-AGEPC. In contrast, these three alkyl-PAF homologs had the same potency for desensitizing PMN to subsequent 16:0-AGEPC-induced lysosomal enzyme secretion and for priming PMN for augmented O2- production in response to FMLP or human recombinant C5a. Paradoxically, however, the rank order of potency of the alkyl-PAF homologs for effecting PMN chemotaxis was 18:0- greater than 18:1- much greater than 16:0-AGEPC. At concentrations as high as 1.0 microM, the acyl-PAF analogs did not initiate PMN lysosomal enzyme secretion, O2- production, or chemotaxis. However, the acyl-PAF analogs induced partial PMN desensitization to 16:0-AGEPC. A novel finding of potential (patho)-physiologic significance was the ability of acyl-PAF at nM concentrations to prime PMN for significantly enhanced O2- production after stimulation with FMLP or human recombinant C5a. The priming action of acyl-PAF was due to an increase in the rate as opposed to a prolongation of O2- production. The differing rank orders of potency of the alkyl-PAF homologs and acyl-PAF analogs for stimulating several physiologic responses of the same target cell, the human PMN, support the premise that there may be more than one PAF receptor subtype on the PMN and/or that differences in the biophysical properties of the various molecular species of PAF modulate their interaction with PAF receptor(s) linked to stimulus-response coupling.

Acylation↗
PubMedDate not supplied

Failure of alkylating agents to improve induction chemotherapy of oropharyngeal squamous cell cancer.

BACKGROUND: This prospective semi-randomized study was undertaken to assess the effects and effectiveness of alkylating drugs in a preoperative setting. PATIENTS AND METHODS: During a 6-year period preceding February 2000, 80 patients with Stage II-IVa (AJCC 2002) squamous cell cancer of the oral cavity were treated. Thirty patients (Group N) received a combination of bleomycin, vincristine and methotrexate (BVM). In the alkylating group, thirty patients (Group A/M) received BVM and mitolactol (dibromodulcitol), while twenty patients (Group A/C) received BVM and cisplatin. Patients underwent surgery within 3 weeks after chemotherapy. Clinical response rate and tumour-free survival were investigated. RESULTS: Clinical complete response was 30%-36% (Group N-A). Partial response was 57%-56% (Group N-A). Side-effects were moderate and reversible. Nausea, anaemia and leucopenia were observed in the alkylating (A) group, while other side-effects (alopecia, mucositis, gastritis) were similar in both groups. The observation time was 36 months. Regional disease-free survival showed a significant difference, favouring the non-alkylating (N) group (p=0.03). A higher metastasis rate was observed in the alkylating (A) group. CONCLUSION: Cisplatin and mitolactol in combination with BVM showed higher local control and lower disease-free survival than BVM alone. That was mostly due to a higher rate of regional metastatis formation in the alkylating-treated patients. This may be a late side-effect caused by the immunosuppressive and myelosuppressive effect of alkylating agents.

Antineoplastic Agents, Alkylating↗
PubMed1989

The search for the molecular lesions responsible for the induction of chromosomal damage by alkylating agents.

Many studies associated specific DNA alkylation products with specific biological effects of alkylating agents. Studies dealing with the identification of DNA lesions that are responsible for chromosomal damage are reviewed in this paper. Although early evidence suggested that alkylation of high nucleophilicity centers such as N-7 of guanine was associated with genetic effects of alkylating agents, recent studies shifted the attention to the alkylation of oxygen atoms. The results of studies based on the use of cells with different capacities to repair O6-alkylguanine (O6-AlkGua) indicate a key role for this alkylation product in the induction of sister chromatid exchanges, chromosomal aberrations and micronuclei. Our own results on the influence of exogenous thymidine on the frequency of micronuclei induced by methylating and ethylating agents further suggest that mispairing of O6-AlkGua with thymine may be involved. Molecular dosimetry studies did not reveal any correlation between individual DNA alkylation products and the induction of chromosomal damage, indicating that multiple lesions are probably involved.

Alkylating Agents↗
PubMed1989

Effect of novobiocin on the antitumor activity and tumor cell and bone marrow survivals of three alkylating agents.

Our previous in vitro studies demonstrated marked synergy with alkylating agents when novobiocin was present during and after alkylating agent exposure. To determine whether this effect is observed in vivo, novobiocin was administered daily for 3 days prior to alkylating agent treatment, during alkylating agent treatment, and for 2 days after completion of alkylating agent treatment. When combined with cis-diamminedichloroplatinum(II), 1,3-bis(2-chloroethyl)-1-nitrosourea, or cyclophosphamide, there was significant enhancement of the growth delay of the FSaIIC fibrosarcoma implanted s.c. in C3H mice when compared with alkylating agents alone. In a second assay using ex vivo studies of tumor cells exposed in vivo, single doses of 100 mg/kg of novobiocin followed by cis-diamminedichloroplatinum(II) resulted in a 3- to 4-fold increase in tumor cell killing by cis-diamminedichloroplatinum(II). At a dose of 100 mg/kg of 1,3-bis(2-chloroethyl)-1-nitrosourea there was about a 7-fold increase in tumor cell kill upon addition of novobiocin. Cyclophosphamide showed a dose response effect with novobiocin, reaching 13-fold at a dose of 300 mg/kg of cyclophosphamide. In all cases bone marrow elements were affected less than were neoplastic cells, suggesting that the combination of novobiocin and alkylating agents may be a clinically useful strategy.

Alkylating Agents↗
PubMed1988

Preclinical studies and clinical correlation of the effect of alkylating dose.

Dose-response studies were performed with the alkylating agents [nitrogen mustard, N,N'-bis(2-chloroethyl)-N-nitrosourea, melphalan, cisplatin (CDDP), 4-hydroperoxycyclophosphamide (4-HC), and trimethyleneiminethiophosphoramide] in both the MCF-7 human breast carcinoma cell line and the EMT6 and FSaIIC murine tumor lines. Increasing selection pressure with the alkylating agents CDDP, melphalan, and 4-HC in vitro produced low levels (6.5- to 9-fold) of drug resistance, despite an intensive and prolonged treatment program. The MCF-7 sublines made resistant to CDDP and 4-HC did not exhibit cross-resistance to other alkylating agents; however, the MCF-7 subline resistant to melphalan was partially cross-resistant to nitrogen mustard, 4-HC, and CDDP. A log-linear relationship was maintained between surviving fraction of MCF-7 cells in culture and drug concentration with alkylating agents, whereas for nonalkylating agents the survival curves tended to plateau at high drug concentrations. Log-linear tumor cell kill was also obtained over a wide dosage range with several alkylating agents in murine tumors treated in vivo. Tumor cell survival assay by colony formation indicated the continuing importance of dose in the action of the drugs even at high levels of tumor cell kill. With some agents, there was a difference between the slopes of the tumor cell killing curves in vivo as compared to in vitro. Cyclophosphamide was far more potent in vitro (4-HC) than in vivo (cyclophosphamide). Trimethyleneiminethiophosphoramide and N,N'-bis(2-chloroethyl)-N-nitrosourea were both more potent in vivo than in vitro. These differences may be explained by the various metabolic patterns of these drugs. Dose of alkylating agents is clearly a crucial variable particularly where multilog tumor cell kill is the goal, and in this regard, the effect of drug dose on the tumoricidal action of the alkylating agents is substantially greater than for nonalkylating agents.

Alkylating Agents↗
PubMed1981

Synthesis and antitumor effect of new biological alkylating agents, isethionic acid esters.

New hydrophilic alkylating agents, isethionic acid esters, are proposed for use as synthetic biological alkylating agents. Methyl, ethyl, and isopropyl esters of isethionic acid were synthesized starting from isethionate and the corresponding alkyl bromides or iodides in good yields. This synthetic procedure might be generally applicable to syntheses of alkyl isethionates. The derivatives thus prepared were water-soluble, as expected, and their alkylating abilities were very similar to those of the corresponding methanesulfonates. Hence, isethinonic acid esters might be suitable for use as hydrophilic biological alkylating agents in place of methanesulfonates. In order to determine the effectiveness of isethionates as anticancer alkylating agents, 1,4-butanediol diisethionate was prepared as a model compound and its anticancer activities against adenocarcinoma 755, sarcoma 180, L1210, and P388 were compared with those of the corresponding methanesulfonate, busulfan. The isethionate was superior to busulfan in all the assay systems employed. 1,5-Pentanediol diisethionate was also prepared and assayed. The results were similar to those for the 1,4-butanediol analog. In conclusion, in the design of molecules for use as cancer chemotherapeutics, the isethionic acid ester group is worth considering, and may be preferable to other commonly used leaving groups, including methanesulfonic acid ester.

Alkanesulfonates↗
PubMed1978

In vivo studies on the relationship between target organ alkylation and the pulmonary toxicity of a chemically reactive metabolite of 4-ipomeanol.

The pulmonary toxin, 4-ipomeanol, selectively alkylates the lungs of rats. Time-course and dose-response studies demonstrate a close correlation between the pulmonary alkylation and the lung toxicity of the compound. Without prior metabolism, 4-ipomeanol is not sufficiently reactive to alkylate tissue macromolecules. Inhibitors of the metabolism of 4-ipomeanol decrease both the pulmonary alkylation and toxicity of the compound, which suggests that the toxicity is due to an alkylating metabolite. Studies with inducers of the hepatic metabolism of 4-ipomeanol are consistent with the view that the toxic metabolite of the compound is actually formed in situ in the target tissue. Pretreatment of animals with diethylmaleate strikingly increases both the pulmonary alkylation and the lung toxicity of 4-ipomeanol. Studies of the tissue alkylating properties and toxicities of 4-ipomeanl analogs demonstrate the requirement for the furan moiety. The toxic metabolites of 4-ipomeanol appears to be a highly electrophilic reactant capable of binding irreversibly with nucleophilic macromolecular constituents of target tissue.

Alkylation↗
PubMedDate not supplied

[Application of alkylating DNA derivatives for addressed modification of the genome].

To affect definite preselected regions of DNA, complementary denaturated DNA fragments carrying alkylating groups were used. The residues of polyfunctional alkylating agent N',N'N'-tri(beta-chloroethyl)-N'-(p-formylphenyl)propylenediamine-1,3 were attached covalently to 4-5% of bases of the T7 phage DNA (T7 DNA) restriction fragment. The alkylating DNA derivatives was found to be stable under hybridisation conditions. It was shown that the DNA fragment carrying alkylating groups is capable of highly specific interaction with complementary DNA. Thus, the alkylating derivative of the T7 DNA restriction fragment retains its capacity to hybridise with T7 DNA, however, it does not interact with the noncomplementary DNA from chick erythrocytes, it was established that the alkylating derivative of DNA fragment efficiently alkylates only the complementary DNA.

Alkylating Agents↗
PubMedDate not supplied

[Complementarily addressed alkylation of yeast tRNA 1 Val with chloroethylmethylaminobenzylidene d(pC-G)-A. Proof of the modification of the third nucleotide located at the 5'-terminus of the complete binding site of the reagent].

Yeast tRNAlVal alkylation with 2',3'-0-[4-(N-2-chloroethyl-N-methylaminobenzylidene]dpCdpGrpA proceeds within complementary complexes that are formed due to attachment of the reagent to three sequences of tRNAlVal. The acetal bond of the initial product of alkylation has been hydrolyzed to yield beta-[N=methyl-N-(4-formylphenyl) amino]ethyl-tRNAlVal (R-tRNA) that contains from 1 to 3 residues of the specifically modified nucleosides: alkyl adenosine (R-A), R-I and probably R-psi. Individual alkylated oligonucleotides were isolated from R-tRNAlVal pyrimidyl-RNAse digest. The alkylated oligonucleotides correspond to 93% of all modified products. The major component is beta-[N-methyl-N(4-formylphenyl)aminoA1ethyl-A53-G-Tp. This indicates that the reagent is attached to complementary psi-C-G-sequence in the T-loop of tRNAlVal and that alkylation of the third nucleotide counting from the 5'-terminus of the sequence which binds the reagent completely takes place within the complementary complexes. This site of the tRNAlVal is modified quantitatively at 20 degrees and 19-fold excess of the reagent. The alkylation of two other sites of tRNA reaches 50% under these conditions.

Alkylating Agents↗
PubMed2003

Mechanistic study of alkyl azacycloheptanones as skin permeation enhancers by permeation and partition experiments with hairless mouse skin.

In previous studies (Yoneto et al., 1995. J Pharm Sci 84:312-317; Kim et al., 1992. Int J Pharm 80:17-31; and Warner et al., 2001. J Pharm Sci 90:1143-53), the transport enhancing effects of four homologous series of enhancers-the n-alkanols, 1-alkyl-2-pyrrolidones, 1,2-alkanediols, and N,N-dimethylalkanamides - on the transport of steroidal permeants across hairless mouse skin (HMS) were investigated. Isoenhancement concentrations are defined as the aqueous concentrations for which different enhancers induce the same extent of permeant transport enhancement, E, for the lipoidal pathway of the stratum corneum (SC). Our studies have shown that the E = 10 isoenhancement concentrations of these four homologous series were nearly the same when compared at the same n-alkyl group chain length and therefore that the contribution of the polar head group toward the enhancer potency was found to be essentially constant. In the present study, we have determined the isoenhancement concentrations (E = 10) for the 1-alkyl-2-azacycloheptanone series [1-butyl-2-azacycloheptanone (BAZ), 1-hexyl-2-azacycloheptanone (HAZ), and 1-octyl-2-azacycloheptanone (OAZ)] and compared the results with those of the previously studied four homologous series. We have found that the E = 10 isoenhancement concentrations (aqueous phase concentrations) of the 1-alkyl-2-azacycloheptanones (Azs) are around 10 times lower than those for the previously studied four homologous series when compared at the same alkyl group chain length. This indicates an approximately 10 times higher potency of Azs. This finding was a point of interest because the polar group of Azs is similar to that of 1-alkyl-2-pyrrolidones (Aps). To further probe the nature of the mechanism of action of the Azs and Aps and to better understand the lower E = 10 isoenhancement concentrations found with the Azs, it was decided (a) to determine the equilibrium partitioning (uptake) of the Azs and the Aps from the aqueous phase into the HMS SC at E = 10, and (b) to determine the equilibrium partitioning (uptake) of a surrogate permeant, estradiol (E2beta), into the SC in the absence of and in the presence of Azs and Aps at E = 10. The following were the outcomes from the two partitioning studies. Firstly, at the E = 10 isoenhancement concentrations, the extent of partitioning (uptake) of the Azs and Aps into the intercellular lipids of the HMS SC was found to be approximately the same, even though the E = 10 isoenhancement concentrations (aqueous phase concentrations) of the Aps were around 10 times greater than those of the Azs. We interpret this to mean (whereas the potencies of the Azs are around ten times greater than those of the Aps when related to their aqueous concentrations) that the potencies of the two enhancer series are about the same when expressed in terms of their concentrations in the intercellular lipid phase of the SC. Another outcome of the partitioning studies has been the finding that the extent of partitioning into the intercellular lipids of the SC at E = 10 isoenhancement conditions for both the Azs and Aps is essentially independent of the n-alkyl chain length (from butyl to octyl). A third result from these experiments has been that the partitioning of E2beta (the surrogate permeant) into the HMS SC under E = 10 isoenhancement concentration conditions is approximately the same with the Aps and Azs as enhancers. For both the Aps and Azs, the E2beta SC partitioning enhancement was found to be in the range of 5-6 at E = 10. This comparable partitioning enhancement for E2beta in the presence of Aps and Azs at E = 10 suggests that the same mechanism was involved and that these enhancers act, in part but to a significant extent, by inducing a higher partitioning tendency of the permeant into the transport rate-limiting lipoidal domains of the SC. (c) 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:297-310, 2003

Algorithms↗
PubMed1995

Mechanistic studies of the 1-alkyl-2-pyrrolidones as skin permeation enhancers.

The influences of 1-ethyl-, 1-butyl-, 1-hexyl-, and 1-octyl-2-pyrrolidone in their saline solutions on the transport of beta-estradiol, corticosterone, and hydrocortisone across hairless mouse skin under in vitro conditions have been investigated by the physical model approach. The experimental data were interpreted with a physical model that treats the stratum corneum as a diffusional barrier with a lipoidal pathway and a pore pathway. Enhancement factors (E values) for the lipoidal pathway were calculated from the permeability coefficients and solubility data as a function of the 1-alkyl-2-pyrrolidone concentration for all three permeants. A pattern of increasing E values with increasing 1-alkyl-2-pyrrolidone chain length was found, and the results were essentially the same for all three steroidal permeants. A nearly semilogarithmic linear relationship was also obtained between the enhancement potency and the carbon number of the alkyl chain; there was about an approximately 3.5-fold increase in the enhancement potency per 1-alkyl-2-pyrrolidone methylene group. An important outcome of this research is that the enhancement potencies of the 1-alkyl-2-pyrrolidones were essentially the same as those for the previously studied n-alkanols when compared at the same carbon numbers of the alkyl groups. This result is somewhat surprising as it suggests that the enhancer action resides (in its entirety) in the alkyl group, and the nature of the polar head group may not be intrinsically important in transdermal enhancement of the lipoidal pathway within a class of permeation enhancers.

Administration, Cutaneous↗
PubMed1997

Stream periphytic biodegradation of the anionic surfactant C12-alkyl sulfate at environmentally relevant concentrations.

The effects of continuous exposure to C12-alkyl sulfate on a periphytic microbial community were determined in an 8-week stream mesocosm study. C12-alkyl sulfate concentrations ranged from environmentally relevant (< 10-20 micrograms/liter) to unrealistically high concentrations (> 1500 micrograms/liter). Endpoints evaluated included turnover rates, bacterial cell density, heterotrophic mixed amino acid uptake, and fatty acid profile evaluations. Predosed periphyton demonstrated a mean turnover rate for C12-alkyl sulfate of 0.08/hr. During the 8-week dosing period, a significant increase in mean turnover rates was observed in streams dosed with > or = 61 micrograms C12-alkyl sulfate/liter, despite a 10 degrees C drop in stream temperature. A significant correlation between turnover rate and C12-alkyl sulfate concentration was also observed. While bacterial cell density increased during the study, it was determined that the biodegradation acclimation to C12-alkyl sulfate was not biomass-specific. Likewise, bacterial activity generally increased over the study, but it did not correlate with either biodegradation or bacterial cell density. Lastly, phospholipid fatty acid profiles indicate that a shift in the microbial community occurred in the high-dose stream as opposed to the control stream. This study demonstrates that C12-alkyl sulfate is rapidly degraded and induces a biodegradative acclimation response at environmentally relevant concentrations.

Amino Acids↗
PubMed1989

Synthesis of trideuterated O-alkyl platelet activating factor and lyso derivatives.

Racemic heavy isotope analogs of 1-O-alkyl-sn-glycero-3-phosphocholine (lysoPAF) and 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine (PAF) were prepared for use as internal standards to facilitate quantitative studies based on mass spectrometry. Starting from pentadecane-1,15-diol and rac-glycerol-1,2-acetonide, a convergent synthesis of 1-O-[16'-2H3]hexadecyl and 1-O-[18'-2H3]octadecyl rac-glycero-3-phosphocholine and their acetyl derivatives is described. Three deuterium atoms were introduced at the terminal position of the 1-O-alkyl group by displacement of the p-toluensulfonyl group from 1-O-alkyl-15'-p-toluensulfonate and 1-O-alkyl-17'-p-toluensulfonate with [2H3]-methylmagnesium iodide. The 1-O-alkyl-17'-p-toluensulfonate was obtained by reaction of the 1-O-alkyl-15'-p-toluensulfonate with allylmagnesium bromide, followed by reductive ozonolysis and treatment with p-toluene-sulfonyl chloride. The hydroxyl group at C-2 was protected by a benzyl group and removed at a late stage in the synthesis. This provided the corresponding lyso-derivatives or allowed preparation of racemic PAF by subsequent acetylation of the free hydroxy group. The phosphocholine moiety was introduced at glycerol C-3 by reaction with bromoethyldichlorophosphate and trimethylamine. The synthetic compounds were analyzed by FAB/MS and GC/NICIMS. They were shown to contain less than 0.6% protium impurity.

Acetylation↗
PubMed2006

Synthesis and antimicrobial activity of some new 1-alkyl-2-alkylthio-1,2,4-triazolobenzimidazole derivatives.

Some new derivatives of 1,2,4-triazolo[2,3-a]benzimidazoles were synthesized through the reaction of 1,2-diaminobenzimidazole with carbon disulfide. The resulting 1,2,4-triazolo-[2,3-a]benzimidazole-2-thione intermediate was reacted with one equivalent of alkyl halides to give the corresponding 2-alkylthio derivatives, which were further alkylated through the reaction with another one equivalent of different alkyl halides to afford the target compounds; 1-alkyl-2-alkylthio-1,2,4-traizolo[2,3-a]benzimidazoles. On the other hand, the 1,2-disubstituted derivatives with two identical alkyl substituents were prepared by the reaction of 1,2,4-triazolo[2,3-a]benzimidazole-2-thione with two equivalents of the alkyl halides. The structures of the new compounds were assigned by spectral and elemental methods of analyses. The synthesized compounds were tested for their antibacterial and antifungal activities. Most of the tested compounds proved comparable results with those of ampicillin and fluconazole reference drugs. The study indicated that, the antibacterial as well as the antifungal activities of the test compounds were improved with increase in the bulkiness of the introduced alkyl groups. Also, some active antibacterial compounds were tested for their antimycobacterial activity. All the test compounds showed equipotent antitubercular activity as that of INH as a reference drug.

Ampicillin↗
PubMed1987

Some unique features of the metabolic conversion of platelet-activating factor (AGEPC) to alkyl acyl PC by washed rabbit platelets.

Recently several synthetic analogs of 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine (AGEPC; platelet-activating factor) were characterized as selective inhibitors of this agonist's effects on rabbit platelets (Tokumura, A., Homma, H., and Hanahan, D. J. (1985) J. Biol. Chem. 260, 12710-12714). In this current investigation, these studies have been extended to include a further inquiry into the biochemical nature of the metabolic inactivation of AGEPC in rabbit platelets, and the effect of these analogs on this process. Two of the latter components (U66985 and CV3988), which blocked AGEPC biological activity on rabbit platelets, also blocked the metabolism of this agonist. The metabolic conversion of AGEPC to alkyl acyl PC was inhibited nearly sevenfold by the most potent analog, U66985. Those analogs with low (U68043) or no biological inhibitory activity (lysoGEPC) had marginal effects on the metabolism of AGEPC. The effects of these compounds on the metabolism of AGEPC was not simply due to competitive inhibition. In platelets which had been pretreated with AGEPC in absence of extracellular Ca2+ (desensitized) and washed, the metabolic conversion of AGEPC to alkyl acyl PC was actually enhanced. This enhanced metabolic inactivation of AGEPC was also observed upon the treatment of the cells with thrombin, collagen, or ionophore A23187, indicating that the metabolism of AGEPC in platelets was enhanced not only by AGEPC itself but by other agonists as well. Nearly 85% of the fatty acyl residues was arachidonate in the alkyl acyl PC derived from AGEPC. This specific acylation with arachidonate was observed in the presence and absence of the inhibitor and in desensitized cells, indicating that selectivity for arachidonate is not dependent on the enhancement of the metabolism of AGEPC. The alkyl acyl PC found in the cells treated with thrombin, collagen, or A23187 was also predominantly alkyl arachidonoyl PC. Thus it has been shown that the inactivation of AGEPC by its conversion to alkyl acyl PC by rabbit platelets is enhanced by this agonist itself and that excess amounts of AGEPC could be further inactivated by the enhanced capacity of the metabolism process.

Animals↗
PubMed1992

Bactericidal activity of alkyl peroxyl radicals generated by heme-iron-catalyzed decomposition of organic peroxides.

To clarify the nature of cytocidal molecular species among the radicals generated in the iron-catalyzed reactions of peroxides (ROOH), we examined the cytocidal effects of these radicals against gram-positive and gram-negative bacteria in the presence or absence of various radical scavengers. Three organic peroxides, t-butyl hydroperoxide (t-BuOOH), methyl ethyl ketone peroxide (MEKOOH), and cumene hydroperoxide, were used. Each radical generated from these peroxides was identified and quantitated by electron spin resonance (ESR) spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). The major cytotoxic radical species generated in the mixtures of various peroxides and heme iron, especially methemoglobin, metmyoglobin, or hemin, was the alkyl peroxyl radical (ROO.). Strong bactericidal action against gram-positive bacteria was observed in the peroxide-heme iron system, especially in the case of t-BuOOH and MEKOOH. Killing curves for gram-positive bacteria showed an initial lag period, which may indicate the multihit/multitarget kinetics of cell killing. When the diethylenetriamine pentaacetic acid (DTPA)-Fe2+ complex was used as a catalyst for decomposition of various peroxides, alkyl, alkoxyl, and alkyl peroxyl radicals were identified by spin-trapping analysis. However, study of the time course of alkyl peroxyl radical production in the DTPA-Fe2+ complex system revealed that radical species generated in this system were very short lived: a maximal level was achieved within 1 min and then declined sharply, and no bactericidal activity was observed after 10 min. In contrast, the alkyl peroxyl radical level generated by the organic peroxide-heme iron system remained high for 30 min or longer. The generation of alkyl peroxyl radicals quantified by ESR correlated quite well with the bactericidal effect of the system of peroxide plus iron. In addition, bactericidal activity was completely inhibited by the addition of the spin trap DMPO, as well as of other various radical scavengers (alpha-tocopherol and L-ascorbic acid), into the peroxide-heme iron system, but this effect was not observed with superoxide dismutase, beta-carotene, dimethyl sulfoxide, diphenylamine, or butylated hydroxyltoluene. In view of these results, it is assumed that alkyl peroxyl radicals are the potent molecular species that are cytotoxic against bacteria, whereas alkoxyl radicals (RO.) generated in this system do not affect bacterial viability.

Benzene Derivatives↗
PubMed1988

Reversal in helix sense of copoly(beta-alkyl-L-aspartate-beta-benzyl-L-aspartate).

The conformation of copoly(beta-alkyl-L-aspartate-beta-benzyl-L-aspartate), in which the alkyl group is ethyl, propyl, butyl, hexyl, nonyl, dodecyl, or stearyl, was studied in solution and the solid state by optical rotatory dispersion and circular dichroism methods. The helix sense of the copolyaspartate studied here is transformed from a left-handed to right-handed alpha-helix as the degree of alkylation increases. Reversal in helix sense occurs, i.e., the left-handed alpha-helix based on the handedness of poly(beta-benzyl-L-aspartate) is transformed into a right-handed alpha-helix with increase in alkyl groups with right-handed nature. Reversal in helix sense is also observed for copolyaspartates with an intermediate or high degree of alkylation as temperature rises. Copolyaspartates with hexyl, nonyl, or dodecyl groups exhibit an induced circular dichroism around 230-238 nm and can form an ordered side chain structure which is broken down at high temperature. One has to consider the conformation of the omega-helix and beta-form of the copolyaspartates in the solid state in addition to the reversal in helix sense. Copolyaspartates with a low degree of alkylation are in the alpha-helical conformation over the low temperature range and adopt the omega-helical conformation in the high temperature range, indicative of a thermal alpha-omega transition. A small number of alkyl groups can be incorporated into the benzene ring stacking of the omega-helix, but not a large number. All the copolyaspartates can assume the beta-form at high temperatures. The helix conformation is not significantly affected by the formation of side chain crystals of the copolyaspartate with a large number of stearyl groups, in contrast to copolyglutamate.

Circular Dichroism↗