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The influence on red blood cells (RBC) of two cancerostatic-(ZIMET 3106 and ZIMET 3393) and two immunomodulating agents (ZIMET 3164 and ZIMET 86/76) administered subcutaneously, or intraperitoneally in case of the radiolabelled N-mustard compounds, to mice, was studied by means of measurements of the radiolabelled compounds in blood, by cell electrophoresis, filipin-induced hemolysis of pretreated RBC and by scanning electronmicroscopy. The portion of doses applied which binds to RBC-surface decreases in the sequence of ZIMET 3106, ZIMET 3164, ZIMET 3393 and ZIMET 86/76. However, the highest reduction of the electrophoretic mobility and protection from filipin-induced hemolysis of pretreated RBC was found with ZIMET 3164. In both tests ZIMET 86/76 proved to be ineffective. These findings are in good agreement with the modifications demonstrated in pretreated RBC after filipin-induced hemolysis by means of SEM. The results presented point to a N-mustard specific interaction between the cholesterol of the membrane and/or other membrane constituents. However, these fundamental differences found in binding affinity, surface-charges and membrane interactions caused by the chemically similar compounds cannot be attributed merely to the N-mustard group.
Nine new nitrogen mustard compounds derived from 2,6-difluoro-4-hydroxy- (3a-e) and 2,6-difluoro-4-amino- (4a-d) aniline were synthesized as potential prodrugs. They were designed to be activated to their corresponding 3,5-difluorophenol and -aniline (4)-nitrogen mustards by the enzyme carboxypeptidase G2 (CPG2) in gene-directed enzyme prodrug therapy (GDEPT) models. The compounds were tested for cytotoxicity in the MDA MB-361 breast adenocarcinoma. The cell line was engineered to express stably either CPG2 tethered to the cell surface stCPG2-(Q)3 or beta-galactosidase (beta-Gal) as control. The cytotoxicity differentials were calculated between CPG 2-expressing and -nonexpressing cells and yielded different results for the two series of prodrugs despite their structural similarities. While the phenol compounds are ineffective as prodrugs, their aniline counterparts exhibit outstanding activity in the tumor cell lines expressing CPG2. [3,5-Difluoro-4-[bis(2-chloroethyl)amino]phenyl]carbamoyl-l-glutamic acid gave a differential of >227 in MDA MB361 cells as compared with 19 exhibited by 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-l-glutamic acid, 1a, which has been in clinical trials.
Diethylstilbestrol, psoralen, and propranolol were used as potential carrier molecules for selective concentrations of a nitrogen mustard moiety in breast, skin, and lung tissues, respectively. The propranolol derivative gave two racemic mixtures, which were tested to ascertain any differences in anticancer activity. The insertion of a P = O group between the carrier and oncolytic portions offsets the excess lipophilic contribution of the latter and possibly provides for latentiation of alkylating activity. Murine tumor testing of the phosphoramide mustard derivatives and two intermediates indicated that two compounds possessed marginal activity against mammary carcinoma and lymphocytic leukemia.
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The interest of cytotoxic-linked estrogens as therapeutical drugs for controlling the growth of breast cancers relies on their potential binding to estrogen receptors (ER) in these cancers. 14, 15-alpha and beta epoxide derivatives of estradiol-17 alpha and 17 beta were investigated for their ER binding affinity and their cytotoxic activities on the MCF-7 and Evsa-T cell lines. 14, 15 alpha and beta-epoxides of estradiol 17 alpha as well as the 14, 15 alpha epoxide of estradiol 17 beta bound to ER. No compound revealed any cytotoxicity on the cell lines. A 11 beta-aziridine derivative of estrone showed significant binding activity to ER. Concentrations of 10(-7) and 10(-8) M of this compound act stimulating on the growth of MCF-7 cell line. 10(-6) M is slightly inhibitory. There is no effect on Evsa-T cells. Binitrogen mustard derivatives of hexestrol and diethylstilbestrol displayed a very low binding activity whereas mononitrogen mustards of estrone showed a significant binding activity. At concentrations of 10(-6) M all mustard compounds inhibited the growth of MCF-7 cell line. The inhibitory influence of the mononitrogen mustards were higher than those of the binitrogen mustards. With regard to the Evsa-T cells only mononitrogen mustard displayed a growth inhibiting effect.
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A procedure for the semi-quantitative determination of thiodiglycol, a metabolite of the vesicant mustard gas, in urine has been developed. Thiodiglycol was converted into mustard gas using concentrated HCl at temperatures close to 100 degrees C. The headspace of the solution containing mustard gas, was trapped on an adsorption tube filled with Tenax-GC which was subsequently analyzed by gas chromatography/mass spectrometry. Using 10 mL of urine, a detection limit of a few ng/mL of thiodiglycol was achieved. The procedure was applied to urine samples obtained from Iranian patients who were the alleged victims of an attack by chemical warfare agents (probably mustard gas). A number of control samples were investigated as well. Thiodiglycol was found in the urine of the Iranian patients in concentrations varying between 3 and 140 ng/mL. However, the detection of thiodiglycol in concentrations up to 55 ng/mL in control samples excluded the unambiguous verification of the use of mustard gas against the Iranian patients.
Investigation of toxicity of mustard compounds to aquatic organisms has been limited although their effects on terrestrial mammal species have been well studied. In this study, the 48-h LC50 values of nitrogen mustard (HN2) are reported for two aquatic invertebrate species (Daphnia magna and Ceriodaphnia dubia) and for one fish species (Pimephales promelas). Mean LC50 values to C. dubia, D. magna, and P. promela were 1.12, 2.52, and 98.86 mg/L, respectively. C. dubia was the species most sensitive to HN2. Seven-day lethal and sublethal tests with P. promelas and C. dubia were also conducted. In chronic tests, fathead minnow growth was significantly reduced by 2.50 mg/L HN2, while C. dubia reproduction was significantly affected by 7.81 mug/L HN2. These adverse effects on aquatic organisms caused by lower-level concentrations of HN2 indicate that a possible aquatic ecosystem disaster could occur either after a chemical spill or during chemical warfare.
Improvements on a procedure for the determination of thiodiglycol in urine are presented. This procedure is based on the conversion of thiodiglycol to mustard gas with concentrated HCl followed by headspace analysis. With deuterated thiodiglycol as the internal standard, more accurate quantitative analyses are possible. Residual amounts of chlorine in the water used for preparation of standard solutions posed problems, and the reaction between chlorine and thiodiglycol in water has been studied. The possible formation of mustard gas from thiodiglycol and sodium chloride was also investigated. The modified procedure was applied to urine samples of several Iranian patients who were victims of an alleged attack with mustard gas and who were treated in European hospitals in 1986. With the exception of one relatively high value (330 ng/mL), the thiodiglycol concentrations were in the same range (10 to 100 ng/mL) as those found during an investigation in 1984. The urine of 20 male controls contained thiodiglycol amounts not above 20 ng/mL. The combined data obtained in 1984 and 1986 (25 Iranian patients and 25 controls) show statistically significant differences. Approximately 80% of the Iranian patients had levels above the 95% confidence limit calculated from the control group.
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6-Bis-(2-chloroethyl)amino-6-deoxy-D-galactopyranose hydrochloride has been synthesized, characterized, and evaluated for antitumor activity and bone marrow toxicity in mice. The 1D- and 2D-NMR studies show the compound to exist as a beta-anomer chair conformation (23%), alpha-anomer chair conformation (22%), and several equilibrating boat conformations or furanose forms (55%). A single ip LD10 dose of 15.0 mg/kg produced antitumor activity against the murine P388 leukemia superior to that achieved with an equitoxic dose of nitrogen mustard. In normal mice, this 15.0-mg/kg dose produced minimal depression of peripheral white blood cells and no significant decrease in absolute neutrophil counts. A reduction in toxicity was also demonstrated for human bone marrow CFU-GM, as compared with nitrogen mustard and L-PAM. This and other sugar-containing mustard compounds may represent a class of antineoplastic alkylating agents with reduced bone marrow toxicity.
Capillary column isobutane chemical ionization was found to be an excellent method for the mass spectral characterization of mustard, other sulfur vesicants and related compounds. Interpretation of [M + H]+ and fragmentation ion information afforded by this technique enabled the identification of many previously unreported mustard impurities. The developed methodology was applied to the analysis of an Iran/Iraq soil sample suspected to have been contaminated with mustard. Mustard and 17 other mustard related impurities were identified and characterized in this sample under electron impact and isobutane chemical ionization conditions.
The alkylation of the cell biopolymers (RNA, DNA, proteins) by reagents Tp'(Et)Tp'(Et)Tp'(Et)TpU(CHRCl) (1) Tp'(Et)Tp''(Et)Tp'(Et)TpU(CHRCl) (2) Tp''(Et)Tp'(Et)Tp''(Et)TpU(CHRCl) (3) Tp''(Et)Tp''(Et)Tp''(Et)TpU(CHRCl) (4) Tp(Et)Tp(Et)Tp(Et)TpU(CHRCl) (5) Tp(Et)Tp(Et)Tp(Et)Tp(Et)U(CHRCl) (6) TpTpTpTpU(CHRCl) (7) where (CHRCl) is the residue of 2',3'-O-[4-N-(2-chloroethyl)-N-methylamino]-benzylidene has been investigated in the case of the ascite carcinoma Krebs-2. p' and p" designate the enantiomeric configurations at the internucleotide phosphorus atoms of the triester fragment--Tp(Et)T--, and p designates the racemic mixture. Completely and partly ethylated reagents (1)-(6) have been found to bind to the cells 4-15 fold more effectively than the diester derivative. The concentration of reagents (1)-(6) in the cells is 2-7 fold higher than in the external medium. Among the diastereomers (1)-(4) reagent (4) with the p"-configuration is the most efficient in binding with the cells 2-3 fold more efficient than reagents (1)-(3). The main targents of modifications performed in the cells by means of reagents (1)-(7) have been established. These are RNA, DNA and proteins. The share of the reagents which react with nucleic acids increases from 45% [reagent (1)] to 80% [reagent (4)], and that reacting with proteins decreases from 50 to 20% correspondingly. Reagent (4) with the p" configurations at phosphotriester fragments alkylates nucleic acids most effectively among the phosphotriester diastereomers (1)-(4): 11-fold more efficient than reagent (1) with configuration p'. The extent of modification of poly(A)+-tracts of m-RNA by reagent (4) in comparison with reagent (1) is 50-fold higher.