Mechanism of action of the nitrosoureas--1. Role of fluoroethylcytidine in the reaction of bis-fluoroethyl nitrosourea with nucleic acids

The nitrosoureas are known to react covalently with nucleic acids and have been shown to decompose in aqueous solution to generate the equivalent of haloethyl carbonium ions. Evidence is presented in this paper that these carbonium ions react with nucleosides to form intermediate haloethyl derivatives. One such haloethyl nucleoside, 3-β-fluoroethylcytidine, has been identified as a reaction product of bis-fluoroethyl nitrosourea (BFNU) and cytidine. Fluoroethylcytidine undergoes an unusual intramolecular cyclization reaction to form 3,N⁴-ethanocytidine. This is a simple intramolecular crosslinking reaction in the terminology of alkylating agent chemistry, and haloethyl nucleosides formed by the nitrosoureas can probably undergo either inter- or intrastrand cross-linking reactions in analogy with the classical alkylating agents. It seems probable that these reactions are important to the cytotoxic and mutagenic actions of these agents.     

Mechanism of action of the nitrosoureas—IV: Reactions of bis-chloroethyl nitrosourea and chloroethyl cyclohexyl nitrosourea with deoxyribonucleic acid

Calf thymus DNA was reacted with ¹⁴C-labeled bis-chloroethyl nitrosourea (BCNU), and chloroethyl cyclohexyl nitrosourea (CCNU), and the nature of the derivatives investigated in an enzymatic digest. In agreement with earlier studies on polyribonucleotides, evidence was obtained for the formation of 7-hydroxyethyldeoxyguanosine, 3-hydroxyethyldeoxycytidine and 3,N⁴-ethanodeoxycytidine. In addition, significant amounts of 7-aminoethylguanine were identified in the hydrolysate of DNA treated with BCNU, but not in the hydrolysate of DNA treated with CCNU. Aminoethylguanine was also formed when DNA was reacted with chloroethylamine, suggesting that BCNU produced aminoethylguanine via chloroethylamine as an intermediate. Because both BCNU and CCNU are effective antitumor agents, the formation of aminoethylguanine is probably not an important cytotoxic reaction, but it may have significance as far as mutagenic or carcinogenic activities are concerned.     

Mechanism of action of the nitrosoureas--II. Formation of fluoroethylguanosine from the reaction of bis-fluoroethyl nitrosourea and guanosine

The haloethyl nitrosoureas evidently decompose in neutral aqueous solution to generate haloethyl carbonium ions. In support of this hypothesis, we have shown that bis-fluoroethyl nitro-sourea (BFNU) reacts with guanosine to generate 7-β-fluoroethylguanosine, in addition to larger amounts of 7-β-hydroxyethylguanosine. This nucleoside analog has been synthesized from guanosine and fluorobromoethane, and identified in a BFNU-guanosine reaction mixture by high pressure liquid chromatography. Fluoroethylguanosine, per se, has an antitumor effect against P-388 murine leukemia, suggesting that it may have some role in mediating the antitumor or toxic effects of BFNU.     

Mechanism of action of 2-haloethylnitrosoureas on deoxyribonucleic acid. Nature of the intermediates from nitrosourea decomposition.

Direct current (DC) and differential pulse polarographic analyses were used to measure the rates of decomposition of a series of 2-haloethylnitrosoureas in aqueous solution. Measured by these methods, the rates of the first and rate-determining step which show a marked pH and solvent dependence agree with the overall rate of decomposition measured by gas evolution. In the 1,3-bis(haloethyl)-1-nitrosourea series, changing the nature of the halogen X has a small effect on the rate of decomposition. In the 3-cyclohexyl-1-(2-haloethyl)-1-nitrosourea series, changing X for OH or OCH₃ results in the rate of hydrolysis being reduced considerably. A free—NH₂ group in the nitrosourea structure as in CNU, MNU, ENU, CPNU, 4-CBNU and 5-CPNU accelerates considerably the rate of decomposition relative to the BCNU and CCNU series. Arrhenius parameters for the decomposition in aqueous pH 7.1 solution in the temperature range 28–47° were obtained for BFNU, BCNU and BBNU: log A, ?20.1± 1.4,?21.6± 0.7 and ?22.3±1.6; E_a, 24.4 ± 2.0, 26.5± 1.0 and 27.2 m 2.3 kcal/mole. The corresponding values for BINU were estimated as log A,?23.3± 3.0; E_a, 28.0± 3.0 kcal/mole. Examination of the decomposition products of 1,3-bis(2-chloropropyl)-1-nitrosourea (BCNU-β-Me) and 1,3-bisl 1-(chloromethyl)ethyl]-1-nitrosourea (BCNU-α-Me) favors decomposition pathway B via the diazohydroxide and cyclic chloronium ion for BCNU-β-Me and via the diazohydroxide and/or 2-chloro-1-methylethyl carbonium ion for BCNU-α-Me. While there is no evidence for the contribution of pathway A via a 2-imino-N-nitrosooxazolidinone for these compounds, consideration of product type and yields implicates a third decomposition pathway, via a 1,2,3-oxadiazoline intermediate. Additional evidence for an oxadiazoline intermediate is obtained by the isolation of 2-bromoethanol when BCNU is decomposed in the presence of a high concentration of sodium bromide.     

Modulation of nitrosourea resistance in human colon cancer by O6-methylguanine.

Human colon cancer is resistant to a variety of alkylating agents including the nitrosoureas. To specifically evaluate nitrosourea resistance, we studied the role of O6-alkylguanine-DNA alkyltransferase (alkyltransferase) which is known to repair nitrosourea-induced cytotoxic DNA damage. Alkyltransferase activity varied over a similar wide range in 25 colon cancer biopsies and 14 colon cancer cell lines but the activity was not correlated with differentiation status, Dukes' classification or in vitro growth characteristics. 1,3-Bis-(2-chloroethyl)-1-nitrosourea (BCNU) resistance and alkyltransferase activity were highly correlated (R2 = 0.929, P less than 0.001) in 7 different colon cancer cell lines, suggesting that the alkyltransferase is an important component of nitrosourea resistance in colon cancer cells. In the BCNU-resistant, high alkyltransferase VACO 6 cell line, inactivation of the alkyltransferase by O6-methylguanine caused a proportional decrease in the BCNU IC50, consistent with that predicted by the regression line. Enzyme inactivation was also associated with a marked increase in DNA cross-link formation. Because alkyltransferase correlates with BCNU resistance in colon cancer, and resistance can be reversed by inactivating the protein, the alkyltransferase may have an important role in nitrosourea resistance in human colon cancer cells. These data provide the rationale for clinical trials in colon cancer with biochemical modulators of the alkyltransferase to increase the therapeutic response to nitrosoureas.     

A chemical basis for the antitumor activity of chloroethylnitrosoureas

A comparison of the aqueous decomposition products of several haloethylnitrosoureas has led to a suggested mode of decomposition and antitumor effect for these compounds. 1,3-Bis-chloroethyl-1-nitrosourea (BCNU), 1-chloroethyl-3-cyclohexyl-1-nitrosourea (CCNU), 1,3-bis-fluoroethyl-1-nitro-sourea (BFNU) and 1-chloroethyl-1-nitrosourea (CNU) decompose in buffered aqueous solution to yield haloethanol, vinyl halide, dihaloethane and acetaldehyde. Evidence is presented that these products are derived from an intermediate haloethyl carbonium ion. On the other hand, 1-chloroethyl-3,3-dimethyl-1-nitrosourea decomposes slowly in aqueous solution, generates acetaldeh?yde, but not the other volatile compounds described above, and is not toxic to murine L1210 leukemia cells in vitro. In contrast to the disubstituted nitrosoureas, chloroethylnitrosourea does not generate an organic isocyanate on aqueous decomposition, but is a very active antitumor agent both in vitro and in vitro. These observations support the hypothesis that the antitumor activity of the chloroethylnitrosoureas is due to the facile decomposition of the parent molecule to form a chloroethyl carbonium ion (or diazonium precursor).     

The role of isocyanates in the toxicity of antitumour haloalkylnitrosoureas

The cytotoxicity of the antitumour nitrosoureas BCNU and CCNU and the isocyanates which they liberate (chloroethylisocyanate and cyclohexylisocyanate respectively) has been measured utilising an in vitro-in vivo bioassay. Lines of the TLX5 lymphoma and L1210 leukaemia were used which were either sensitive or resistant to nitrosoureas in vivo. An estimated logarithmic cell kill produced by each compound in vitro (before injecting the cells into animals) was calculated by reference to assays of the survival time of animals given from 2 × 10⁵ to 2 × 10⁰ cells of each line. Resistance to both BCNU and CCNU was observed in vitro in the cell lines of the TLX5 lymphoma made resistant to either BCNU or a dimethyltriazene in vivo. The latter tumour was cross-resistant in vivo to nitrosoureas. Resistance in vitro to nitrosoureas was also observed in a line of L1210 leukaemia which had had resistance to BCNU induced in vivo. The nitrosourea resistant TLX5 lymphomas were cross-resistant in vitro to both cyclohexylisocyanate and chloroethylisocyanate whereas the nitrosourea resistant L1210 line showed no cross-resistance to cyclohexylisocyanate and marginal cross-resistance to chloroethylisocyanate. The results suggest that the TLX5 lymphoma, which is naturally resistant to alkylating agents of the 2-chloroethylamine type, may be sensitive in vivo to nitrosoureas as a consequence of the intracellular release of isocyanates. This hypothesis was supported by the finding that the resistant TLX5 lymphoma showed no cross-resistance to other electrophilic agents, for example formaldehyde, monomethyltriazene or HN2. The transport of nitrosoureas into the sensitive and resistant cell lines was similar in profile and there was no difference in the concentration of non-protein thiols.     

O~6-苄基鸟嘌呤增强 1,3-二 (2 -氯乙基)-亚硝基脲对人肝癌细胞及其移植瘤的抗肿瘤作用(英文)

应用噻唑蓝 (MTT)法检测 O6-苄基鸟嘌呤(O6- BG)与 1 ,3-二 (2 -氯乙基 ) -亚硝基脲 (BCNU)合用的细胞毒作用及透射电镜检测凋亡细胞的方法研究了 O6- BG对 O6-烷基鸟嘌呤 - DNA烷基转移酶(O6- AGT )阳性的人肝癌细胞 SMMC- 772 1对BCNU细胞毒作用敏感性的影响及其与 BCNU合用治疗移植瘤的协同效果 .结果显示 :1 .5- 6.0 mg· L-1的 O6- BG预先作用 2 h后 ,SMMC- 772 1细胞对 BCNU的敏感性明显增加 ;0 .75- 6.0 mg· L-1的 O6- BG可完全快速地抑制肿瘤细胞的 AGT活性并持续 1 2 h;ip 90 mg· kg-1的 O6- BG预处理 2 h后给予 2 5mg·kg-1的 BCNU治疗 ,可使动物 sc接种的人肝癌移植瘤生长延迟 38.6d,诱导肿瘤细胞凋亡 ,并且可明显抑制肿瘤组织的转移酶活性 .说明 O6- BG与 BCNU合用于 AGT阳性的肿瘤将具有明显的治疗效果     

Mechanism of action of 2-haloethylnitrosoureas on deoxyribonucleic acid. Nature of the chemical reactions with deoxyribonucleic acid.

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) covalently cross-links DNA under physiological conditions. Methyl substitution at either carbon atom of the 2-chloroethyl portion of the molecule prevents cross-linking. Haloalkyi nitrosoureas including 3-chloropropyl, 4-chlorobutyl and 5-chloropentyl, although they readily alkylate DNA, exhibit no ability to cross-link DNA. 3-(2-Chloroethyl)-1-methylcytosine hydrochloride and N⁴-(2-chloroethyl)- 1-methylcytosine hydrochloride, similar to intermediates suggested in the cross-linking process, alkylate PM2-CCC-DNA readily. These two cytosine derivatives also cyclize readily to give 3,N⁴-ethano-1-methylcytosine closely similar to a species isolated from the treatment of poly-C with BCNU. A number of processes including the extent of DNA alkylation, measured with [¹⁴C]CCNU labeled in the ethylene portion of the molecule, as well as concomitant DNA single strand scission, and intramolecular alkylation and/or hydrolysis of the chloroethyl cytidine intermediate were investigated as to their effects upon the interstrand cross-linking process.     

Nitrosourea-induced DNA single-strand breaks.

Reaction of DNA with nitrosoureas in vitro results in extensive formation of alkali labile sites. Two types of single-strand scission (SSS) processes may be distinguished by their different rates: (1) type I SSS which occurs relatively fast at high pH, and (2) type II SSS which is a much slower process. Neither of these processes is affected by free radical traps. Dimethyl sulfate, which is known to alkylate DNA bases but not phosphate residues, shows no type I SSS but does show extensive type II SSS. That the latter process involves alkylation of bases followed by the formation of apurinic sites was confirmed by using endonuclease VI, an enzyme specific for apurinic positions. Reactions of chloroethylnitrosoureas with DNA produces both type I and type II SSS. Aliphatic amines produced in the decomposition of alkyl nitrosoureas do not contribute significantly to the scission of apurinic sites via Schiff base formation. However, this process may be significant for aryl nitrosoureas. Ethyl nitrosourea (ENU), 1, 3-bis(2-chloroethyl)nitrosourea (BCNU), and 3-cyclohexyl-1-(2-hydroxyethyl)-1-nitrosourea (CHNU) readily degrade poly A by phosphate alkylation, with rates that parallel their relative rates of decomposition. The relative rates of hydrolysis of triethylphosphate and β-hydroxyethyl diethyl phosphate parallel the type I SSS observed for ENU and CHNU with DNA. The type I SSS of DNA by these compounds appears to involve a similar phosphotriester formation and hydrolysis. The type I SSS is in accord with the observed extreme liability of β-hydroxyethyl diethyl phosphate which is attributed to participation of the OH group, and by the fact that methylation of the OH completely inhibits the type I SSS process.     

Pharmacokinetic profile of fotemustine in rat plasma by electrochemical detection

1. A differential pulse polarographic (DDP) assay of diethyl-1-[3-(2-chloroethyl)-3-nitrosoureido] ethylphosphonate (fotemustine) was developed to determine the kinetics of this nitrosourea in plasma, brain, liver, lung and kidney. The optimized polarographic determination, previously applied to BCNU and CCNU, attained a limit of detection of 0.3 micrograms fotemustine/ml plasma and 1 microgram/g in other tissues; the calibration curve in electrolyte or in plasma was linear between 0.5 and 100 micrograms/ml. 2. The choice of electrolyte, the effects of pH, temperature, light, and the stability of fotemustine in samples were investigated. Recovery of fotemustine was 76-90% from lung greater than kidney greater than plasma greater than brain greater than liver; the variability coefficients were low (4.0-7.3%). Tissue samples could be stored for 20 days at -20 degrees C without loss of the compound. 3. Plasma kinetics of fotemustine and BCNU given to male rats at therapeutic doses (20 mg/kg i.v.) fitted a bi-exponential equation. Two minutes after injection plasma, levels of unchanged nitrosoureas were 15 and 11 micrograms/ml respectively. Fotemustine could be measured (0.92 microgram/ml) for 3 h, while BCNU could not be detected after 60 min. Unchanged fotemustine was cleared from the blood stream 3-5 times more slowly than BCNU.     

Capillary Gas Chromatography and Thermionic N-P-Specific Detection of 13-Bis(2-chloroethyl)-l-nitrosourea (BCNU) or l-(2-Chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) in Stability and Pharmacokinetic Studies

An expedient, rapid, and sensitive capillary gas chromatographic method for the analysis of l,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) or l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) in plasma is described. Separation of the underivatized nitrosourea compounds was performed on a 0.33-mm-i.d., 25-m fused-silica, SE-30 capillary column, and detection was carried out using a thermionic N–P-specific detector. The compounds were extracted from plasma with benzene with a yield of >87%. The assay was linear in the ranges of 0.001 to 0.5 and 0.5 to 25 µg/ml for CCNU or 0.003 to 0.50 and 0.5 to 25 µg/ml for BCNU, with correlation coefficients from 0.9914 to 0.9999 and coefficients of variation (CV) of <3.3%. Other antineoplastic agents did not interfere in the assay. The method was employed to study the pharmacokinetics of BCNU in rabbits. The plasma concentration-time curves were fit to a two-compartment model with a mean (SE) , , and total-body clearance of 2.898 (0.913) hr^–1, 0.1228 (0.0179) hr^–1, and 7.211 (2.862) liters/hr · kg, respectively. Further, the stability of BCNU and CCNU in solution was examined at different temperatures. Both compounds were stable in benzene or acetone (4 to 37°C) but labile in plasma even if refrigerated. The apparent rate constants for degradation of BCNU and CCNU were 0.09921 and 0.02853 hr^–1 at 4°C and 5.998 and 2.553 hr^–1 at 37°C, respectively.     

N-Methylformycins. Reactivity with adenosine deaminase, incorporation into intracellular nucleotides of human erythrocytes and L 1210 cells and cytotoxicity to L 1210 cells.

The N-methyl derivatives of the C-nucleoside, formycin (7-amino-3(β-d-ribofurano-syl)pyrazolo[4, 3-d]pyrirnidine) were compared to formycin and adenosine with regard to their substrate activity with human erythrocytie adenosine deaminase (ADA), their ability to form intracellular nucleotides and their cytotoxicity to L1210 cells. Only 2-methylformycin (K_m = 6.1 mM, relative V_max = 396) and N^? -methylformycin (K_m = 0.1 mM, relative V_max = 3) showed substrate activity with ADA (corresponding kinetic parameters for adenosine were: K_m = 0.025 mM, relative V_max = 100). In contrast to previous hypotheses, these results suggest that the conformation (either syn or anti) of an adenosine analog is not a major factor in determining substrate activity with ADA. Neither 4-methylformycin nor 6-methylformycin formed their corresponding nucleotides when incubated with human erythrocytes, whereas both 1-methylfor-mycin and 2-methylformycin formed large amounts of their corresponding mono-, di- and triphosphate nucleotides. Inhibition of ADA by pretreatment of the erythrocytes with the potent ADA inhibitor, 2'-deoxycoformycin, had no effect on the incorporation of 1-methylformycin into erythrocytic nucleotides but greatly increased the incorporation of 2-methylformycin and N⁷-methylformycin. The conversion of both 1-methylformycin and 2-methylformycin into nucleotides was almost complete after 18 hr of incubation (in the presence of 2'-deoxycoformycin in the case of 2 methylformycin), whereas that of N⁷-methylformycin was only partially complete in the presence of 2'-deoxycoformycin. With both 1-methylformycin and N⁷-methylformycin, transient accumulation of the corresponding nucleoside 5'-monophosphate derivative was observed prior to the accumulation of the triphosphate nucleotide. Results, qualitatively similar to those found with erythrocytes, were obtained when the effects of 2'-deoxycoformycin on the incorporation of 1-methyl- and 2-methylformycins into the nucleotide pools of L 1210 cells in vitro were examined. Compounds capable of forming analog nucleotides in human erythrocytes or L1210 cells if deamination is prevented either by the molecular structure of the analog or by pretreatment of the cells with 2'-deoxycoformycin, also showed marked cytotoxicity to L1210 cells in culture, i.e. 1-methyl-, 2-methyl- and N⁷-methylformycin exhibited id₅₀ values of 0.5 to 2 μM, whereas 4-methyl- and 6-methylformyein were not significantly growth inhibitory. The potential usefulness of the various N-methyl derivatives of formycin (alone or in combination with an ADA inhibitor) as cytotoxic or antiviral agents is discussed.     

Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents

Background

Chronic and oral administration of benzylamine improves glucose tolerance. Picolylamine is a selective functional antagonist of the human adenosine A_2B receptor. Phosphonic diamide derivatives enhance the cellular permeability and in turn their biological activities.

Methods

A series of heteroaryl phosphonicdiamide derivatives were designed as therapeutics to control and manage type2 diabetes. Initially defined Lipinski parameters encouraged them as safer drugs. Molecular docking of these compounds against Protein tyrosine phosphatase (PTP), the potential therapeutic target of type 2 diabetes, revealed their potential binding ability explaining their anti-diabetic activity in terms of PTP inhibition. Human intestinal absorption, Caco-2 cell permeability, MDCK cell permeability, BBB penetration, skin permeability and plasma protein binding abilities of the title compounds were calculated by PreADMET server. A convenient method has been developed for the synthesis of title compounds through the formation of 1-ethoxy-N,N’-bis(4-fluorobenzyl/pyridin-3-ylmethyl)phosphinediamine by the reaction of 4-fluorobenzylamine/ 3-picolylamine with ethyldichlorophosphite, subsequently reacted with heteroaryl halides using lanthanum(III) chloride as a catalyst.

Results

All the compounds exhibited significant in vitro anti-oxidant activity and in vivo evaluation in streptozotocin induced diabetic rat models revealed that the normal glycemic levels were observed on 12^th day by 9a and 20^th day by 5b, 5c, 9e and 9f. The remaining compounds also exhibited normal glycemic levels by 25^th day.

Conclusion

The results from molecular modeling, in vitro and in vivo studies are suggesting them as safer and effective therapeutic agents against type2 diabetes.

Graphical Abstract

Open in a separate windowDevelopment of PTPs inhibitors.

Electronic supplementary material

The online version of this article (doi:10.1186/s40199-014-0076-3) contains supplementary material, which is available to authorized users.     

A New Method for the Measurement of Nitrosoureas in Plasma: an H.P.L.C. Procedure for the Measurement of Fotemustine Kinetics

1. An analytical method for a novel nitrosourea, fotemustine, has been developed using solid-phase extraction and?h.p.l.c. with u.v. detection. As part of the development, different methods for stabilising fotemustine after sample collection have been investigated. The method has been successfully applied to pharmacokinetic studies in monkeys and man.

2. Providing plasma was separated immediately from blood and frozen within 3?min of collection, negligible degradation of fotemustine occurred. The samples could then be stored at —20°C in the dark for up to six days particularly if thawing prior to analysis was accelerated using a 50°C water-bath so that it was complete within 3?min. Equivalent results were also obtained with samples stabilised with 0·1?m citric acid immediately after the preparation of plasma.

3. The analytical method showed good precision with a within-day variation ranging between ±10.7% at the lowest concentration investigated (0.1 μg ml^?1) to 2.0% at 50.0 μgml^?1. The accuracy of measurement was from 108.9% to 97.6% at 0.1 and 50.0 μg ml^?1 respectively and the response was linear up to 50 μg ml^?1. The minimum level of quantitation was 20 ng ml^?1.

4. After a single intravenous bolus dose of [¹⁴C]fotemustine (100mg m^?2) to Cynomolgus monkeys, intact drug levels rapidly declined (t_1/2 12.6±0.5?min) although the halflife of radioactivity (approx 100?h) was much longer. The plasma clearance of fotemustine was 225±63 ml min^?1 with a volume of distribution based on area of 4.1±1.2 litres.

5. As with monkey, plasma levels of intact fotemustine in a patient given [¹⁴C]-drug as a 1?h constant rate intravenous infusion (approx. 100?mg m^?2), declined rapidly but with a half-life of 23.2?min. Again, the half-life for total radioactivity was considerably longer (30.8?h). The plasma clearance was 1426 ml min^?1 and the volume of distribution based on area was 47.71.     

Anti-tumour,toxicological and pharmacokinetic properties of a novel taurine-based nitrosourea (TCNU)

Summary A novel nitrosourea, 1-(2-chloroethyl)-3-[2-(dimethylaminosulfonyl) ethyl]-1-nitrosourea (TCNU) tauromustine, has been investigated in a broad anti-tumour screen and, in depth toxicology and initial pharmacokinetics carried out.TCNU and its two metabolites were found to exhibit equal or better oral efficacy than that of BCNU, CCNU, MeCCNU or chorozotocin against L1210 leukemia, Walker mammary carcinoma, Lewis Lung, Harding Passey melanoma and colon carcinoma C26. The toxicological profile of TCNU after acute and 3 months treatment was similar in mice and rats to that of CCNU, with the exception that, TCNU did not cause the chronic liver disturbances found for CCNU. In dogs treated for 6 weeks with TCNU leucopenia and thrombocytopenia were the major side effects. Parent TCNU was found in all dogs. The absorption was fast, the maximum level being reach after 25 mins and the mean absorption time was 22 mins. The mean half life was 16.1 mins after intravenous and 17.4 after oral administration. The combination of these factors make TCNU an interesting clinical candidate.     

Studies of the mechanism of action of the tumour-inhibitory nitrosoureas.

BCNU [1,3 bis-(2-chloroethyl)-1-nitrosourea] and some related nitrosoureas have been shown to have a wide spectrum of action against a number of transplanted rodent tumours. No correlation was found between the chemical instability of a nitrosourea and its antitumour activity. Unlike difunctional alkylating agents, the nitrosoureas inhibit the incorporation of tritiated precursors in DNA, RNA and protein to equal extents, the inhibition of tritiated thymidine incorporation into DNA occurring within 5 min of incubating cells with BCNU. Although the biological half life of BCNU was found to be very short (15 min by bioassay) a single injection was as effective against the established and widely-disseminated TLX5 lymphoma as against the early transplant. BCNU interfered specifically with the incorporation of labelled thymidine triphosphate into DNA, but no inhibition of DNA polymerase could be demonstrated at physiological dose levels. In their mechanism of action and in their biological properties the tumour inhibitory nitrosoureas are quite distinct from the bifunctional alkylating agents.     

Rigidified A3 Adenosine Receptor Agonists: 1-Deazaadenine Modification Maintains High in Vivo Efficacy

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Pathways of nucleotide metabolism in schistosoma mansoni—VI adenosine phosphorylase

Schistosoma mansoni worms have been found to have an adenosine phosphorylase enzyme which requires inorganic phosphate during cleavage and α-ribose-1-phosphate for synthesis of adenosine from adenine. Kinetics of the reaction show a K_m of 5.6 × 10^?5 M for adenosine and a broad pH activity range from 6.0 to 8.0. The adenosine phosphorylase activity can be distinguished from purine nucleoside phosphorylase by substrate specificity and by product inhibition studies.     

Synthesis and antitumor evaluation of some nitrosourea and nitrogen mustard amino acid derivatives

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