Utilizing a D-amino acid as a drug carrier for antineoplastic nitrogen mustard groups

The evaluation of an alkylating nitrogen mustard agent that utilizes D-alanine as a drug carrier for three chloroethyl substituents (ClCH₂CH₂-) is shown. Various important pharmacological properties were determined including polar surface area, partition coefficient, molar volume, polarizability, numbers of -OH and -NH₂ groups, and aqueous solubility. The synthetic approach utilizes 1,2-dichloroethane reaction with the primary amine of D-alanine resulting in chloroethyl (ClCH₂CH₂-) substituents. A nitrogen mus-tard group results, and this agent showed alkylation activity in aqueous solution directed toward a nucleophilic primary amine group. Kinetics of alkylation activity is determined by placing p-chloroaniline and the nitrogen mustard agent in sodium bicarbonate buffered aqueous solution at physiological pH 7.4 and 37°C. Samples taken from the test solution are injected with fluorescamine that reacts specifically with primary amine functional groups. Absorbance measurements obtained at 400 nm by UV-Vis spectrometer indicates the relative amounts of nonalkylated p-chloroaniline in the test solution. The D-alanine nitrogen mustard agent effectively alkylated the nucleophilic primary amine of p-chloroaniline with zero-order kinetics. The rate constant was determined to be 7.445E-04 mol/l/min. Formula weight, polar surface area, Log P, molar volume, violations of Rule of 5 for D-alanine mustard agent are 276.59, 29.543 angstroms², 1.605, 222.3 cm³, and zero violations, respectively. Cluster analysis of molecular properties showed D-alanine mustard agent to be quite similar to cyclophosphamide. This agent showed good druglikeness and zero violations of the Rule of 5, indicating good bioavailability. Molecular properties calculated for the mustard agent are numerically comparable to some clinical anticancer drugs.     

Bioreversible quaternary N-acyloxymethyl derivatives of the poorly soluble tertiary amine Lu 28-179—Synthesis, pharmaceutical chemical characterization and bioavailability studies in dogs

Quaternary prodrug types of poorly water-soluble tertiary amines have been shown to possess significantly enhanced solubilities as compared to the parent amine. In the present study, the N-acyloxymethylation approach to improve the aqueous solubility of Lu 28-179 a tertiary amine exhibiting an intrinsic solubility in the nanomolar range, have been investigated. The acetyl-, propanoyl-, butanoyl-, isobutanoyl- and pivaloyloxymethyl derivatives were isolated as chloride salts and the aqueous solubilities (S) far exceeded that of the parent tertiary amine (S₀). S/S₀ ratios in the range 2–4 × 10⁶ were found for the most soluble prodrugs. The prodrugs were reasonable stable to hydrolysis in aqueous buffer solutions (pH 0.1–7.4), but susceptible to undergo enzyme-mediated regeneration of Lu 28-179 after incubation in human plasma, simulated intestinal fluid and duodenum juice from pigs and dogs. Despite promising in vitro properties the prodrugs were unable to improve the oral bioavailability of Lu 28-179 as compared to that obtained after administration of a reference formulation of the parent drug in the dog.     

叔胺药物在酸水溶液中的分配率研究

氯仿作抽提溶剂,用8～11种叔胺药物在6种无机酸、8种有机酸水溶液中,研究了叔胺分子与分配率的关系;无机酸、有机酸分子与叔胺分配率的关系;酸的pKa与叔胺分配率的关系。得出了一些结果。实验表明:各叔胺间在酸水中的分配率的差别,较在中性、碱性水中时大。还证明即使在无机强酸水溶液中,很多叔胺盐也能被氯仿抽出。     

Utilizing a D-Amino Acid as a Drug Carrier for Antineoplastic Nitrogen Mustard Groups

The evaluation of an alkylating nitrogen mustard agent that utilizes D-alanine as a drug carrier for three chloroethyl substituents (ClCH₂CH₂-) is shown. Various important pharmacological properties were determined including polar surface area, partition coefficient, molar volume, polarizability, numbers of -OH and -NH₂ groups, and aqueous solubility. The synthetic approach utilizes 1,2-dichloroethane reaction with the primary amine of D-alanine resulting in chloroethyl (ClCH₂CH₂-) substituents. A nitrogen mus-tard group results, and this agent showed alkylation activity in aqueous solution directed toward a nucleophilic primary amine group. Kinetics of alkylation activity is determined by placing p-chloroaniline and the nitrogen mustard agent in sodium bicarbonate buffered aqueous solution at physiological pH 7.4 and 37°C. Samples taken from the test solution are injected with fluorescamine that reacts specifically with primary amine functional groups. Absorbance measurements obtained at 400 nm by UV-Vis spectrometer indicates the relative amounts of nonalkylated p-chloroaniline in the test solution. The D-alanine nitrogen mustard agent effectively alkylated the nucleophilic primary amine of p-chloroaniline with zero-order kinetics. The rate constant was determined to be 7.445E-04 mol/l/min. Formula weight, polar surface area, Log P, molar volume, violations of Rule of 5 for D-alanine mustard agent are 276.59, 29.543 angstroms², 1.605, 222.3 cm³, and zero violations, respectively. Cluster analysis of molecular properties showed D-alanine mustard agent to be quite similar to cyclophosphamide. This agent showed good druglikeness and zero violations of the Rule of 5, indicating good bioavailability. Molecular properties calculated for the mustard agent are numerically comparable to some clinical anticancer drugs.     

Deamination of fumonisin B(1) and biological assessment of reaction product toxicity

Fumonisin B(1), a potent mycotoxin found in grain, has been resistant to degradation and detoxification by a variety of methods, including milling, fermentation, ammoniation, and ozonation. The primary amine of this compound contributes significantly to its toxicity; therefore, the major aim of this research was to remove this moiety via diazotization. In this study, fumonisin B(1) was deaminated in aqueous solution under conditions of acidic pH and low temperature (pH 1.0 and 5 degrees C) with the addition of NaNO(2). The concentration of fumonisin B(1) in the solution was analyzed by HPLC using o-phthaldialdehyde to derivatize the primary amine. Progress of the reaction was monitored as a loss of the derivatized peak as observed by HPLC with fluorescence detection. TLC analysis showed the disappearance of fumonisin B(1) following diazotization. Further, TLC displayed at least four reaction products that were not primary amines. Matrix-assisted laser desorption/ionization mass spectrometry coupled with time-of-flight analysis of the diazotization products also showed a diminished amount of authentic fumonisin B(1) and allowed identification of a product formed by the replacement of the primary amine with a hydroxyl group. The adult Hydra attenuata bioassay indicated a marked decrease in the toxicity of the products in comparison to parent fumonisin B(1). Optimization of this reaction could result in a rapid and practical method for the reclamation of fumonisin B(1)-contaminated feeds.     

N-(Acyloxyalkoxycarbonyl) derivatives as potential prodrugs of amines. II. esterase-catalysed release of parent amines from model prodrugs

N-(Acetoxyethoxycarbonyl) derivatives of primary amines released a major fraction of the parent amine in the desired free form in plasma but a significant fraction of the undesired N-acetylated parent amine was also produced. The fraction of the parent amines released from the carbamate derivatives of the primary amines was greater in human plasma than in pH 7.4 buffer. In human plasma, the N-(acetoxyethoxycarbonyl) derivative of a secondary amine released the parent amine in a quantitative manner at a rate higher than that observed in pH 7.4 buffer. Experimental results suggested that the observed catalysis of the release of the parent amines from N-(acetoxyethoxycarbonyl) derivatives of primary and secondary amines was due to participation by plasma esterases. The data suggested that N-(acetoxyethoxycarbonyl) derivatives are well suited for use as prodrugs of secondary amines. Their utility as prodrugs of primary amines is more problematic and cannot be predicted prior to in-vivo studies for the individual compound.     

用人工神经网络研究过碳酸钠的合成工艺

目的用前馈(BP)神经网络对过碳酸钠合成工艺进行研究,筛选新的复合稳定剂。方法采用液相法合成过碳酸钠,测定其活性氧含量并考察合成条件。结果在原料体积比1.0∶1.0~1.0∶2.4、反应温度-15~20℃、反应时间10~100 min、稳定剂用量质量分数为0.1%~1.8%时,具有3层的BP神经网络可较好地体现过碳酸钠合成规律,对其合成结果由较高有较高的预测能力。结论延长反应时间和增加稳定剂用量对收率影响不大,而反应温度和原料配比对收率影响显著。在上述反应条件下,当反应时间85 min、反应温度15℃、稳定剂用量质量分数为0.95%、原料体积比为1.0∶1.8时收率和活性氧含量最大,实验值是收率为98.0%,活性氧含量14.50%,网络预测值为收率为98.274%、活性氧含量14.58%。     

The kinetics of the alkaline degradation of daptomycin

The aqueous degradation of daptomycin, a lipopeptide antibiotic, was investigated as a function of substrate concentration (0.5-10.0 mM), pH (9.0-10.5), buffer concentration (0.06-0.20 M borate, glycinate, or carbonate buffers), temperature (20-50 degrees C), and ionic strength (0.1-0.8). The primary degradation pathway was determined by electrospray-mass spectroscopy (ES-MS), Fourier transform infrared (FTIR), and fluorescence spectroscopy to be hydrolysis of the ester linkage between the C-terminus (kynurenine) and the side chain of the fourth residue (threonine). The reaction was first order with respect to time; however, the reaction order with respect to substrate concentration was <1 at substrate concentrations >1 mM. Insignificant buffer effect was observed. The reaction was subject to specific base catalysis. Activation parameters were E(a) = 13.6 kcal/K.mol, DeltaH++ = 13.0 kcal/K.mol, and DeltaS++ = -19.2 eu. The positive primary salt effect was observed with negative deviation at high concentration of salt. The magnitude of the salt effect depended on salt identities in the order sodium < potassium < calcium chloride.     

Synthese und zentrale Wirkungen von 4-hydroxy-(alkyl)- und 4-amino-(alkyl)-substituierten 2,6-Epoxy-3-benzoxocinen

Synthesis and Central Effects of 4-Hydroxy-(alkyl)- and 4-Amino-(alkyl)-Substituted 2,6-Epoxy-3-benzoxocines The tricyclic hemiacetal 1 is transformed with amines to the N/O-acetals 3 and 10 , with nitromethane to the 4-nitromethyl derivative 13 , and with the Wittig reagents 15a and 15b to the 2-benzopyrans 16 and 19 . Reduction and methylation of 13 yield the tertiary amine 4; through three steps the secondary amine 18 and the tertiary amine 5 are prepared from 16 and 19 , respectively. The 1,3-dioxane ring of all these 2,6-epoxy-3-benzoxocine derivatives exists in the chair conformation with an equatorial C-4 substituent. After application of the amines 5 , 11c , and 18 mice do not show any symptoms of central activity; weak CNS-effects are observed with the alcohols 1 and 2 . For the tertiary amine 4 , which causes considerable central effects (Straub-tail-phenomenon, convulsions, etc.), an ED₅₀ of 78 mg/kg is determined in the mouse “writhing”-test.     

Aporphines. 50. Kinetics of solvolysis of N-(2-chloroethyl)norapomorphine, an irreversible dopamine receptor antagonist

The rates and mechanism of solvolysis of (-)-N-(2-chloroethyl)norapomorphine (NCA, 1c) in aqueous solution have been examined by reversed-phase liquid chromatography (HPLC) to follow the levels of starting material and products. The first-order rate constants for aziridinium ion formation at 25 and 37 degrees C at pH 7.0 are 0.024 and 0.096 min-1, respectively. Determination of the first-order rate constant for the disappearance of NCA as a function of pH has allowed the calculation of an approximate pKa of 6.3 for the tertiary amine, while the influence of reaction conditions (e.g., pH, buffer salt and concentration, and added nucleophiles) on product distribution support the view that NCA solvolysis proceeds through an intermediate aziridinium ion. Application of the HPLC procedure allowed us to observe simultaneously the loss of NCA and the appearance of an intermediate and multiple products at trace levels; it also permitted the facile isolation and subsequent identification of small amounts of hydrolysis products. At pH 7, maximum aziridinium concentration is reached only after 10 min at 37 degrees C and at 25 degrees C after 1 h. Increased temperatures and pH facilitate the rate of aziridinium ion formation, as well as of non-dopamine antagonist solvolysis products. The significance of these findings, including the ease with which buffer ions add to the intermediate ion, are discussed in relation to the use of NCA and its tritiated isomer, [3H]NCA, in dopamine receptor studies.     

Assessment of the combined approach of N-alkylation and salt formation to enhance aqueous solubility of tertiary amines using bupivacaine as a model drug.

Quaternary prodrug types of poorly water-soluble tertiary amines have been shown to exhibit significantly enhanced solubilities as compared to the parent amine. In the present study the combined effect of N-alkylation and salt formation to enhance aqueous solubility of tertiary amines have been investigated using bupivacaine as a model compound. X-ray structure analyses of selected salts were included to investigate the potential existence of correlations between salt solubility and crystal packing modes. Alkyl groups were methyl, ethyl, propyl, and butyl and the derivatives were isolated as their iodide salts. Chloride, mesylate, formate, acetate, glycolate, and tosylate salts were obtained by anion exchange of the N-methyl-bupivacaine derivative. N-Alkylation and salt formation afforded quaternary ammonium salts possessing pH-independent aqueous solubilities far exceeding that of the parent tertiary amine (up to a factor of 3200 at pH 8). A moderate reduction in solubility with increasing length of the alkyl chain was observed for the iodide salts of the N-alkylated bupivacaine derivatives. In case of the N-methyl-bupivacaine derivative variation of the counterion had a significant impact on the solubility with the iodide salt being 200 times less soluble than the chloride salt. X-ray analysis revealed that both the alkyl substituent and the anionic counterion influenced salt packing modes, however, in an unpredictable manner making establishment of quantitative correlations between crystal packing and solubility difficult even for a series of closely related derivatives.     

Studies on reaction control and development of new practical reagents based on characteristics of reaction field

Reaction rates and selectivities can be critically affected by the reaction field. Using a diverse set of reagents and reaction systems, the author reviews a variety of ways to control the reaction field. In the first example, we discuss 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), which serves as an exceptionally convenient reagent for dehydrocondensation. In particular, formation of carboxamide by DMT-MM was found to take place even if water or alcohol were used as a reaction medium. Thus, chemical modification of carboxyl groups and/or amino groups of highly polar substrates, such as amino acid derivatives, peptides, glyco-chains, and nucleotides, can be simply effected by mixing them with DMT-MM in aqueous or alcoholic solvents. The author also found that a tertiary amine catalyzes the activation step of carboxylic acid with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) via in situ generation of coupling reagents. Proceeding further in this direction, we determined that artificial acyltransferase and cyclotransferase could be formed by conjugation of a tertiary amine catalyst to host-molecules to mimic a substrate binding site. Finally, the micellar interface, well known for promoting hydrolysis, clearly provides a superior reaction field for dehydrocondensation. When a 1,3,5-triazine-type amphiphilic dehydrocondensing agent was used, bimolecular dehydrocondensation between amphiphilic carboxylate and amines was highly accelerated (2000-fold) in a micellar system. Spontaneous membrane fusion was induced by adoption of the micellar reaction in the ceramide synthesis at the surface of membranes. All together, these diverse findings strongly support the central importance of the reaction field in controlling reaction rates and selectivity.     

Prodrugs as drug delivery systems. Part 42. 2-Hydroxymethylbenzamides and 2-acyloxymethylbenzamides as potential prodrug forms for amines

Several 2-hydroxymethylbenzamides derived from various primary and secondary amines were prepared and evaluated as potential prodrug models for the amino group occurring in several drugs. The hydroxy-amides were found to undergo a quantitative cyclization in aqueous solution to phthalide and the parent amine. The lactonization was specific acid- and base-catalyzed as well as subject to buffer catalysis. The structural factor being predominantly responsible for the different reactivities of the hydroxy-amides was found to be the steric properties of the amines, the amine basicity being only of minor importance. The cyclization proceeded only slowly at pH 7.4 and 37°C and in order to be a useful prodrug principle it may be necessary to accelerate the reaction rate, e.g. by introducing sterically or catalytically accelerating substituents in the hydroxy-amide moiety. Acylation of the hydroxymethyl group was shown to block the lactonization and hence to stabilize the hydroxy-amides. However, in the presence of human plasma the ester grouping was readily hydrolyzed yielding the parent 2-hydroxymethylbenzamide. Such cascade latentiation may thus be a particularly useful prodrug principle affording at the same time adequate in vitro stability and in vivo lability.     

Chemical reactions in cephalosporin allergy: high-pressure liquid chromatographic analysis of cephalosporin aminolysis kinetics.

Cephalosporin reaction with protein amino groups is fundamental to cephalosporin allergy. Cephalothin and cefazolin reaction kinetics with epsilon-aminocaproic acid, B-alanine, and glycine in aqueous solution were investigated. All reactions were conducted at 35 degrees and 0.5 ionic strength and were followed by ion-exchange high-pressure liquid chromatography. The aminolysis rate constants can be expressed as terms representing uncatlyzed or water-catalyzed amine reaction, self-assited nucleophilic reaction, and hydroxide-ion-catalayzed nucleophilic amine attack on the beta-lactam moiety. Cephalothin and cefazolin react with amines as readily as penicillin G. The UV spectra of several cephalothin-glycine reaction products were recorded, and their possible structures are discussed.     

Metabolic N-oxidation products of aliphatic amines as potential mediators in amine pharmacology.

Whilst it has long been recognized that many tertiary amines are converted by the body into the corresponding amine oxides, little attention has, until recently, been paid to the metabolic oxidation of the nitrogen occurring in primary and secondary basic amines. Moreover, the extreme water solubility of tertiary amine oxides generally rendered them pharmacologically inert. In contrast, the primary and secondary hydroxylamines derived from aralkylamines are lipophilic substances and could well be involved in the pharmacological activity of this group of drugs. Data are presented on the metabolic formation of these N-oxidation products from a variety of basic drugs, and evidence for the involvement of these metabolites in the pharmacology of these drugs is discussed.     

Chemical reactions involved in penicillin allergy: kinetics and mechanism of penicillin aminolysis.

In view of the fundamental importance of the reaction of penicillins with amino groups of proteins to the penicillin allergy, the aminolysis of benzylpenicillin by various amines was kinetically investigated. The formation rate constants, kamide, of benzylpenicilloylamides were determined at 35 degrees, 45 degrees and 60 degrees (mu equals 0.5), and found to obey the general rate law: kamide equals k1[amine] + k2[amine H+] [amine] + k3[amine]2 + k4[amine]aoh. All of the amines exhibited the unassisted nucleophilic rate constant, k1. The relative importance of the other kinetic terms depends on the basicity and the chemical structure of amines. The reaction mechanism of penicillin aminolysis was discussed. Bronsted relations for k1, k2 and k3, except for hydrazines, were satisfactory.     

N-(Acyloxyalkoxycarbonyl) derivatives as potential prodrugs of amines. I. kinetics and mechanism of degradation in aqueous solutions

Four acetoxyethoxycarbonyl derivatives of closely related primary and secondary amines were synthesized as model prodrugs. The degradation kinetics of these compounds were studied in aqueous solutions as a function of pH and temperature to determine their stability and to assess their suitability as potential prodrugs of amines. At pH 相似文献   

Evoked efflux of 3H-bretylium by sympathomimetic amines from the rat vas deferens in vitro

The efflux of 3H-bretylium in rat vas deferens in vitro evoked by a number of sympathomimetic amines was examined. The tissue was preloaded with 3H-bretylium (2 x 10(-7) M) and the efflux of bretylium to the incubation medium in the presence of the amines during 20 min, was determined. The efflux evoked by (+)-amphetamine was almost abolished at 0 degrees and by desipramine. The dose response curves showed that some of the amines at high concentrations markedly antagonized their own effect. It could be demonstrated that (+)-amphetamine and N-methylamphetamine at a high concentration also antagonized the efflux evoked by low external Na+ concentrations and it is suggested that this effect is produced by inhibition of the outward transport of bretylium through the neurone membrane. The structure activity relationship obtained shows that the non-hydroxylated amines are most potent in evoking bretylium efflux and that the potency diminished with the number of hydroxyl groups. The tertiary amine analogue of amphetamine is less active and the quaternary derivative much less active than amphetamine and N-methylamphetamine. A hydroxyl group at 3-position gives a somewhat higher potency than that at 4-position. This structure activity relationship is similar to that previously reported for the sympathomimetic amines in reversing the adrenergic neurone blockade for bretylium and it is proposed that this reversal is induced by the reduction of the intraneuronal concentration of bretylium as a result of the evoked efflux.     

Adjacent-group effects of aliphatic amines

Neighbouring Effects of Aliphatic Amines The mercuric-EDTA-dehydrogenation of cyclic tertiary amines with aliphatic amine neighbour groups, which are able to cyclisize in the course of reaction in an intramolecular Mannich reaction to 5- or 6-membered rings, gives the following results: Secondary/tertiary and ditertiary diamines yield the corresponding aminolactams. Primary/tertiary diamines give cyclic amidines. The mercuric-acetate-dehydrogenation in two cases produces the hexahydropyrimidine derivatives.     

Intraliposomal chemical activation patterns of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (L-NDDP)-a potential antitumour agent

L-NDDP is a liposome-entrapped platinum compound currently in phase 2 clinical trials that has been shown to undergo intraliposomal activation. The degradation/activation kinetics of liposome entrapped cis-bis-neodecanoato-trans-R,R-1,2-diamminocyclohexane platinum (II) [L-NDDP] at different conditions of pH, and temperature is presented. Liposomes were reconstituted in a solution of 0.9% sodium chloride (NaCl) in water (pH 5) at room temperature (formulation conditions currently used in the ongoing clinical trials). In the temperature experiments, L-NDDP 0.9% sodium chloride liposomes were incubated in a water-bath at 40, 60, and 80 degrees C. In the pH experiments, these solutions were compared to water, phosphate with and without chloride ion present, phosphate buffer without chloride ion at pH 3.1, 5.0, and 7.4, and glycine buffer with and without chloride ion. In 0.9% sodium chloride at room temperature, the chemical degradation/activation of liposome-bound NDDP was biphasic, with most of the degradation (approximately 45% conversion) occurring during the first hour after formation of the liposome suspension. NDDP degradation was pH dependent: when using pH 3 phosphate buffer as a reconstituting solution, liposome-bound NDDP degraded rapidly, whereas in pH 7.4 phosphate buffer it was stable for > 72 h. NDDP degradation was also temperature-dependent, the 50% point decreasing from 12 h at 25 degrees C to 9.5 h at 40 degrees C, 3.8 h at 60 degrees C, and 0.3 h at 80 degrees C when using 0.9% NaCl in water as a reconstituting solution. Using glycine buffer solution with and without NaCl at room temperature, no NDDP degradation over a 72 h period was observed at 25 degrees C; however, at 40 degrees C, only 68% NDDP remained intact at 72 h. Atomic absorption spectrophotometry (AAS) analysis of the eluting fractions after injection of L-NDDP samples reconstituted in chloride-containing and non chloride-containing solutions clearly indicated that the formation of DACH-Pt-Cl2 was only observed when chloride-containing solutions were used and was first detected at 3 h when using 0.9% NaCl in water as a reconstituting solution. These results indicate that pH and temperature, and not the presence of chloride ion, are the main factors leading to the activation of NDDP. Since 45% of NDDP is already degraded at 1 h in the same conditions, it is concluded that (1) the first active intermediates of L-NDDP formed within the liposomes are the DACH-Pt chloro-aquo and diaquo intermediates, and (2) the in vivo, antitumour activity of L-NDDP is most likely mediated by direct intracellular delivery of the active species.