Structure-activity relationship investigation of bis(2-chloroethyl)aminoethyl esters of some carboxylic acids

A study of quantitative structure-activity relationships (QSAR) in a series of carboxylic acid bis(2-chloroethyl)aminoethyl esters with potential antitumor activity was carried out. The statistical-heuristic technique was applied to estimate the contributions of the structural features of the compounds to the probability of their activity in vivo against lymphoid leukemia L1210. The results obtained were compared with those of the pharmacological screening of the esters. Some assumptions are made concerning the difference in antileukemic activity of compounds based on the computed weights of their structural features.     

Kinetics of the intramolecular cyclization of bis(2-chlorethyl)aminoethyl esters of carboxylic acids

Using a direct protentiometric method the kinetics of the intramolecular cyclization of 12 synthesized bis(2-chlorethyl)-aminoethyl esters of carboxylic acids has been studied. To determine the rate constants of hydrolysis (in 50% water-ethanol medium) the model of successive reactions of first order A----B----C has been used. An attempt has been made to relate the values obtained for the rate constants with the chemical structures of the compounds studied. The kinetic characteristics have been compared to the data of the antileucemic activity of the compounds against tumor models in vivo.     

Synthesis and some biological properties of 2-xanthonylalkyl-(alkoxy) carboxylic acids

2-Xanthonylacetic acids 5a-5d and alpha-methyl-2-xanthonyloxyacetic acid 8 were obtained as potential anti-inflammatory compounds. Preliminary evaluation was carried out for anti-inflammatory and analgesic activity of acids 5a, 5c and 5d and for inhibition of blood platelets aggregation by compounds 5a-5d and 8. In the inhibition of carrageenin-induced rat edema the highest activity shown by acids 5a and 5c was similar to that of ketoprofen.     

Paracetamol (acetaminophen) esters of some non-steroidal anti-inflammatory carboxylic acids as mutual prodrugs with improved therapeutic index

Paracetamol (acetaminophen) esters [4a-f] of some acidic NSAIDs were synthesized and evaluated as mutual prodrug forms with the aim of improving the therapeutic index through prevention of the gastrointestinal toxicity. The structures of the synthesized esters were confirmed by IR and ¹H-NMR spectroscopy and their purity was established by elemental analyses and TLC. In-vitro stability studies revealed that the synthesized ester prodrugs 4a-f are sufficiently chemically stable in non-enzymatic simulated gastric fluid (hydrochloric acid buffer of pH 1.3 (t _1/2 ∼ 15–45 h)) and in phosphate buffer of pH 7.4 (t _1/2 ∼ 4–40 h). In 80% human plasma and 10% rat liver homogenate, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis releasing the corresponding NSAID and paracetamol at relatively faster rates (t _1/2 ≈ 15–385 min and 1–140 min, respectively). Calculated log P values indicated that the prodrugs 4a-f are more lipophilic than the parent drugs. In-vivo experiments in rabbits showed higher plasma levels of ibuprofen after oral administration of its ester prodrug 4b compared with those resulting from an equivalent amount of the corresponding physical mixture. Moreover, significant improvement in latency of pain threshold in mice has been observed up to 4 h after po administration of 0.02 mmol/kg of the prodrugs, compared with the corresponding physical mixtures. Gross observations and scanning electromicrographs of the stomach showed that the prodrugs induced very little irritancy in the gastric mucosa of mice after oral administration for 4 days. These results suggest that the synthesized mutual ester prodrugs were characterized by a better therapeutic index than the parent drugs.     

Interaction study of paracetamol with saturated (capric) and unsaturated (oleic) fatty acids

Interaction study of paracetamol with saturated and unsaturated fatty acids, namely, capric and oleic acid have been performed by using serial dilution method, release behavior, FT-IR, and DSC study. Preliminary investigations by release studies indicated the possibility of interaction between paracetamol and fatty acids. UV-studies failed to detect any interaction between paracetamol and fatty acids. The possibility of hydrogen bonding between amino group of paracetamol and carbonyl group of fatty acids was revealed by FT-IR study. Polymorphic transition of paracetamol in the binary sample of paracetamol-capric acid was identified by DSC studies. However, no such possibility was detected in paracetamol-oleic acid mixture.     

Synthesis and bronchodilator action of 4-(methoxycarbonylalkylsulfinyl)-4-pyrrol carboxylic esters

The dihydro-dimethoxyfuran carboxylic ester 3 reacts with different mercaptoalkyl carboxylates to give the carbomethoxyalkylthio-tetrahydrofuran carboxylic esters 4. Methanol elimination of 4 yields the dihydrofuran derivatives 5. 4 and 5 can be oxidized to afford the sulfoxides 6 and the sulfones 7, respectively. 4 reacts with primary amines to give the title compounds 8. Derivatives of 8 can be cyclized to afford the thienopyrroles 11 and 12 as well as the thienopyranopyrrole 14. The mercaptopyrrole carboxylic ester 10 is obtained from 8f by elimination of propenic acid. 8e shows bronchodilatoric activity in low concentration.     

In vitro dipeptide, nucleoside, and glutathione alkylation by S-(2-chloroethyl)glutathione and S-(2-chloroethyl)-L-cysteine

S-(2-Chloroethyl)glutathione (CEG) and S-(2-chloroethyl)-L-cysteine (CEC) are putative glutathione-dependent metabolites of 1,2-dichloroethane bioactivation and have been shown to be direct-acting alkylating agents. A group of dipeptides, nucleosides, and glutathione were used as model compounds to investigate CEG and CEC alkylation events. The extent of glutathione and cysteinyltyrosine alkylation was much greater than histidyltyrosine greater than lysyltyrosine, glycyltyrosine, glycyltryptophan, and 2'-deoxyguanosine greater than 2'-deoxyadenosine, 2'-deoxycytidine, and thymidine for both CEG and CEC. The rate of S-alkylation of cysteinyltyrosine by CEG and CEC occurred at rates 54 and 72 times that for the N7 position of 2'-deoxyguanosine and 16 and 10 times that for histidyltyrosine imidazole nitrogen, respectively. The rate of S-alkylation of glutathione by CEG was found to be 27% faster than that for S-alkylation of cysteinyltyrosine whereas S-alkylation of glutathione by CEC was 22% slower than that for cysteinyltyrosine. Both CEG and CEC demonstrated a selectivity for cysteinyl thiol alkylation over a wide variety of other nucleophilic sites. These findings demonstrate a wide range of functional group reactivity that should be taken into consideration when assessing the alkylation of cellular macromolecules by such glutathione-derived metabolites of the 1,2-dihaloethanes in vivo.     

Thiodiglycolic acid: a major metabolite of bis(2-chloroethyl)ether.

Male rats were given a single oral dose (40 mg/kg) of bis(2-chloroethyl)ether (BCEE). Less than 2% of the dose was recovered from the expired air as the unaltered parent compound during an 8-hr collection period. Urine samples representing 48 hr of collection were analyzed by gas chromatography-mass spectrometry. Methyl ester/trimethylsilyl ether derivatives of the isolated urinary acid fraction were prepared for gas-phase analysis. Two metabolites were identified in this fraction: thiodiglycolic acid (TDGA) and 2-chloroethyl β-d-glucosiduronic acid. Quantitative analysis for TDGA gave an average (seven rats) yield for 48 hr of 33 ± 11.8 mg (± SD) of TDGA/kg from a single dose of 40 mg/kg BCEE. The glucuronide of 2-chloroethanol was synthesized using rabbit liver microsomes in an incubation mixture. The matching mass spectrum of the glucuronide prepared in vitro to that identified in the urine of the rats verified 2-chloroethyl β-d-glucosiduronic acid as a metabolite of BCEE.     

Analysis of structure-cytotoxicity in vitro relationship (SAR) for perfluorinated carboxylic acids.

Perfluorinated carboxylic acids (PFAs) represent derivatives of naturally occurring compounds and have been widely used in various industrial fields for decades. They are known to be environmentally persistent. Thus far numerous reports have been focused on reproductive toxicity of PFAs in animals but few studies have been carried out on toxicity towards human cells. Viability tests were performed here at varying time-exposures on C6-C18 PFAs with human colon carcinoma (HCT116) cells. These cells were found earlier as the most useful line for in vitro assays. A chain length-EC50 dependence has been clearly observed. Estimated values of EC50 decreased with elongation of fluorocarbon chain (PFHxA > PFHpA > PFOA > PFNA > PFDA > PFDoA > PFTeDA). Further elongation (C16 and C18) did not deepen the effect but even partially reversed it. The effect was intensified after longer exposure (72 h); at relatively low 40 microM PFTeDA, the viability decreased to approximately 50%. It seems that PFAs are not acutely toxic at the cellular level. Even so, however, they can trigger cell apoptosis, which is prominent in the case of myristic acid perfluorinated analogue.     

The cytotoxic action in vitro of catalytically sulphurated unsaturated fatty acids on Ehrlich's ascites cancer and normal peritoneal exudate (leucocytes)

Diethanolamine salts of the catalytically sulphurated oleic acid (X-303/1) and of the catalytically sulphurated fatty acids isolated from linseed oil (X-303/2) were found to exhibit a strong cytotoxic in vitro activity against Ehrlich ascites cancer cells with minimal cytotoxic effect on normal cells (leukocytes) of the peritoneal exudate in rabbits.