No abstract

By the interaction of heterocyclic thiols with sulfoxides of 6,6-dihydro-and 6a-chloropenicillanates, derivatives of 4-heteryldithio-2-azetidinones have been synthesized, as well as products of their cyclization to form 213-heterylthiomethyl-and 21]-halomethyl-substituted penicillanates and an ester of 3-chloro-3-methyl-7et-chlorocepham-4-carboxylic acid. Also, the desulfurization of 6~t-chloropenicillanate by Raney nickel has been accomplished. For the substances that have been synthesized, a direct relationship has been established between the intensity of their cytotoxic action/n vitro with respect to tumor cells and the influence of these compounds on the intracellutar generation of nitric oxide radicals.Previously, in the example of sulfones of 7c~-chloro-and 7a-methoxycephalosporanates, we had discovered that these compounds are capable of suppressing the in vitro growth of various types of tumor cells; we also observed simultan.eous, intense intracellular generation of nitric oxide radicals [1]. We are now reporting on an analogous study in which the main objects of investigation were 4-heteryldithio-substituted azetidinones, formed by the interaction of heterocyclic thiols with sulfoxides of 6,6-dihydro-and 6ct-chloropenicillanates, as well as products of their cyclization to form the corresponding 213-heterylthiomethyl-and 213-halomethyl-substituted penicillanates.Procedures described in [2-4] were used to accomplish the thermal cleavage of the thiazolidine ring in sulfoxides of esters of penicillanic acids I to form intermediate sulfenic acids that enter into reaction with 2-mercaptobenzothiazole (IIa, BT) or 1-methyl-2-mercaptoimidazole (IIb, MI), to obtain the isomeric 4-heteryldithio-substituted azetidinones III and IV (see Scheme 1).Analysis of the structure of the reaction products demonstrated that the benzothiazole heterocyclic system influences the preferential formation of only certain isopropenyl isomers of azetidinone IIIa-d. The isomerization of IIIa to the isopropylidene-substituted IVa was accomplished by the use of aluminum oxide.The analogous reaction of I with IIb leads to the formation of a complex mixture consisting of the isomeric azetidinones IIIe-g and IVb-d and the penicillanates Va, b. The ratio of isomeric azetidinones containing this heterocycle was established by means of HPLC (Table 1). From these data it can be seen that the ratio of isomers depends on the presence or absence of a chlorine atom in position 3 of the azetidinone and on the nature of the ester group.

New derivatives of 2-oxo-1-azetidinylacetamide have been synthesized by the four-component condensation of β-amino acids with aldehydes and isonitriles. Study of their cytotoxic activity in vitro revealed a cytotoxic effect of individual compounds in relation to cancer cells of human fibrosarcoma, mouse hepatoma, and mouse neuroblastoma. activity.In a continuation of investigations devoted to the synthesis of 1,3,4-trisubstituted β-lactams and to the analysis of the interconnection between their structure and cytotoxic properties [1-3], we have selected derivatives of 2-oxo-1-azetidinylacetamide as the next subject.The Ugi one-step four-component condensation of β-amino acids with aldehydes and isonitriles [4-7] was used for their preparation. Its advantage in comparison with other methods of obtaining 2-oxo-1azetidinylacetamide is the possibility of the simultaneous introduction of substituents directed into the 3C and 4C positions of the heterocycle, and also of replacing protons in the methylene and amide fragments of acetamide.The synthesis of the new azetidinones 4a-j with the aid of this condensation was effected by the interaction of structural analogs of β-amino acids 1a-e, aldehydes 2a-e, and isocyanates 3a,b (Scheme 1).The condensation was carried out in methanol at room temperature during 3-5 days. The end of the reaction was checked by TLC. Substances were isolated from the reaction mixtures by column chromatography. Their structures were demonstrated by 1 H NMR spectra, elemental analysis, and their homogeneity by HPLC.The structural specificity of this reaction is characterized by the formation of a chiral center at the C-5 atom of the resulting compounds 4a-j. Additional chiral centers are formed at the C-3 and C-4 atoms of 4a-i due to the presence of substituents in the αand β-positions of the initial amino acids 1b-e. Theoretically this must lead to the preparation of the final product as a complex diastereoisomeric mixture. However, judging by HPLC data and 1 H NMR spectra the majority of the isolated products were equilibrium mixtures of only two isomers. In the case of azetidinone 4f their ratio proved to be displaced in the direction of one representative (1:4), but azetidinones 4h and 4j proved to be diastereoisomeric products. __________________________________________________________________________________________

acid have been synthesized. Results of cytotoxic screening of these compounds in relation to cancer and normal cells in vitro are correlated and analyzed.Keywords: esters of 7α-chloro-3-methyl-2-dimethylaminomethylene-1,1-dioxoceph-3-em-4-carboxylic acid, esters of 7α-chloro-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid, cytotoxic activity.The directed structural modification of substituents in penicillin, cephalosporin, and 2-azetidinone carried out in the past 20 years has led to the discovery of compounds with anti-inflammatory, antiviral, anticancer, anticoagulant, and other activities "unplanned by nature". Their mechanism of action at the molecular level consists of the inhibition of specific serine-and cysteine-containing proteases as a result of acylation of hydroxyl or mercapto groups found in their active centers by the β-lactam ring [1].The literature data referring to this investigation indicate that the structural variations of substituents in the β-lactam pharmacophore directed towards achieving effective inhibition of the target protease are accompanied by analogous, although less marked, effects on one or several related enzymes [2][3][4][5]. The negative side of this phenomenon consists of the probability of displaying undesirable secondary activity, but the positive is the possibility of using it for the targeted development of substances with new biological properties. Such an interpretation of the secondary activity of clavulanic acid ester, which is a specific inhibitor of the bacterial enzyme β-lactamase, in relation to Human Leucocyte Elastase (HLE) enabled the design of anti-inflammatory analogs of cephalosporin [6].We encountered an analogous secondary effect on studying the biological properties of structural analogs of the tert-butyl ester of 7α-chloro-1,1-dioxoceph-3-em-4-carboxylic acid 1 and 2 [7].