Synthesis and cytotoxic properties of 7α-chloro-3-methyl-1,1-dioxoceph-3-ems, substituted with amide or keto group at position 4

7α-Chloro-3-methyl-1,1-dioxoceph-3-ems with amide or keto group at position 4 have been synthesized by structural modification of 7α-chloro-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid. Screening of these compounds for cytotoxic activity revealed compounds with specific activity against cancer cells in vitro, capable of effective inhibition of the growth of sarcoma S-180 in vivo. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, 1849–1859, December 2007.     

Novel Sulfonamide Derivatives as Inhibitors of Histone Deacetylase

Inhibition of the enzyme histone deacetylase (HDAC) is emerging as a novel approach to the treatment of cancer. A series of novel sulfonamide derivatives were synthesized and evaluated for their ability to inhibit human HDAC. Compounds were identified which are potent enzyme inhibitors, with IC₅₀ values in the low nanomolar range against enzyme obtained from HeLa cell extracts, and with antiproliferative effects in cell culture. Extensive characterization of the structure–activity relationships of this series identified key requirements for activity. These include the direction of the sulfonamide bond and substitution patterns on the central phenyl ring. The alkyl spacer between the aromatic head group and the sulfonamide functionality also influenced the HDAC inhibitory activity. One of these compounds, m 11.1 , also designated PXD101, has entered clinical trials for solid tumors and haematological malignancies.     

Synthesis and cytotoxic activity of derivatives of the <Emphasis Type="Italic">tert</Emphasis>-butyl ester of 7<Emphasis Type="Italic">Z</Emphasis>-acetylmethylene-3-methyl-3-cephem-4-carboxylic acid

The condensation of the acetylmethylene group in the tert-butyl esters of 7Z-acetylmethylene-3-methyl-3-cephem-4-carboxylic acid and 7Z-acetylmethylene-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid and in 7Z-acetylmethylene-3-methylene-1,1-dioxo-3-cephem with arylmethoxyamines and O-alkylation of the tert-butyl ester of 7Z-(2-hydroxyimino)propylidene-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid using substituted benzyl bromides as well as pyridylmethyl chlorides gave arylmethoxyimino and pyridylmethoxyimino derivatives of these compounds in the syn and anti isomeric forms. The Vilsmaier reagent was used to introduce the N,N-dimethylaminomethylene group at C-2 of the cephem system in the tert-butyl esters of 7Z-[2-(arylmethoxyimino)propylidene]-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid. Subsequent transformation of the N,N-dimethylaminomethylene cephems using hydroxylamine led to 3Z-[2-(anti-arylmethoxyimino)propylidene]-tert-butoxycarbonylmethyl-4-(5-methyl-4-isoxazolylsulfonyl)- azetidin-2-ones. Condensation of the acetyl group in the tert-butyl ester of 7Z-acetylmethylene- 3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid with 4-bromophenylhydrazine gave a cephem with a 2-(4-bromophenylhydrazono)propylidene group at C-7. Acylation of the tert-butyl ester of 7Z-(2-hydroxyimino)propylidene-3-methyl-1,1-dioxo-3-cephem-4-carboxylic acid by 2-bromobenzoyl chloride gave a cephem with a 2-(2-bromo-benzoyloxyimino)propylidene group at C-7. Biological screening of these products towards to malignant and normal cells in vitro showed that their antitumor activity and cytotoxic selectivity towards to malignant and normal cells depend on the structure and configuration of the arylmethoxyimino and pyridylmethoxyimino groups in the 7-alkylidene substituent as well as on the presence or absence of N,N-dimethylaminomethylene and carboxyl groups, respectively, at C-2 and C-4 of the cephem system.     

Synthesis and structural modification of <Emphasis Type="Italic">tert</Emphasis>-butyl ester of 7α-chloro-2-(N,N-dimethylaminomethylene)-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid

The reaction of tert-butyl 7α-chloro-and 7-β-chloro-7α-isopropoxy-3-methyl-1,1-dioxoceph-3-em-4-carboxylates with the Vilsmeier reagent was carried out with introduction of N,N-dimethylaminomethylene group at position 2 in the E-and Z-isomeric forms. Prolonged treatment of tert-butyl 7α-chloro-3-methyl-2-(N,N-dimethylaminomethylene)-1,1-dioxoceph-3-em-4-carboxylate with hydroxylamine hydrochloride in acetonitrile at 40–50°C gave tert-butyl 10(S)-chloro-6-methyl-5-oxa-1,1,9-trioxo-1-thia-4,8-diazatricyclo[7,2,0,0^2,6]undecane-7(R)-carboxylate which isomerized into 1-tertbutoxycarbonylmethyl-3α-chloro-4-(5-methylisoxazole-4-sulfonyl)azetidin-2-one. In the case of tertbutyl 7β-chloro-7α-isopropoxy-3-methyl-2-(N,N-dimethylaminomethylen)-1,1-dioxoceph-3-em-4-carboxylate the analogous reaction gave tert-butyl 10β-chloro-(2S,6S,7S,10R,11R)-10α-isopropoxy-6-methyl-5-oxa-1,1,9-trioxo-1-thia-4,8-diazatricyclo[7,2,0,0^2,6]undecane-7(R)-carboxylate, the struc-ture of which was determined by 2D-NOESY two-dimensional spectroscopy. The compounds synthesized showed weak or no cytotoxic activity with respect to monolayers of cancer cells in vitro.     

Synthesis and biological activity of alkylidene-substituted cephems and penams

The condensation of tert-butyl esters of 3-methyl-7-oxoceph-3-em-4-carboxylic and 6-oxopenicillanic acids with a series of 2-oxoalkylidene(triphenyl)phosphoranes gave tert-butyl esters of new cephalosporin and penicillin analogs with an alkylidene substituent in the β-lactam ring. Most of these products were oxidized by meta-chloroperbenzoic acid to the corresponding sulfones. The cephemes and penams synthesized including the oxidized products displayed high cytotoxicity relative to cancer cells in vitro. Some of the alkylidene-substituted cephems as the free acids, similar to Tazobactam, inhibit the catalytic activity of Enterobacter cloacae penicillinase.     

Sulfones of 7-silyl- and 7-germylcephalosporanates

7-Silyl- and 7-germylcephalosporanates in the form of a mixture of 7a and 7b stereoisomers were prepared by the interaction of hydrosilanes and a hydrogermane^* with sulfones of tert-butyl esters of 7-diazocephalosporanic acid and 7-diazodesacetoxycephalosporanic acid in the presence of rhodium diacetate. Some of the synthesized substances manifest cytotoxic effects in relation to tumor cellsin vitro, and also inhibit the catalytic activity of the enzyme elastase.Generic terms for compounds with the general formula HSiX₃ or HGeX₃-Translator.Latvian Institute of Organic Chemistry, Riga LV-1006, Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1504–1509, November, 1998.     

Mechanism of the zinc-catalyzed addition of azide ion to unsaturated compounds: Synthesis of 5-substituted 1<Emphasis Type="Italic">Н</Emphasis>-tetrazoles from nitriles and of 1-substituted 1<Emphasis Type="Italic">Н</Emphasis>-tetrazole-5-thiols from isothiocyanates

The mechanism of the formation of 5-substituted 1H-tetrazoles from organic nitriles and thiocyanates in the presence of NaN₃ and ZnCl₂ in aliphatic alcohols was studied. The results of this study allowed efficient methods of synthesis of substituted tetrazoles from nitriles, thiocyanates, and isothiocyanates to be proposed.