Novel quinuclidinone derivatives induce apoptosis in lung cancer via sphingomyelinase pathways.

We previously reported novel quinuclidinone analogs which induced apoptosis in lung and breast cancer cells. In this study, we designed and synthesized novel quinuclidinone analogs that showed cytotoxicity in lung cancer cells. The effects of these analogs were studied in H1299 human large cell lung carcinoma cells that are null for p53 and normal lung epithelial cell lines (NL-20). The effects of the analogs were investigated by MTT assay, ELISA based apoptotic assay, TUNEL assay, sphingomylinase activity, flow cytometry and western blot analysis. Our data indicated that derivatives 4 and 6 decreased cell proliferation and induced apoptosis in H1299 cells more than NL-20 cells. Derivatives 4 and 6 reduced percent of cells in G2/M phase in H1299 cells more than NL-20 cells and these results were confirmed by increased expression levels of cyclin E. Furthermore, derivatives 4 and 6 increased sphingomyelinase activity, caspase-8, and caspase-9 and JNK-1 expression level in H1299. Additionally, derivatives 4 and 6 induced Procaspase-3, PARP-1 cleavage, and increased caspase-3 activity. All these results confirm that our quinuclidinone derivatives provoke cytotoxicity in lung cancer cells through the interplay of key apoptosis molecules in different compartments of the cell beginning with an increase in sphingomyelinase activity.

Synthesis and antibacterial activity of some glucosyl- and ribosyl-pyridazin-3-ones.

Reaction of 5,6-diphenylpyridazin-3(2H)-one 1a,b with 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl bromide 2 in K(2)CO(3)/acetone gave 5,6-diphenyl-N(2)-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyl)pyridazin-3-one 5a,b. The same nucleosides 5a,b were obtained by reaction of 1a,b with peracetylated glucose 3 under MW irradiation. Mercuration of 1a,b followed by reaction with glucosyl bromide 2 gave the same nucleosides 5a,b. The riboside 4-cyano-5,6-diphenyl-N(2)-(2',3',5'-tri-O-acetyl-beta-D-ribofuranosyl)-pyridazin-3-one 8 was obtained by reaction of 4-cyanopyridazinone 1b with peracetylated ribose 7 under MW irradiation. The deprotected nucleosides 6a,b and 9 were obtained by stirring of 5a,b and 8 in methanol and TEA/H(2)O. The structure was confirmed using (1)H and (13)C-NMR spectra. Selected members of these compounds were screened for antibacterial activity.

Synthesis and evaluation of antimicrobial activity of some pyrimidine glycosides.

Reaction of ethyl 4-thioxo-3,4-dihydropyrimidine-5-carboxylate derivatives 1a,b and ethyl 4-oxo-3,4-dihydropyrimidine-5-carboxylate 1c with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide in KOH or TEA afforded ethyl 2-aryl-4-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosylthio or/ oxy)-6-methylpyrimidine-5-carboxylate 6a-c. The glucosides 6a and 6b were obtained by the reaction of 1a and 1b with peracetylated glucose3 under MW irradiation. Mercuration of 1a followed by reaction with acetobromoglucose gave the same product 6a. The reaction of 1a-c with peracetylated ribose 4 under MW irradiation gave ethyl 2-aryl-4-(2',3',5'-tri-O-acetyl-beta-D-ribofuranosylthio)-6-methylpyrimidine-5-carboxylate 8a-c. The deprotection of 6a-c and 8a-c in the presence of methanol and TEA/H(2)O afforded the deprotected products 7a-c and 9a-c. The structure were confirmed by using (1)H and (13)CNMR spectra. Selected members of these compounds were screened for antimicrobial activity.

Microwave-assisted organic synthesis of 3-(D-Gluco-pentitol-1-yl)-1H-1,2,4-triazole.

The condensation of D-glucono- and D-galactono-1,5-lactone and thiocarbohydrazide to give 3-(D-alditol-1-yl)-4-amino-5-mercapto-1,2,4-triazoles 4 and 5 is accelerated by the use of microwave-assisted organic reaction (MAOS). The deamination and dethiolation of compound 4 to give 6 was also accelerated by the use of MAOS. Condensation of 4 and 5 with p-nitrobenzaldehyde afforded Schiff bases 8 and 9, respectively, within 4 min under microwave irradiation (MWI), whereas with ethyl chloroacetate the thioalkylated products 14 and 15 were obtained in 8 min. The structures of the synthesized compounds were confirmed by 1H NMR, 2D NMR, and mass spectra.

Microwave irradiation for accelerating the synthesis of acyclonucleosides of 1,2,4-triazole.

The 3-(D-alditol-1-yl)-4-amino-5-mercapto-1,2,4-triazoles 4 and 5 can be successfully prepared using microwave irradiation. Condensation of 4 and 5 with p-nitrobenzaldehyde afforded Schiff bases 6 and 7, respectively. Reaction 4 and 5 with ethylchloroacetate gave the corresponding alkylated products 10 and 11. Better yields and much less time were the characteristic features of using the microwave heating over the conventional one. The structure of the prepared compounds was confirmed by 1H-NMR, 2D-NMR and mass spectra.

Double-headed acyclo C-nucleoside analogues. Functionalized 1,2-bis-(1,2,4-triazol-3-yl)ethane-1,2-diol.

Reaction of L-tartaric acid with thiocarbohydcrazide afforded (1R, 2S)-1,2-bis(4-amino-5-mercapto-1,2,4-triazol-3-yl)-ethane-1,2-diol (3). The functional groups in 3 allowed the construction of fused heterocycles on the 1,2,4-triazole rings, mainly of the 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine type as in 4, 5, 7, 10, 13 and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole type as in 14.

Reaction of sugars with 2-hydrazinopyridine, precursors for seco C-nucleosides of 1,2,4-triazolo[4,3-a]pyridine.

Reaction of 2-hydrazinopyridine (1) with D-xylose, D-galactose, D-glucose and D-fructose afforded the corresponding hydrazones mainly in the acyclic forms 2, 3, 6 and 11 with minor amounts of the cyclic structures. Oxidative cyclization of the hydrazones with bromine in methanol resulted in the formation of the 3-(polyhydroxyalkyl)-1,2,4-triazolo[4,3-a]pyridine derivatives 13-15 whose acetylation afforded the acetylated derivatives 16-18. Assignment of 1D and 2D NMR spectral data in addition to 15N NMR experiments led to complete characterization of the products.

Synthesis of some functionalized arylaminomethyl-1 ,2,4-triazoles, 1,3,4-oxa- and thiadiazoles.

Thiosemicarbazides undergo different cyclization reactions to give five membered heterocycles. The product of cyclization depends on the reagent used. This cyclization leads to the formation of 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole derivatives. The reaction of thioglycolyl hydrazide derivatives of the 1,2,4-triazole compounds was discussed. The activity against hepatitis B virus (HBV) has been tested.

Components, therapeutic value and uses of myrrh.

Occurrence, constituents and medicinal use of myrrh, obtained from the stem of different Commiphora species are reviewed. The constituents of the volatile oil, the resin and the gum are outlined in detail. Myrrh has considerable antimicrobial activity and is medicinally used in a variety of diseases.

Synthesis of chitotetraose and chitohexaose based on dimethylmaleoyl protection.

tert-Butyldimethylsilyl 3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranoside was readily transformed into the disaccharide glycosyl donor, 3,4,6-tri-O-acetyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranosyl-(1 --> 4)-3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-alpha/beta-D-glucopyranosyl trichloroacetimidate, and the disaccharide glycosyl acceptor, tert-butyldimethylsilyl 3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranosyl-(1 --> 4)-3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranoside. A TMSOTf-catalysed coupling of the acceptor with the donor afforded the respective tetrasaccharide derivative, which can be transformed to chitotetraose. tert-Butyldimethylsilyl 3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-4-O-phenoxyacetyl-beta-D-glucopyranosyl-(1 --> 4)-3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranoside was converted into donor 3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-4-O-phenoxyacetyl-beta-D-glucopyranosyl-(1 --> 4)-3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranosyl trichloroacetimidate. Its coupling with benzyl 3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranosyl-(1 --> 4)-3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranoside, followed by dephenoxyacetylation, gave benzyl 3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranosyl-(1 --> 4)-3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranosyl-(1 --> 4)-3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranosyl-(1 --> 4)-3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranoside, whose glycosylation furnished, after replacement of the DMM-group by the acetyl moiety and subsequent deprotection, chitohexaose.

Novel synthesis of seco type of acyclo C-nucleosides of 1,2,4-triazole and 1,2,4-triazol.

The seco C-nucleosides 3-(1,2,3,4,5-penta-O-acetyl-D-gluco- and D-galacto-pentitol-1-yl)-1H-1,2,4-triazoles (8 and 9) were obtained in a one pot by deamination and dethiolation of 4-amino-3-(D-gluco- and D-galacto-pentitol-1-yl)-5-mercapto-1,2,4-triazoles (1 and 2), respectively, using sodium nitrite in orthophosphoric acid and subsequent acetylation. Condensation of 1, 2, and 4-amino-3-(D-glycero-D-gulo-hexitol-1-yl)-5-mercapto-1,2,4-triazole (12) with phenacylbromide (11) afforded the corresponding 3-(D-gluco-, D-galactopentitol-1-yl) and 3-(D-glycero-D-gulo-hexitol-1-yl)-6-phenyl-7H-1,2,4-triazolo[3,4-b][1,3,4] thiadiazines (15, 16, and 17). Acetylation of 15-17 gave the penta- and hexa-O-acetyl derivatives 18-20, respectively. The structures were confirmed by using 1H, 13C, and 2D NMR spectra, DQFCOSY, HMQC, and HMBC experiments. The favored conformational structures were deduced from the vicinal coupling constants of the protons.

Glycosidase inhibitors and their chemotherapeutic value, Part 3.

The various compounds that have been investigated as glycosidase inhibitors are reviewed. The last one of three parts of this review article covers the following classes of compounds: amidines, amidrazones, amidoximes, sugars with sulphur in the ring, carba sugars, pseudo oligosaccharides, cyclitols and trehazolamine analogues, fused heterocycles and trehazolin analogues, dioxane derivatives, open chain compounds, heterocyclic compounds with hydroxyalkyl residues, aromatic compounds, amino acids and other derivatives.

Glycosidase inhibitors and their chemotherapeutic value, Part 1.

The various compounds that have been investigated as glycosidase inhibitors are reviewed. The first of three parts of this review article covers the following classes of compounds: sugar, lactones and hydroximolactones, glycosyl halides, oligosaccharides, glycosides and their derivatives, deoxy thiosugar derivatives, thioglycosides, deoxy amino and guanidino sugars, glycosylamines, anhydrosugars and their analogues, deoxysugars, glycals, C-glycosides and C-nucleosides.

Glycosidase inhibitors and their chemotherapeutic value, Part 2.

The various compounds that have been investigated as glycosidase inhibitors are reviewed. The second of three parts of this review article covers the following classes of compounds: sugars with nitrogen in the ring, e.g. azepine analogues, piperidine analogues and pyrrolidine analogues and fused rings with a bridgehead nitrogen.

Homoacyclovir analogues of unnatural bases and their activity against hepatitis B virus.

The ambident nucleophilic nature of the sodium salts of 2(1H)-qunioxalinone (2) and the phthalazinedione (3) has been realized from their alkylation with 2-(2-chloroethoxy)ethylacetate (1) to afford 1-[2-(2-acetoxyethoxy)ethyl]-2(1H)-quinoxalinone (8) and 2-[2-(2-acetoxyethoxy)ethoxy]qunioxaline (9) as well as 10 and 11, respectively. The corresponding derivatives 12-15 were similarly prepared by the alkylation of the unnatural bases 4-7 with 1. Treatment of the alkylated derivatives 8-15 with methanolic ammonia solution (1:1) at room temperature gave the corresponding hydroxyalkyl derivatives 16-23. The site of the alkylation was deduced from the spectral characteristics of the products. The activity of compounds 16-22 against Hepatitis B virus (HBV) in HepG2 cell has been tested. Some of the compounds showed high viral replication inhibition with low cytotoxicity.

Sugarhydrazones of 2-hydrazinoquinolines and their antimicrobial activity.

Sugar hydrazones from 2-hydrazinoquinoline, 2-hydrazino-6-methyllepidine, 6-chloro-2-hydrazino lepidine, 7-chloro-2-hydrazinolepidine, and 7-chloro-2-hydrazino-3-nitroquinoline were prepared. Their acetylation, benzoylation, periodate oxidation, oxidation with lead tetraacetate and bromination have been investigated. The antimicrobial activities of the hydrazones were evaluated. Some compounds showed moderate activity.

Acyclonucleosides: Part 2. diseco-Nucleosides.

This chapter is the second of a sequence of three chapters that appears in successive volumes of this series dealing with the chemistry of acyclonucleosides. The first chapter appeared in the previous volume [97AHC391] and dealt with seco-nucleosides (one bond disconnection). This chapter deals with diseco-nucleosides (two bond disconnections). The final chapter of this series will deal with tri-, tetra-, and pentaseco-nucleosides, as well as contain an appendix of the literature that appeared after the three chapters were prepared.

Mode of formation of quinoxaline versus 2[1H]-quinoxalinone rings from dehydro-D-erythorbic acid.

The mode of formation of the quinoxaline versus 2[1H]-quinoxalinone rings by the reaction of o-diamines with dehydro-D-erythorbic acid has been investigated. The study was carried out by using one and two molar equivalents of 1,2-diamino-4,5-dimethylbenzene (3b) to give 6,7-dimethyl-3-(1-oxo-D-erythro-2,3,4-trihydroxybutyl)-2[1H]-quino xalinone (4b) and 2-(2-amino-4,5-dimethylphenylcarbamoyl)-3-(D-erythro-glycerol-1-yl )- 6,7-dimethylquinoxaline (6), respectively. The former product exists predominantly as the two furanosyl anomers. Sequential reaction of 4a with 3b has been studied, and the location of each diamine in the product was deduced by using 1H-n.m.r. spectroscopy. A mechanism for the reaction is proposed. Acetate and acetal derivatives of the compound are prepared.

The scope of the reactions of hydrazines and hydrazones. Part 4: Trisubstituted pyrazoles of possible hypoglycemic and antibacterial activity.

Condensation of ethyl 2,4-dioxo-6-phenyl hex-5-enoate (1) with 4-substituted sulphamyl phenylhydrazines (2) led to 1-aryl-3-ethoxycarbonyl-5-styrylpyrazoles (3) which on hydrolysis gave 1-aryl-5-styrylpyrazole-3-carboxylic acids (4) and upon permanganate oxidation gave 1-aryl-3-ethoxycarbonylpyrazole-5-carboxylic acids (5). Similar condensation of hydralazine (6) with (1) gave the corresponding pyrazole (7) which on hydrolysis gave the acid 8.