Syntheses and antitumor activities of N6,N6-dimethyladenosine carboxylate analogues

Several analogues substituted with fatty acid at the 2'-, 3'-, or 5'-position of the ribose moiety of N6,N6-dimethyladenosine were synthesized and tested for antitumor activity against cultured cells of L1210 leukemia and/or Ehrlich ascites. The cytotoxicity and increase of life span obtained with congeners in the N6,N6-dimethyladenosine 3'- or 5'-substituted series were comparable to in vitro or several times better in vivo than those of the mother compound.     

Synthesis of potential antifilarial agents 2 . methyl 2-substituted purine 8-carbamates and related compounds

A series of methyl 2-substituted purine 8-carbamates was prepared and evaluated for antifilarial activity. These purines were synthesized as aza congeners of benzimidazole carbamates which have shown significant anthelmintic activity to determine the effect that this modification might have on anthelmintic activity. The compounds were tested against the filarial infection, B. pahangi, in jirds. None of the compounds prepared in this study demonstrated antifilarial activity.     

Studies on quinoline derivatives and related compounds. IV. Synthesis of 4-substituted 1-alkyl-1,4-dihydro-3-quinolinecarboxylic acid

By the displacement reactions of 1-ethyl-4-chloro-3-carboethoxy-6,7-methylenedioxyquinolinium iodide ( 3a ), several 4-substituted derivatives including the 4-thioxo ( 1c ) and 4-amino derivatives ( 6 ) of oxolinic acid were prepared. The acid 1c and its N₁-substituted derivatives ( 18a-h ) were prepared alternatively by alkylation of ethyl 4-ethylmercapto-6,7-methylenedioxy-3-quinolinecarboxylate ( 15 ) followed by treatment with sodium hydrosulfide and hydrolysis.     

Total synthesis of novel 6-substituted lavendamycin antitumor agents

[structure: see text] Novel 6-substituted lavendamycins have been synthesized for the first time. The key step in these syntheses is a Pictet-Spengler condensation (Scheme 1). Efficient methods for the synthesis of each compound, including a novel reaction for the facile introduction of alkylamino groups at the C-6 position of the lavendamycin system, are discussed. Possible mechanisms for these reactions are also presented.     

Studies on quinoline derivatives and related compounds. II. Synthesis of 5-substituted 1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

The cyclization of m-substituted anilinomethylenemalonates ( 1 ) in the presence of polyphosphate ester and some other cyclizing agents gave mixtures of the isomeric ethyl 5- ( 2 ) and 7-substituted 4-hydroxy-3-quinolinecarboxylates ( 3 ), which led to mixtures of the corresponding quinolinecarboxylic acids ( 4 and 5 ) by hydrolysis. The proportions of 4 and 5 in the mixtures were determined on the basis of their nmr spectra. Novel 5-chloro- ( 8a ), 5-methyl- ( 8b ) and 5-nitro-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids were prepared and evaluated for antimicrobial activities. No significant activity, however, was noted.     

Studies on isocyanides and related compounds. Synthesis of furan derivatives and their transformation into indole derivatives

The intramolecular Knoevenagel condensation of N‐cyclohexyl 3‐aryl‐2‐(2‐nitrophenyl)acetoxy‐3‐oxopropionamides 4 obtained from 2‐nitrophenylacetic acid (1), arylglyoxals 2 and cyclohexyl isocyanide (3) afforded N‐cyclohexyl 3‐aryl‐2,5‐dihydro‐2‐(2‐nitrophenyl)‐5‐oxofuran‐2‐carboxamides 6 which underwent reductive cleavage to N‐cyclohexyl (Z)‐3‐aryl‐2‐hydroxy‐3‐(2,3‐dihydro‐2‐oxoindol‐3‐ylidene)propionamides 8 probably via the labile intermediates 7.     

Studies on gastric antiulcer active agents. II. Synthesis of tetrazole alkanamides and related compounds

A series of tetrazole alkanamides was synthesized and tested for antiulcer activity against acetic acid-induced gastric ulcer in rats. These compounds were prepared by the reaction of tetrazole alkanoic acids and various amines by the mixed anhydride method or acid chloride method. Among them, 3-[(1-ethyl-5-tetrazolyl)methylthio]propionamide (IIn) was found to have the most potent activity. The structure-activity relationships are discussed.     

Studies on antidiabetic agents. X. Synthesis and biological activities of pioglitazone and related compounds

Various analogues of a new antidiabetic agent, pioglitazone (AD-4833, U-72107), were synthesized in order to study in more detail the structure-activity relationships of this class of drug. 5-(4-Pyridylalkylthiobenzyl)-2,4-thiazolidinediones (I), thia-analogues of pioglitazone, were prepared via Meerwein arylation of the alkylthioanilines (IV). 5-(4-Pyridylalkoxybenzylidene)-2,4-thiazolidinediones (IIa) and related heterocyclic analogues (IIb) were synthesized by Knoevenagel condensation of the aldehydes (VIII) with the corresponding azolidinones. Compounds I and II were evaluated for hypoglycemic and hypolipidemic activity in genetically obese and diabetic yellow KK (KKAy) mice. Several 5-[4-[2-(2-pyridyl)ethoxy]-benzylidene]-2,4- thiazolidinediones (IIa) were equipotent to pioglitazone. However, the thia-analogues (I) and the benzylideneheterocycles (IIb) had decreased activity. Catalytic hydrogenation of the 5-benzylidene analogue (14) was found to be a convenient new synthetic method for pioglitazone. The configuration of 14 is also discussed.     

Studies on antiallergy agents. III. Synthesis of 2-anilino-1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acids and related compounds

A series of 2-anilino-1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acids with various substituents was synthesized and evaluated in the rat passive cutaneous anaphylaxis test for antiallergic activity. High activity by intraperitoneal and oral administrations was observed for the 3-trifluoromethyl and 2-alkoxyanilino derivatives (64, 79, 81, 82 and 85). Structure-activity relationships are discussed.     

Studies on gastric antiulcer active agents. III. Synthesis of 1-substituted 4-(5-tetrazolyl)thio-1-butanones and related compounds

Many 1-substituted 4-(5-tetrazolyl)thio-1-butanones were synthesized and tested for antiulcer activity against acetic acid-induced gastric ulcer in rats. These compounds were prepared by the reaction of 5-mercaptotetrazoles and 4-halogeno-1-butanones. Among them, 1-cyclohexyl-4-(1-phenyl-5-tetrazolyl)thio-1-butanone (VIIIp) was found to have the most potent activity. The structure-activity relationships are discussed.     

Synthesis and antitumor activities of novel 1,4-substituted phthalazine derivatives

<正>A series of 1,4-substituted phthalazine derivatives were designed and synthesized.All the prepared compounds were screened for their cytotoxic activities against A549.HT-29 and MDA-MB-231 cell lines in vitro.Among them,compounds 7a-7h showed excellent selectivity for MDA-MB-231 cell line with IC_(50) values from 1 nmol/L to 0.92μmol/L.A preliminary SAR study of these derivatives was performed.     

Studies on isoindoline derivatives and related compounds. I Synthesis and reduction of 1,3-dicarboethoxymethyleneisoindoline

The reaction of iminoether III with benzyl cyanoacetate gave ethyl 1-(α-cyanocarbobenzyl-oxymethylene)isoindoline-3-acetate (V) in a 26% yield. Decarboxylation of ethyl 1-(α-cyanocarboxymethylene)isoindoline-3-acetate (VI), obtained by hydrogenolysis of V, gave a mixture of 1-carboethoxymethyleneisoindoline-3-acetonitrile (VII) as major component and 1-carboethoxymethylene-3-cyanomethyleneisoindoline (VIII) as minor component, which were reconvertible into each other. On the other hand, decarboxylation of VI was successfully carried out to give VII as a single product under a nitrogen atmosphere. Ethanolysis and autoxidation of VII gave crystalline diethyl 1,3-dicarboethoxymethyleneisoindoline (XIII). Catalytic hydrogenation of of XIII over platinum oxide gave diethyl isoindoline-cis-1,3-diacetate (XIV) in a yield of 92%. The uv spectra of these 1,3-disubstituted isoindoline derivatives are summarized in Table I.