Structure-activity studies of 3-benzoylpropionic acid derivatives suppressing adjuvant arthritis.

3-Benzoylpropionic acid derivatives possess an immunomodulative activity and suppress adjuvant arthritis. To understand how substituents affect the biological activity, the quantitative structure-activity relationships of 30 compounds were analyzed by the adaptive least-squares method. For the suppressing activity in rats, the electronic effects and the structural feature of the substituent on benzene ring were suggested to be important. To reinforce and confirm the correlation, 4 additional compounds of phenoxybutyric acid derivatives were synthesized and tested with the rat adjuvant-induced arthritis. These compounds were found to have potent suppressing activity.     

Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives

A novel series of oxyiminoacetic acid derivatives were synthesized in an effort to develop a potent antidiabetic agent, which does not contain the 2,4-thiazolidinedione moiety. These compounds were evaluated for glucose and lipid lowering effects in genetically obese and diabetic KKA(y) mice. Several of the compounds showed strong antidiabetic activity, including functional potency at peroxisome proliferator-activated receptor (PPAR)-gamma. (Z)-2-[4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino]-2-(4-phenoxyphenyl)acetic acid (25) significantly reduced plasma glucose (33%, p<0.01) and plasma triglycelide levels (43%, p<0.01) even at a dosage of 0.001% in diet. Pharmacokinetic analyses of 25 are also reported.     

Studies on hypolipidemic agents. IV. 3-[4-(Phenylthio)benzoyl]propionic acid derivatives

2-Acetylthio-3-benzoylpropionic acid derivatives having two benzene rings or condensed-ring moieties were prepared, and tested for hypolipidemic activity in normal rats. Some of these compounds were active. 2-Acetylthio-3-[4-(phenylthio)benzoyl]propionic acid (10) and its derivatives seemed to have the most potent hypocholesterolemic activities. Compound 10 showed strong activity, especially in cholesterol-fed rats.     

Studies on pyrrolidinones. Synthesis of 4,5-fused-3-hydroxypyridinyl-2-propionic acid derivatives

The synthesis of some condensed indolizinediones derived from pyroglutamic acid is described. Treatment of these ketones in HCl, HBr or MeONa/MeOH furnished aryl propionic acid derivatives. During the ketone transformations, two sequential processes could take place in competitive manner to provide heterocyclic systems bearing carboxylic acid or hydroxycarboxylic acid function. Easy synthesis of amides indicates that potential DNA-intercalating heterocyclic systems fused on γ-carboline and isoquinoline nucleus could be obtained from these series.     

Studies on cardiotonic agents. I. Synthesis of some quinazoline derivatives

A series of quinazoline derivatives with various 4-heterocyclylpiperidino groups at the 4-position was synthesized and tested for cardiotonic activity in anesthetized dogs. Among them, several 6,7-dimethoxyquinazoline derivatives showed potent cardiotonic activity.     

Studies on halogen derivatives of phenylazochromotropic acid: I. The acid-base properties

The acid-base properties of six halogen derivatives of phenylazochromotropic acid have been studied in an attempt to apply them as metallochromic or chromophoric indicators. The absorption spectra are studied in buffer solutions of varying pH values. The variation of spectra with pH indicates the presence of two equilibria between H₂D^2?, HD^3? and D^4? species. The pK values of the naphthlenic OH groups are determined spectrophotometrically and are discussed in relation to molecular structure while those of the sulfonic acid groups are determined potentiometrically.     

Studies in trifluoromethaneslphonic acid—I: Protonation of aromatic derivatives

Solutions of aromatic compounds in trifluoromethanesulphonic acid have been investigated using ¹H-NMR and UV specstrocpy. In addition, conductivity measurements were made over a wide concentration range. At low concentrations ( < 0.001M) all derivatives were completely protonated. For 0.2-1.0M evidence was obtained for ion pairing in the cases of benzene and toluene. An intimate ion pair is postulated in which the partial charges on the arenium ion and on the sulphonate anion match up to maximise electrostatic interaction. The stability of these two species is discussed for a series of methylbenzenes.Exchange reactions are also discussed in terms of ion pairing. Preliminary results show that both trans alkylation and isomerisation reactions occur with great facility in this solvent. Dihydroanthreacene undergoes a disproportionation reaction in which it acts as a very powerful hydride donor.     

Aza-crown macrocycles as chiral solvating agents for mandelic acid derivatives

A series of new chiral macrocycles containing the trans-1,2-diaminocyclohexane (DACH) subunit and arene- and oligoethylene glycol-derived spacers has been prepared in enantiomerically pure form. Four of the macrocycles have been characterized by X-ray crystallography, which reveals a consistent mode of intramolecular N-H···N hydrogen bonding and conformational variations about the N-benzylic bonds. Most of the macrocycles were found to differentiate the enantiomers of mandelic acid (MA) by (1)H NMR spectroscopy in CDCl(3); within the series of macrocycles tested, enantiodiscrimination was promoted by (i) a meta-linkage geometry about the arene spacer, (ii) the presence of naphthalene- rather than phenylene-derived arene spacers, and (iii) increasing length of the oligoethylene glycol bridge. (1)H NMR titrations were performed with optically pure MA samples, and the data were fitted to a simultaneous 1:1 and 2:1 binding model, yielding estimates of 2:1 binding constants between some of the macrocycles and MA enantiomers. In several cases, NOESY spectra of the MA:macrocycle complexes show differential intramolecular correlations between protons adjacent to the amine and carboxylic acid groups of the macrocycles and MA enantiomers, respectively, thus demonstrating geometric differences between the diastereomeric intermolecular complexes. The three most effective macrocycles were employed as chiral solvating agents (CSAs) to determine the enantiomeric excess (ee) of 18 MA samples over a wide ee range and with very high accuracy (1% absolute error).     

Synthesis of new boswellic acid derivatives as potential antiproliferative agents

Abstract

In the current investigation, a series of heterocyclic derivatives of boswellic acids were prepared along with new monomers of 3-O-acetyl-11-keto-β-boswellic acid (AKBA, 1) 11-keto-β-boswellic acid (KBA, 2) and several new bis-AKBA and KBA homodimers and AKBA-KBA heterodimers. The effects of these compounds on the proliferation of different human cancer cell lines, viz., FaDu (pharynx carcinoma), A2780 (ovarian carcinoma), HT29 (colon adenocarcinoma), and A375 (malignant melanoma), have been evaluated. Thus, KBA homodimer 21 effectively inhibited the growth of FaDu, A2780, HT29, and A375 cells with EC₅₀ values below 9?μM. In addition, compounds 7, 8, 11, 12, 15, 16, and 17 also exhibited cytotoxic effects for A2780, HT29, and A375 cancer cells. In particular, the pyrazine analog 8 was highly cytotoxic for A375 cancer cells with an EC₅₀ value of 2.1?μM.     

Studies on halogen derivatives of phenylazochromotropic acid: II. Spectrophotometric microdetermination of thorium

A new rapid and accurate method for the spectrophotometric microdetermination of thorium using o, p-dichloro-, p-bromo-, and p-iodophenylazochromotropic acids is given. The optimum conditions favoring the formation of the complexes are extensively investigated. The molecular structure was found to be 1:1 and 1:2 Beer's law is obeyed up to 16.24, 18.56, and 11.60 ppm of Th using the three reagents, respectively.