Three series of 2-arylidenebenzocycloalkanones 1-3 were prepared in order to compare the topography of the molecules with cytotoxicity. These compounds contain two aryl rings whose spatial relationships to each other were influenced by the size of the alicyclic ring and the nature of the substituents in the arylidene aryl rings. All compounds were evaluated against murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. From these results, 1l and 2c,l emerged as useful lead molecules and 1l was shown to significantly inhibit macromolecular DNA, RNA, and protein syntheses in L1210 cells. Various interatomic distances, bond angles, and a torsion angle of 19 representative compounds were determined by X-ray crystallography, and correlations between these data and the cytotoxicity were noted in nearly 40% of the cases examined. Structure-activity relationships revealed that in general, the steric properties of the groups in the arylidene aryl ring, as revealed by measurements of the molar refractivity values, contributed more to bioactivity than the electronic and hydrophobic properties of the aryl substituents. The compounds displayed little murine toxicity, which favors the decision to develop these molecules as cytotoxic and anticancer agents.
The interaction of caffeine and theophylline with sodium benzoate and sodium salicylate has been studied in deuterium oxide at 35°C by measnring the aromatic salt-induced changes in the chemical shifts of the N-methyl protons. Taking into account the self-association of the N-methylxanthines, on the basis of a 1 : 1 complexation model the association constants for caffein-odium benzoate, theophylline-sodium benzoate, deine-sodium salicylate and theophylline-sodium salicylate were-found to be 2.1 0.1, 1.5 f 0.2, 7.8* 0.2 and 5.0 =t 0.2 1 mol-l, respectively.
Hexahydrobenzo[6,7]cyclohepta[l,2-c] pyrazoles have been synthesized by treating 2benzylidene-Ibenzosuberone with hydrazine derivatives. The cis and trans isomers have been distinguished and conformational equilibria studied by NMR techniques.
The interaction of caffeine and theophylline with purine and pyrimidine was studied in deuterium oxide at 35 "C by measuring the concentration-dependent selective changes in the chemical shifts of the N-methyl protons of the xanthine derivatives. Using a competitive dimer model, the equilibrium constants give a decreasing tendency for hetero-association within the series caffeine-purine (2.97 f 0.15 1 mol-') > theophylline-purine (2.44 & 0.10 I mol-') > caffeine-pyrimidine (1.18 f 0.20 1 mol-') > theophylline-pyrimidine (0.70 0.08 I mol-I), and the upfield dimer shifts suggest a plane-to-plane arrangement.
The self-association of Qmethylpurine and 4-methylpyrimidine and their hetero-association with caffeine and theophylline in deuterium oxide at 35 OC were studied by measuring the concentrationdependent changes in proton chemical shift. The association parameters were calculated using simple and competitive dimer models. The selfassociation constants for Qmethylpurine and 4methylpyrimidine were found to be 2.24 f 0.07 and 0.200 f 0.007 I mol-', respectively, and the hetero-association constants could be ordered in the decreasing series caffeine-6-methylpurine (4.85 f 0.12 1 mol-') > theophyUine-6-methylpurine (4.11 f 0.15 1 mol-') > caffeindmethylpyrimidine (1.45 f 0.13 1 mol-') > theophylline-4-methylpyrimidine (0.98 f 0.10
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