Preparation of 5,5-dicyano- and 5-cyano-5-ethoxycarbonyl-5,6-dihydro-3,7-diphenyl-4H-1,2-diazepines and their halogenations

5,5-Dicyano- and 5-cyano-5-ethoxycarbonyl-5,6-dihydro-3,7-diphenyl-4H-1,2-diazepines were prepared by the condensation of α-bromoacetophenone azine with malononitrile and ethyl cyanoacetate in the presence of sodium ethoxide, respectively. Halogenations of the dihydrodiazepines gave pyridazines, diazanorcaradienes, 4,4,6,6-tetrachlorodihydrodiazepines, and/or a 4-chloropyrazole whose relative yields strongly depended upon the nature of 5-substituents of the dihydrodiazepines as well as the reaction conditions.     

Synthesis and evaluation of novel pyrimido-acridone, -phenoxadine, and -carbazole as topoisomerase II inhibitors

As part of a series of studies to discover new topoisomerase II inhibitors, novel pyrimidoacridones, pyrimidophenoxadines, and pyrimidocarbazoles were synthesized, and in vitro and in vivo antitumor activities and DNA-protein and/or DNA-topoisomerase II cross-linking activity as an indicator of topoisomerase II-DNA cleavable complex formation were evaluated. The pyrimidocarbazoles possessed high in vitro and in vivo potencies. Compound 26 (ER-37326), 8-acetyl-2-[2-(dimethylamino)ethyl]-1H-pyrimido[5,6,1-jk]carbazole-1,3(2H)-dione, showed in vitro growth inhibitory activity with respective IC(50) values of 0.049 microM and 0.35 microM against mouse leukemia P388 and human oral cancer KB. In vivo, this compound inhibited the tumor growth of mouse sarcoma M5076 implanted into mice with T/C values of 42% and 13% at 3.13 and 6.25 mg/kg/d respectively without significantly affecting the body weight. In addition, compound 26 (ER-37326) increased the formation of DNA-topoisomerase II cross-linking in P388 cells.     

Asymmetric total synthesis of (-)-azaspirene,a novel angiogenesis inhibitor

The asymmetric total synthesis of (-)-azaspirene, an angiogenesis inhibitor, has been accomplished, establishing its absolute stereochemistry. The key steps are a MgBr2.OEt2-mediated, diastereoselective Mukaiyama aldol reaction, a NaH-promoted, intramolecular cyclization of an alkynylamide, and the aldol reaction of a ketone containing functionalized gamma-lactam moiety without protection of tert-alcohol and amide functionalities.     

Heterogeneously catalyzed aerobic oxidative biaryl coupling of 2-naphthols and substituted phenols in water

The oxidative coupling reaction can efficiently be promoted by supported ruthenium catalyst Ru(OH)x/Al2O3. A variety of 2-naphthols and substituted phenols can be converted to the corresponding biaryl compounds in moderate to excellent yields using molecular oxygen as a sole oxidant in water without any additives. The catalysis is truly heterogeneous in nature, and Ru(OH)x/Al2O3 can easily be recovered after the reaction. The catalyst can be recycled seven times with the maintenance of the catalytic performance, and the total turnover number reaches up to 160. The results of competitive coupling reactions suggest that the present oxidative biaryl coupling reaction proceeds via the homolytic coupling of two radical species and the Ru(OH)x/Al2O3 catalyst acts as an one-electron oxidant. Two radical species are coupled to give the corresponding biaryl product, and the one-electron reduced catalyst is reoxidized by molecular oxygen. The amounts of O(2) uptake and H(2)O formation were almost one-quarter and one-half the amount of substrate consumed, respectively, supporting the reaction mechanism. The kinetic data and kinetic isotope effect show that the reoxidation of the reduced catalyst is the rate-limiting step for the coupling reaction.     

Enantio- and diastereoselective total synthesis of EI-1941-1, -2, and -3, inhibitors of interleukin-1beta converting enzyme, and biological properties of their derivatives

[reaction: see text] The first asymmetric total synthesis of EI-1941-1, -2, and -3, inhibitors of the interleukin-1beta converting enzyme (ICE), has been accomplished, starting from a chiral epoxy iodoquinone 11, a key intermediate in our total synthesis of epoxyquinols A and B. Despite a failure to synthesize the inhibitors by our postulated biosynthetic route, we were able to diastereoselectively synthesize them via an intramolecular carboxypalladation with the key steps being a 6-endo cyclization mode followed by beta-hydride elimination. The investigation of the biological properties of EI-1941-1, -2, and -3 and their derivatives disclosed them to be potent and effective ICE inhibitors with less cytotoxicity than EI-1941-1 and -2 in a cultured cell system.     

Effects of cationic and anionic nanoparticles on the stability of the secondary structure of DNA

The effects of anionic and cationic nanoparticles (15 and 100 nm in diameter) on the stability of the secondary structure of DNA were studied in DNA denaturation and renaturation processes. The results showed that DNA denaturation is greatly inhibited in the presence of cationic nanoparticles. In contrast, in the presence of even large amounts of anionic nanoparticles, the DNA melting transition occurs at the original melting temperature. The effects of the size and concentration of nanoparticles on DNA denaturation are discussed.