Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues

Bongkrekic acid (BKA), isolated from the bacterium Burkholderia cocovenenans, is an inhibitor of adenine nucleotide translocator, which inhibits apoptosis, and is thus an important tool for the mechanistic investigation of apoptosis. An efficient total synthesis of BKA has been achieved by employing a three‐component convergent strategy based on Kocienski–Julia olefination and Suzuki–Miyaura coupling. It is noteworthy that segment B has been prepared as a new doubly functionalized coupling partner, which contributes to shortening of the number of steps. Torquoselective olefination with an ynolate has also been applied for the efficient construction of an unsaturated ester. Furthermore, it is revealed that 1‐methyl‐2‐azaadamantane N‐oxyl is an excellent reagent for final oxidation to afford BKA in high yield. Based on the total synthesis, several BKA analogues were prepared for structure–activity relationship studies, which indicated that the carboxylic acid moieties were essential for the apoptosis inhibitory activity of BKA. More easily available BKA analogues with potent apoptosis inhibitory activity were also developed.     

Adsorption of bile acid by chitosan-orotic acid salt and its application as an oral preparation

The orotic acid (OT) salt of chitosan (CS), CS-OT, and that of a CS derivative, CP, were prepared, and the adsorption of primary or secondary bile acid was investigated. Calcium-induced alginate gel beads (Alg-Ca) containing CS-OT were also prepared and autoclaved, and the possibility of these beads to act as a vehicle for oral administration to prevent hyperlipidemia was investigated. When taurocholate (TCA) and glycocholate (GCA) were present together in the medium, CS-OT adsorbed identical amounts of both bile acids. This trend was seen in all CPs, although the capacity to adsorb bile acid was affected by the number and/or structure of the amino groups in the CP. On the other hand, taurodeoxycholate, a secondary bile acid was preferentially adsorbed over TCA and GCA. Alg-Ca containing CS-OT took up bile acids in a similar manner as CS-OT irrespective of the water content of the gel matrix. As all elements can be taken as a food, Alg-Ca containing CS-OT could serve as a useful dietary agent for the prevention of hyperlipidemia, which is a lifestyle-related disease.     

Molecular recognition in a supramolecular hydrogel to afford a semi-wet sensor chip

This communication describes a new molecular recognition chip using a semi-wet microenvironment provided by a self-assembled hydrogel. On the basis of the evidence that the molecular recognition capability of artificial chemosensors are practically retained even in the hydrogel compared to those in aqueous solution, we miniaturized the functionalized hydrogel to produce an unprecedented molecular recognition chip. We believe that the present noncovalent immobilization method is generally applicable to many chemosensors, which leads to a unique semi-wet sensor chip suitable to convenient and high-throughput assay to plural analytes.     

Laser defocusing effects on laser ablation inductively coupled plasma-atomic emission spectrometry: different ablation interactions between the laser and low-alloy steel, Fe pellets, and a pond sediment pellet.

The ablation interaction between a laser and solid samples, which affects the analytical performance for laser ablation inductively coupled plasma atomic emission spectrometry (LA-ICP-AES), was studied. The emission intensities of elements observed by LA-ICP-AES (LA-ICP-AES element signal intensities) for different solid samples were measured under different laser defocusing conditions with a fixed laser output energy. It was found that the optimum laser defocusing conditions were dependent on the different solid samples with different sample characteristics, and also on the different elements with different elemental characteristics in each solid sample. A low-alloy steel, pellets containing different Fe concentrations (0 - 100% Fe pellet), and a pond sediment pellet were used as different solid samples. The variations of the LA-ICP-AES Fe signal intensities observed under different laser defocus conditions were completely different between the low-alloy steel and the pond sediment pellet. The changes in the LA-ICP-AES Fe signal intensities for 90 and 100% Fe pellets were similar to that of the low-alloy steel. However, pellets with lower Fe concentrations (less than 70%) showed different trends and the defocusing behavior became closer to that of the pond sediment pellet. The LA-ICP-AES signal intensities of other elements were also evaluated, and were compared for different solid samples and different defocusing behavior. It was observed that the changes in the LA-ICP-AES signal intensities of almost all elements in the pond sediment pellet showed a similar trend to those of Fe for different laser defocus positions; that is, the elemental fractionation for these elements in the pond sediment pellet seemed to be relatively small. On the contrary, it was found that the LA-ICP-AES Si, Ti, and Zr signal intensities for low-alloy steel showed different trends compared to those of other elements, including Fe, under different defocusing conditions; that is, the elemental fractionation observed for the low-alloy steel was larger than that of the pond sediment pellet. From these results, different ablation interactions between the laser and the different solid samples were considered, and attributed to the sample characteristics, such as the matrix, hardness, and conductivity. Elemental fractionation was attempted to be explained by using elemental characteristics, such as the melting point and ionization energy of the elements.     

An efficient in silico screening method based on the protein-compound affinity matrix and its application to the design of a focused library for cytochrome P450 (CYP) ligands

A new method has been developed to design a focused library based on available active compounds using protein-compound docking simulations. This method was applied to the design of a focused library for cytochrome P450 (CYP) ligands, not only to distinguish CYP ligands from other compounds but also to identify the putative ligands for a particular CYP. Principal component analysis (PCA) was applied to the protein-compound affinity matrix, which was obtained by thorough docking calculations between a large set of protein pockets and chemical compounds. Each compound was depicted as a point in the PCA space. Compounds that were close to the known active compounds were selected as candidate hit compounds. A machine-learning technique optimized the docking scores of the protein-compound affinity matrix to maximize the database enrichment of the known active compounds, providing an optimized focused library.     

Syntheses of 4-(benzo[b]furan-2 or 3-yl)- and 4-(benzo[b]-thiophen-3-yl)piperidines with 5-HT2 antagonist activity

The syntheses of 4-(benzo[b]furan-3-yl)piperidines, 4-(benzo[b]furan-2-yl)piperidines and 4-(benzo[b]thiophen-3-yl)piperidines with 5-HT₂ antagonist activity are described. Reaction of 1-acetyl-4-(2,4-difluorobenzo-yl)piperidine 2 with methyl glycolate gave methyl 6-fluoro-3-(1-acetylpiperidin-4-yl)benzo[b]furan-2-carboxylate 3 , which was converted to 2-[2-[4-(benzo[b]furan-3-yi)piperidin-1-yl]ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo-[4,3-a]pyridin-3(2H)-one hydrochloride 9 . Analogous benzo[b]furans 17a-d and benzo[b]thiophenes 10a,b and 18a were prepared by a similar method. Cyclization of 4-fluoro-2-(4-pyridinylmethoxy)acetophenones 20a,b afforded 4-(benzo[b]furan-2-yl)pyridines 21a,b , which were converted to 2-[2-[4-(benzo[b]furan-2-yl)-piperidin-1-yl]ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one hydrochlorides 24a,b. Among them, benzo[b]furans 9 and 17a,d and benzo[b]thiophenes 10 and 18a showed potent 5-HT₂ antagonist activity in vitro.     

Synthesis of bicyclic 1,3,5-triazine-2,4(3H)-diones: Reaction of amidines with diphenyl iminodicarboxylate

The preparation of bicyclic 1,3,5-triazine-2,4(3H)-diones 3 has been investigated. Diphenyl iminodicarboxylate ( 2 ) reacted smoothly with cyclic amidines to give bicyclic triazinediones in good yields.