A new synthetic route to a variety of novel delta 16-17-azolyl steroids is described: it involves the nucleophilic vinylic "addition-elimination" substitution reaction of 3 beta-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) and azolyl nucleophiles. Some of these novel delta 16-17-azolyl steroids, 6, 17, 19, and 27-29, prepared in good overall yields, are very potent inhibitors of human and rat testicular P450(17) alpha. They are shown to be noncompetitive and appear to be slow-binding inhibitors of human P450(17) alpha. The most potent compounds are 3 beta-hydroxy-17-(1H-imidazol-1-yl)androsta-5,16-diene (17), 3 beta-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,-16-diene (19), and 17-(1H-imidazol-1-yl)androsta-4,16-dien-3-one (28), with Ki values of 1.2, 1.4, and 1.9 nM, respectively, being 20-32 times more potent than ketoconazole (Ki = 38 nM). Spectroscopic studies with a modified form of human P450(17) alpha indicate that the inhibition process involves binding of steroidal azole nitrogen to the heme iron of the enzyme. Furthermore, some of these potent P450(17) alpha inhibitors (27-29) are also powerful inhibitors of steroid 5 alpha-reductase, and others (17 and 19) appear to exhibit strong antiandrogenic activity in cultures of the LNCaP human prostatic cancer cell line. These novel compounds with impressive dual biological activities make them strong candidates for development as therapeutic agents for treatment of prostate cancer and other disease states which depend on androgens.
Hydroxyapatite is mineralized along the long axis of collagen fiber during osteogenesis. Mimicking such biomineralization has great potential to control inorganic structures and is fast becoming an important next-generation inorganic synthesis method. Inorganic matter synthesized by biomineralization can have beautiful and functional structures that cannot be created artificially. In this study, we applied biomineralization to the synthesis of the only photocatalyst in practical use today, titanium dioxide (TiO(2)). The photocatalytic activity of TiO(2) mainly relates to three properties: morphology, crystal phase, and light-use efficiency. To optimize TiO(2) morphology, we used a simple sequential peptide as an organic template. TiO(2) mineralized by a β-sheet peptide nanofiber template forms fiber-like shapes that are not observed for mineralization by peptides in the shape of random coils. To optimize TiO(2) crystal phase, we mineralized TiO(2) with the template at 400 °C to transform it into the rutile phase and at 700 °C to transform it into a mixed phase of anatase and rutile. To optimize light-use efficiency, we introduced nitrogen atoms of the peptide into the TiO(2) structure as doped elemental material during sintering. Thus, this biomineralization method enables control of inorganic morphology, crystal phase, and light-use efficiency in a single process.
There was a somewhat lower incidence of ILD with erlotinib therapy than with gefitinib therapy, despite no statistically significant difference. Patient selection based on awareness by Japanese physicians of the risk factors for ILD, rather than the type of agent, may explain the difference in ILD incidence between the two treatments.
In the last decade, cooperative catalysis has received considerable attention as a powerful synthetic method. [1] Two or more catalysts function simultaneously or sequentially in a single reaction vessel to construct complicated molecules, which provides a means to perform unprecedented syntheses that cannot be achieved by a single catalyst. Various catalytic combinations involving transition metals, organocatalysts, and biocatalysts have been developed thus far. [2] A typical example is the combined use of lipases and transition metals to attain the dynamic kinetic resolution (DKR) of racemic secondary alcohols for producing single enantiomer products in up to 100 % yields, [3] in contrast to the use of lipases alone, which can only achieve maximum yields of 50 %. In this DKR process, the enzymatic enantioselective esterification of racemic alcohols is combined with the transition-metal-catalyzed continuous racemization of optically active alcohols, which remain intact during the enzymatic reaction, through a redox process. However, such cooperative cocatalysis often encounters crucial issues of low compatibility between the lipases and the transition metals. Although intense efforts have been devoted to developing highly active racemization catalysts, [4, 5] only a few ruthenium complexes have met both the requirement of sufficient compatibility with lipases and high racemization activity. [5] We recently reported that a combination of oxovanadium compounds (4 or 5) with lipases accomplished the efficient and direct conversion of racemic allylic alcohols (AE)-1 and (AE)-2 into optically active allyl esters (R)-3. [6] This method featured a unique racemization process wherein 4 (or 5) catalyzed the racemization of (S)-1 with 1,3-transposition of the hydroxy group of 1 or 2, while the lipases effected chemoand enantioselective esterification. This is significantly different from the above-mentioned ruthenium-catalyzed DKRs and offered a synthetic advantage in that both (AE)-1 and (AE)-2 were available as equivalent substrates. However, this method required further improvement in both catalytic activity and compatibility of the oxovanadium catalysts with the lipases. [7,8] Herein, we report the preparation of a novel oxovanadium catalyst (V-MPS) immobilized inside mesoporous silica (MPS) with pores of approximately 3 nm in diameter, which enabled a complete division of the racemization site and the enzymatic reaction site. The combined lipase-V-MPS catalyst is reusable and achieved DKR of a wide range of racemic alcohols with excellent chemical and optical yields (Scheme 1).The immobilization of oxovanadium species inside a solid carrier with microsized pores or multilayered structures [9] enables the minimization of interactions between the oxovanadium species and lipases while maintaining easy access of substrate molecules to the metal center. The solid carrier should be neutral and non-charged in order to exert little adverse effect on the lipases. Among the various potential solid carriers, [10,11] MPS,...
In the present study, malignant mesothelioma (MM) cases in Japan were investigated retrospectively. We extracted records for 6030 cases of death due to MM between 2003 and 2008 to clarify the clinical features of MM, including its association with asbestos exposure (AE). Of all these cases, a clinical diagnosis of MM was confirmed for 929. The origin of MM included the pleura in 794 cases (85.5%), the peritoneum in 123 cases (13.2%), the pericardium in seven cases (0.8%), and the testicular tunica vaginalis in five cases (0.5%). The histological subtypes of MM included 396 epithelioid (55.9%), 154 sarcomatoid (21.7%), 126 biphasic (17.8%), and 33 cases (4.7%) classified as “other types”. Of all the MM cases, AE was indicated in 76.8% and pleural plaques were detected in 34.2%. The number of asbestos particles was determined in 103 cases of MM. More than 1000 asbestos particles per gram dried lung tissue were detected in 74.8% of cases and more than 5000 particles were detected in 43.7% of cases. We compared patient characteristics and the diagnostic procedures for MM before and after the “Kubota shock”. Compared with the early phase of this study (2003–2005), the median age at diagnosis of MM was higher, the number of cases without definite diagnosis of MM was lower, the proportion of cases diagnosed by thoracoscopy was higher, and the percentage of cases in which the occupational history was described in the medical records was significantly higher in the later phase (2006–2008). Our study confirmed that more than 70% of MM cases in Japan are associated with AE. The “Kubota shock” may affect some features pertaining to MM. (Cancer Sci 2012; 103: 483–490)
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