Discovery of 3-aryloxy-lactam analogs as potent androgen receptor full antagonists for treating castration resistant prostate cancer

High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities.     

Synthesis of a novel ester analog of nucleic acids bearing a serine backbone

A novel analog of nucleic acids bearing an optically active serine ester backbone, serine-based nucleobase-linked polyester (SNE), was synthesized. Monomers containing a thymine base were synthesized from L- and D-serines. Furthermore, reaction conditions were thoroughly examined for the ester bond formation by using a new phosphonium-type condensing reagent on a solid support without racemization. The release of the dimer from the resin was also investigated using a new type of linker, which could be cleaved under neutral conditions.     

Resonance Raman characterization of archaeal and bacterial Rieske protein variants with modified hydrogen bond network around the [2Fe-2S] center

The rate of quinol oxidation by cytochrome bc(1)/b(6)f complex is in part associated with the redox potential (E(m)) of its Rieske [2Fe-2S] center, for which an approximate correlation with the number of hydrogen bonds to the cluster has been proposed. Here we report comparative resonance Raman (RR) characterization of bacterial and archaeal high-potential Rieske proteins and their site-directed variants with a modified hydrogen bond network around the cluster. Major differences among their RR spectra appear to be associated in part with the presence or absence of Tyr-156 (in the Rhodobacter sphaeroides numbering) near one of the Cys ligands to the cluster. Elimination of the hydrogen bond between the terminal cysteinyl sulfur ligand (S(t)) and Tyr-Oeta (as with the Y156W variant, which has a modified histidine N(epsilon) pK(a,ox)) induces a small structural bias of the geometry of the cluster and the surrounding protein in the normal coordinate system, and significantly affects some Fe-S(b/t) stretching vibrations. This is not observed in the case of the hydrogen bond between the bridging sulfide ligand (S(b)) and Ser-Ogamma, which is weak and/or unfavorably oriented for extensive coupling with the Fe-S(b/t) stretching vibrations.     

Effects of short-term W-CDMA mobile phone base station exposure on women with or without mobile phone related symptoms

To investigate possible health effects of mobile phone use, we conducted a double-blind, cross-over provocation study to confirm whether subjects with mobile phone related symptoms (MPRS) are more susceptible than control subjects to the effect of electromagnetic fields (EMF) emitted from base stations. We sent questionnaires to 5,000 women and obtained 2,472 valid responses from possible candidates; from these, we recruited 11 subjects with MPRS and 43 controls. There were four EMF exposure conditions, each of which lasted 30 min: continuous, intermittent, and sham exposure with and without noise. Subjects were exposed to EMF of 2.14 GHz, 10 V/m (W-CDMA), in a shielded room to simulate whole-body exposure to EMF from base stations, although the exposure strength we used was higher than that commonly received from base stations. We measured several psychological and cognitive parameters pre- and post-exposure, and monitored autonomic functions. Subjects were asked to report on their perception of EMF and level of discomfort during the experiment. The MPRS group did not differ from the controls in their ability to detect exposure to EMF; nevertheless they consistently experienced more discomfort, regardless of whether or not they were actually exposed to EMF, and despite the lack of significant changes in their autonomic functions. Thus, the two groups did not differ in their responses to real or sham EMF exposure according to any psychological, cognitive or autonomic assessment. In conclusion, we found no evidence of any causal link between hypersensitivity symptoms and exposure to EMF from base stations.     

Availability of tyrosine amide for α-chymotrypsin-catalyzed synthesis of oligo-tyrosine peptides

Oligo-tyrosine peptides such as Tyr-Tyr having angiotensin I-converting enzyme (ACE) inhibitory activity could be synthesized by α-chymotrypsin-catalyzed reaction with l-tyrosine ethyl ester in aqueous media. However, peptide yield in the reaction was below 10%. Since l-tyrosine amide showed highly nucleophilic activity for the deacylation of enzyme through which a new peptide bond was made, its application to the enzymatic peptide synthesis was evaluated in this study. Addition of tyrosine amide into the reaction produced Tyr-Tyr-NH₂, of which yield exceeded 130% on the basis of tyrosine ethyl ester. Although purified Tyr-Tyr-NH₂ did not inhibit ACE activity, α-chymotrypsin could act on the dipeptide amide and convert about 40% of it to Tyr-Tyr. The use of both ester and amide forms of tyrosine is expected to be a potent procedure for α-chymotrypsin-catalyzed synthesis of antihypertensive peptides.     

Genetic diversity and structure of natural fragmented Chamaecyparis obtusa populations as revealed by microsatellite markers

The genetic diversity and population structure of hinoki (Chamaecyparis obtusa) in Japan were investigated by examining the distribution of alleles at 13 microsatellite loci in 25 natural populations from Iwaki in northern Japan to Yakushima Island in southern Japan. On average, 26.9 alleles per locus were identified across all populations and 4.0% of the genetic variation was retained among populations (G _ST = 0.040). According to linkage disequilibrium analysis, estimates of effective population size and detected evidence of bottleneck events, the genetic diversity of some populations may have declined as a result of fragmentation and/or over-exploitation. The central populations located in the Chubu district appear to have relatively large effective population sizes, while marginal populations, such as the Yakushima, Kobayashi and Iwaki populations, have smaller effective population sizes and are isolated from the other populations. Microsatellite analysis revealed the genetic uniqueness of the Yakushima population. Although genetic differentiation between populations was low, we detected a gradual cline in the genetic structure and found that locus Cos2619 may be non-neutral with respect to natural selection.     

A poly(dimethylsiloxane)-based device enabling time-lapse imaging with high spatial resolution

We have developed a regulator-free device that enables long-term incubation of mammalian cells for epi-fluorescence imaging, based on a concept that the size of sample to be gassed and heated is reduced to observation scale. A poly(dimethylsiloxane) block stamped on a coverslip works as a long-lasting supplier of CO₂-rich gas to adjust bicarbonate-containing medium in a tiny chamber at physiological pH, and an oil-immersion objective warms cells across the coverslip. A time-lapse imaging experiment using HeLa cells stably expressing fluorescent cell-cycle indicators showed that the cells in the chamber proliferated with normal cell-cycle period over 2 days.