Deguelin exhibits potent apoptotic and antiangiogenic activities in a variety of transformed cells and cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogues do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To determine the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its antiproliferative and antiangiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogues 54 and 69, the B- and C-ring-truncated compounds, exhibited excellent antiproliferative activities with IC(50) of 140 and 490 nM in the H1299 cell line, respectively, and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 μM).

In this paper, a new concept of a wall-climbing robot able to climb a vertical plane is presented. A continuous locomotive motion with a high climbing speed of 15m/min is realized by adopting a series chain on two tracked wheels on which 24 suction pads are installed. While each tracked wheel rotates, the suction pads which attach to the vertical plane are activated in sequence by specially designed mechanical valves. The engineering analysis and detailed mechanism design of the tracked wheel, including mechanical valves and the overall features, are described in this paper. It is a self-contained robot in which a vacuum pump and a power supply are integrated and is controlled remotely. The climbing performance, using the proposed mechanism, is evaluated on a vertical steel plate. Finally, the procedures are presented for an optimization experiment using Taguchi methodology to maximize vacuum pressure which is a critical factor for suction force.

The natural compound deguelin has promising preventive and therapeutic activity against diverse cancers by directly binding to heat shock protein-90 and thus suppressing its function. Potential side effects of deguelin over a certain dose, however, could be a substantial obstacle to its clinical use. To develop a derivative(s) of deguelin with reduced potential side effects, we synthesized five deguelin analogues and compared them with the parent compound and each other for structural and biochemical features; solubility; and antiproliferative effects on normal, premalignant, and malignant human bronchial epithelial (HBE) and non-small-cell lung cancer (NSCLC) cell lines. Four derivatives destabilized hypoxia-inducible factor-1α as potently as did deguelin. Reversephase protein array (RPPA) analysis in H460 NSCLC cells revealed that deguelin and the derivatives suppressed expression of a number of proteins including heat shock protein-90 clients and proteins involved in the phosphoinositide 3-kinase/Akt pathway. One derivative, SH-14, showed several features of potential superiority for clinical use: the highest apoptotic activity; no detectable influence on Src/signal transducer and activator of transcription signaling, which can promote cancer progression and is closely related to pathogenesis of Parkinson's disease (deguelin, SH-02 and SH-03 strongly activated this signaling); better aqueous solubility; and less cytotoxicity to immortalized HBE cells (versus deguelin) at a dose (1 μmol/L) that induced apoptotic activity in most premalignant and malignant HBE and NSCLC cell lines. These collective results suggest that the novel derivative SH-14 has strong potential for cancer chemoprevention and therapy, with equivalent efficacy and lesser toxicity (versus deguelin).Cancer remains one of the leading causes of death worldwide despite several decades of intensive efforts to prevent and treat it. Most effective cancer therapy agents are toxic in normal tissue, indicating the need for novel preventive and therapeutic drugs with no or low toxicity. Deguelin, a rotenoid isolated from the African plant Mundulea sericea (Leguminosae) and other plants (1), is a heat shock protein-90 (Hsp90) inhibitor with potent apoptotic and antiangiogenic effects on transformed cells and a variety of cancer cells but without cytotoxicity in normal cells (2, 3), making it a promising cancer prevention and therapy agent. We recently showed that deguelin has promising activity against a number of human cancers, at least in part, because it binds to the ATP pocket of Hsp90α, which leads to decreased expression of a number of Hsp90 client proteins, including mutated p53, cyclin-dependent kinase 4, mitogen-activated protein kinase kinase-1/2, Akt, and hypoxia-inducible factor (HIF)-1α, in addition to decreased expression of previously known deguelin targets such as cyclooxygenase-2, necrosis factor κB, and nucleoporin 98 kDa (Nup98).Hsp90 facilitates the adaptation of cancer cells to many environmental stresses owing to its functi...

Using the approach of ligand-based drug design, we discovered a novel series of 4,6-disubstituted 2-aminopyrimidines as RAGE inhibitors. In transgenic mouse models of AD, one of the 4,6-bis(4-chlorophenyl)pyrimidine analogs, 59, significantly lowered the concentration of toxic soluble Aβ in the brain and improved cognitive function. SPR analysis confirmed the direct binding of 59 with RAGE, which should contribute to its biological activities via inhibition of the RAGE-Aβ interaction. We also predicted the binding mode of the 4,6-bis(4-chlorophenyl)pyrimidine analogs to the RAGE V-domain through flexible docking study.

This paper presents traffic measurement of a Massively Multiplayer On-line Role Playing Game (MMORPG). This analysis characterizes the MMORPG traffic and shows its implications for future research issues. The target game is 'Lineage II' developed by NCsoft, which is one of the world's largest MMORPGs in terms of the number of concurrent users. We collected about 1 tera bytes of packets for four consecutive days including a weekend. The MMORPG traffic consists of two kinds of packets: client-generated packets and server-generated packets. We observe that the client packet has an average of 19 bytes payload size, while the average payload size of server packets is about 318 bytes. This asymmetry is due to the fact that the server transmits all the information to construct the visual environment for the clients in the same region. Likewise, the bandwidth usage of the server traffic is about ten times larger than that of the client traffic. The analysis of RTT reveals that client packets and server packets are transmitted mostly at the interval of 200 milliseconds due to TCP's delayed ACK. We find that there is a linear relationship between the number of users and the bandwidth usage except when the number of users is around 5000.

Cyclopenta­[b]­thiopyran, isomeric to benzo­[b]­thiophene while isoelectronic to azulene, is involved as a building block to construct soluble organic semiconductors for field-effect transistors. Two series of angular-shaped heteroarenes based on cyclopenta­[b]­thiopyran, that is, C n -SS (n = 4, 6, 8, 10) with different linear alkyl groups and C 8 -SS-Cl m (m = 2, 3, 4) with chlorides substituted at different positions, have been straightforward synthesized. The obtained seven S-heteroarenes exhibit intriguing and similar photophysical and electrochemical properties, such as near-infrared absorption and high-energy levels of the highest occupied molecular orbitals. Nevertheless, the S-heteroarenes with identical π-conjugated skeletons demonstrate completely different molecular packing structures, which is proofed to be the key determinate factor for the charge carrier mobilities. Upon the engineering of the pendant alkyl lengths, the highest hole mobility in the C n -SS series is achieved for C 8 -SS (1.1 cm2 V–1 s–1) with moderate alkyl length. The further incorporation of chlorides on C 8 -SS results in the shortened intermolecular H···S contacts and the interplane distances. Most interestingly, when chlorine-containing chloroform and chlorobenzene are used as crystallization solvents, single crystals of C 8 -SS-Cl m with different packing structures are produced owing to the intermolecular interactions among the solute and solvent molecules. Upon further engineering of the chlorination position and the crystallization solvent, the maximum hole mobility in the ambient air improves to 2.7 cm2 V–1 s–1 for C 8 -SS-Cl 2 crystallized from chlorobenzene, suggesting that the introduction of the accessible chlorides is a feasible pathway to engineering the crystal structures and controlling the charge transport characteristics.

In diabetic retinopathy (DR), visual deterioration is related with retinal neovascularization and vascular hyperpermeability. Anti-vascular endothelial growth factor (VEGF) agents are currently utilized to suppress retinal neovascularization and macular edema (ME); however, there are still concerns on the widespread use of them because VEGF is a trophic factor for neuronal and endothelial cells in the retina. As an alternative treatment strategy for DR, it is logical to address hypoxia-related molecules to treat DR because the retina is in relative hypoxia as DR progresses. In this study, we demonstrate that destabilization of hypoxia-inducible factor-1α (HIF-1α) by SH-1242 and SH-1280, novel heat shock protein 90 (hsp90) inhibitors, leads to suppression of hypoxia-mediated retinal neovascularization and vascular leakage in diabetic retina. In vitro experiments showed that these inhibitors inhibited hypoxia-induced upregulation of target genes of HIF-1α and further secretion of VEGF. Furthermore, these inhibitors effectively suppressed expression of target genes of HIF-1α including vegfa in the retina of oxygen-induced retinopathy (OIR) mice. Interestingly, despite hsp90 inhibition, these inhibitors do not induce definite toxicity at the level of gene expression, cellular viability, and histologic integrity. We suggest that SH-1242 and SH-1280 can be utilized in the treatment of DR, as an alternative treatment of direct VEGF inhibition. Key message: SH-1242 and SH-1280 are novel hsp90 inhibitors similar to deguelin. HIF-1α destabilization by hsp90 inhibition leads to anti-angiogenic effects. Despite hsp90 inhibition, both inhibitors do not induce definite toxicity. HIF-1α modulation can be a safer therapeutic option than direct VEGF inhibition.

Blue photoluminescent emission was observed in pure nanometer-sized ␥-Al 2 O 3 powders prepared by the sol-gel process, with aluminum alkoxide as the precursor. The photoluminescent excitation spectrum detected at em ‫ס‬ 422 nm showed four peaks located at 238, 255, 278.5, and 348.5 nm, respectively, the first having the strongest intensity. The photoluminescent emission spectra were made up of a broad band with four peaks located at 404.5, 422, 447, and 484.5 nm. The emission band of 422 nm had the intensity. We suggest that the defect level in the nanometer alumina powder also is the main reason for the appearance of new luminescent emission bands.