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...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.