Iron‐deficient bean plants (Phaseolus vulgaris L. cv. Prélude) exhibited a ferric reducing activity in the roots, with kinetics characteristic for matrix‐bound enzymes: the reaction rate was proportional to substrate (Fe‐EDTA) concentration until 100 μM, and at higher concentrations it leveled off to a maximum; the Lineweaver‐Burk plot yielded a non‐linear relationship between rate −1 and substrate −1. The Arrhenius plot yielded apparent activation energies which were dependent on substrate concentration. No evidence was obtained for the secretion by roots of a low molecular weight metabolite involved in the reduction of iron prior to its uptake. The results are interpreted to indicate that the ferric reducing activity in the roots of iron‐deficient bean plants is located in an enzyme in the plasmalemma of the cortex or epidermis cells.
The pochoximes, based on the radicicol pharmacophore, are potent inhibitors of heat shock protein 90 (HSP90) that retain their activity in vivo. Herein we report an extended library that broadly explores the structure-activity relationship (SAR) of the pochoximes with four points of diversity. Several modifications were identified that afford improved cellular efficacy, new opportunities for conjugation, and further diversifications. Cocrystal structures of pochoximes A and B with HSP90 show that pochoximes bind to a different conformation of HSP90 than radicicol and provide a rationale for the enhanced affinity of the pochoximes relative to radicicol and the pochonins.
Heat shock protein 90 (Hsp90) is an ATP-dependent chaperone which is involved in the post-translational maturation and stabilization of over one hundred proteins ("its clients"). In the absence of Hsp90's chaperoning, its clients are misfolded and degraded via ubiquitin-proteasome pathway. It has become the focus of intense drug discovery efforts as its activity has been implicated in diverse pathologies ranging from oncology to neurodegenerative and infectious diseases. The most promising inhibitors reported to date inhibit the ATPase activity by binding to the N-terminal ATP pocket. Radicicol, a member of the resorcylic acid lactones (RALs), represents an important pharmacophore to this end. Efforts towards the development of this pharmacophore and its SAR are reviewed herein.
Make a clean breast of it: The generation of a library of pochonin D derivatives by a solid-phase approach has led to the discovery of pochoxime (see scheme), a potent inhibitor of the heat-shock protein 90, with over 100-fold improved incellular activity. Pochoxime was found to be effective in breast tumor xenografts, leading to a reduction in the tumor size
The heat-shock protein 90 (HSP90) has emerged as one of the most exciting therapeutic targets in recent years. [1,2] Despite the seemingly ubiquitous function of this constitutively expressed chaperone, its role in stabilizing conformationally labile proteins has implications in pathologies ranging from oncology to neurodegenerative diseases. Most endogenous clients [3] of HSP90s are key regulators of cell signaling which are destabilized and degraded in the absence of the chaperoning activity of HSP90. The dependence of transformed cells on HSP90 is further heightened by the fact that many oncogenic mutations, while increasing the activity of progrowth signaling pathways, are less stable than their wild-type counterparts and have an increased dependence on the chaperoning activity of HSP90.[4] A clinically relevant example is the heightened dependence of drug-resistant Bcr-Abl mutants on the activity of HSP90, and the fact that HSP90 inhibitors in combination with Abl inhibitors remain effective against such mutants.[5, 6] Accordingly, HSP90 inhibition provides a broad and effective target for the treatment of cancer. Furthermore, HSP90 inhibitors can act synergistically with a cytotoxic agent. [7] HSP90 is also implicated in regulatScheme 1. Structure of radicicol, geldanamycin, 17AAG, pochonin D, and general structure of the pochonin library (5). [*] Dr.
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