Halogenated natural products constitute diverse and promising feedstock for molecular pharmaceuticals. However, their solution-structure elucidation by NMR presents several challenges, including the lack of fast methods to compute C chemical shifts for carbons bearing heavy atoms. We show that parametric corrections to DFT-computed chemical shifts in conjunction with rff-computed spin-spin coupling constants allow for fast and reliable screening of a large number of reported halogenated natural products, resulting in expedient structure validation or revision. In this paper, we examine more than 100 structures of halogenated terpenoids and other natural products with the new parametric approach and demonstrate that the accuracy of the combined method is sufficient to identify misassignments and suggest revisions in most cases (16 structures are revised). As the 1DH and C NMR data are ubiquitous and most routinely used in solution structure elucidation, this fast and efficient two-criterion method (nuclear spin-spin coupling andC chemical shifts) which we term DU8+ is recommended as the first essential step in structure assignment and validation.
Structure-based design, synthesis and biological evaluation of a series of peptidomimetic β-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K i 1.8 nM) and cellular (IC 50 = 1 nM in Chinese hamster cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma Aβ) in transgenic mice. The X-ray structure of protein-ligand complexes of memapsin 2 revealed critical interactions in the memapsin 2 active site. KeywordsAlzheimer; design; synthesis; inhibitor; memapsin 2; secretase Memapsin 2 (β-secretase, BACE 1) has become a major target for the development of inhibitor drugs for the treatment of Alzheimers's Disease (AD). 1 Memapsin 2 is the first protease that cleaves β-amyloid precursor protein (APP) in the pathway leading to the generation of amyloid-β peptide (Aβ) in the brain. 2,3 The excess level of Aβ results in the formation of amyloid plaques and neurofibrillary tangles. The neurotoxicity of Aβ ultimately leads to neuronal death, brain inflammation, dementia and AD. 4 Consequently, inhibition of memapsin 2 has emerged as an excellent therapeutic target for the intervention of AD. On the basis of initial kinetics and substrate specificity information, we designed a number of potent inhibitors incorporating a nonhydrolyzable Leu-Ala hydroxyethylene dipeptide isostere. 5, 6 One of the early key inhibitors was OM99-2 (1 , Figure 1). It has shown potent inhibitory activity (K i = 1.6 nM) for human memapsin 2. 6a An X-ray crystal structure of 1-bound memapsin 2 provided critical molecular insight and drug-design templates for the memapsin 2 active site. 7 Based upon the crystallographic information and preliminary structure-activity relationship studies, we then designed a number of highly potent and selective inhibitors. 8 Inhibitor 2 incorporating Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. methylsulfonyl alanine as the P 1 -ligand and oxazolylmethyl urethane as the P 3 -ligand exhibited excellent potency (K i = 0.12 nM against memapsin 2) and selectivity over BACE-2 (3800-fold) and cathepsin D (2500-fold). 8 However, its cellular inhibitory potency was in the low micromolar range (IC 50 of 1.4 μM) in Chinese hamster ovary cells. NIH Public AccessTo further improve inhibitor properties, we subsequently developed inhibitors incorporating substituted isophthalamides as P 2 -P 3 ligands in combination with the Leu-Ala hydroxyethylene dipeptide isostere. 9 As shown in Figure 1, inh...
Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.
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