α-Boryl ethers, carbonates, and acetals, readily prepared from the corresponding alcohols that are accessed through ketone diboration, react rapidly with hydrogen peroxide to release alcohols, aldehydes, and ketones through the collapse of hemiacetal intermediates. Experiments with α-boryl acetals containing a latent fluorophore clearly demonstrate that cargo can be released inside cells in the presence of exogenous or endogenous hydrogen peroxide. These experiments show that this protocol can be used for drug activation in an oxidative environment without generating toxic byproducts.
Edited by Norma M. Allewell Betaglycan (BG) is a membrane-bound co-receptor of the TGF- family that selectively binds transforming growth factor- (TGF-) isoforms and inhibin A (InhA) to enable temporal-spatial patterns of signaling essential for their functions in vivo. Here, using NMR titrations of methyl-labeled TGF-2 with BG's C-terminal binding domain, BG ZP-C , and surface plasmon resonance binding measurements with TGF-2 variants, we found that the BG ZP-C -binding site on TGF-2 is located on the inner surface of its extended finger region. Included in this binding site are Ile-92, Lys-97, and Glu-99, which are entirely or mostly specific to the TGF- isoforms and the InhA ␣-subunit, but they are unconserved in other TGF- family growth factors (GFs). In accord with the proposed specificity-determining role of these residues, BG bound bone morphogenetic protein 2 (BMP-2) weakly or not at all, and TGF-2 variants with the corresponding residues from BMP-2 bound BG ZP-C more weakly than corresponding alanine variants. The BG ZP-C -binding site on InhA previously was reported to be located on the outside of the extended finger region, yet at the same time to include Ser-112 and Lys-119, homologous to TGF-2 Ile-92 and Lys-97, on the inside of the fingers. Therefore, it is likely that both TGF-2 and InhA bind BG ZP-C through a site on the inside of their extended finger regions. Overall, these results identify the BG ZP-C -binding site on TGF-2 and shed light on the specificity of BG for select TGF--type GFs and the mechanisms by which BG influences their signaling.Betaglycan (BG) 3 is a co-receptor of the highly diversified transforming growth factor  family (TGF-) of signaling proteins, which have essential roles in diverse processes, ranging from patterning of embryos and organs in embryogenesis to regulation of the endocrine and adaptive immune systems in adults (1-3). BG is expressed by epithelial, mesenchymal, and other cell types, but unlike the type I and type II signaling receptors (4 -6) that bind TGF- family growth factors (GFs) to transduce the signal by phosphorylating Smads and other effectors (7-9), it is not required for signal transduction (10). BG is nonetheless essential in vertebrates, such as mice, where knockout of the BG gene is embryonic lethal (11).BG is a membrane-anchored proteoglycan composed of a large extracellular domain (766 amino acids in humans), a single transmembrane-spanning helix, and a short (43 amino acids in humans) highly-conserved cytoplasmic tail (Fig. 1A). BG's extracellular domain is composed of two subdomains, each roughly equal in size: the membrane-distal orphan domain (BG O ) and the C-terminal membrane-proximal zona pellucida domain (BG ZP ). The structure of BG's orphan domain is not known, but it is likely two tandem -sandwiches, designated BG OR1 and BG OR2 , similar to that of endoglin (12), a homologous co-receptor of the TGF- family with the same overall domain structure (13). BG ZP is likely composed of tandem immunoglobulin-like domains, d...
(−)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). “Body” and “tail” interactions with opioid receptors (a subset of Portoghese’s message-address theory) were used for molecular modeling and simulations, where the “address” can be considered the “body” of the hydromorphone molecule and the “message” delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.
A diverted total synthesis effort is described that is designed to prepare potent cytotoxins based on the actin-binding natural product bistramide A. The major focus of this study is the preparation of analogues that contain oxygenation at the C29 position, which is necessary for a key reaction in the sequence but is not present in the natural product. This process showed that C29 ketone analogues are accessed more readily and show similar potency compared to the natural product. The ability to incorporate C29 oxygenation and to replace a secondary alcohol by a primary alcohol allowed for the development of a more convergent approach that provides a potent analogue in just eight steps in its longest linear sequence.
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