Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.
An enantioselective total synthesis of the Strychnos alkaloid (+)-minfiensine has been accomplished. Prominent features of this synthesis include (i) a new enantioselective organocatalytic Diels–Alder/amine cyclization sequence to build the central tetracyclic pyrroloindoline framework in four steps from commercial materials and (ii) a 6-exo-dig radical cyclization to forge the final piperidinyl ring system. This total synthesis of (+)-minfiensine was completed in nine chemical steps and 21% overall yield.
ABSTRACT:In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC 50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC 50 = 2 nM), PK properties, and a robust PK/PD relationship. KEYWORDS: Autotaxin, tool molecule, osteoarthritis, LPA O steoarthritis (OA) is a highly prevalent disease affecting many adults including more than one out of three individuals aged 65 or older in the United States.1 In addition to significant accompanying pain, OA frequently leads to pronounced disability resulting in the loss of work, hospitalization, and joint replacement procedures.2 Current first-line pharmacological treatment options for OA focus on reducing inflammation and the associated pain. Nonsteroidal antiinflammatory drugs (NSAIDS) and selective COX-2 inhibitors are among the most prescribed medications for OA pain but unfortunately are also frequently accompanied by gastrointestinal, renal, and CV side effects, limiting their use. 3 Recently, the role of lyosophosphatidic acid (LPA) in certain inflammatory conditions has been studied. 4 LPA exists as a number of molecular species that have variable saturated and unsaturated fatty acid chains.5 Signaling of LPA through six GPCRs (LPA Receptors 1−6) has been shown to lead to the upregulation of inflammatory cytokines and matrix metalloproteinases, which contribute to the pathogenesis of OA. 6LPA signaling has also been associated with many other pathologies, such as pulmonary fibrosis and cancer. In vivo, the enzyme autotaxin (ATX), with lyosophosopholipase D activity, is the primary source of extracellular LPA, which results from the cleavage of choline from lysophosphatidylcholine (LPC) (Figure 1). LPA is also produced through action of secreted phospholipases A2 (sPLA2) on phosphatidic acid (PA), although this is believed to be a minor route of extracellular LPA production in vivo. 8,9 Autotaxin is an extracellular, 125 kDa protein that was originally characterized in 1993 by Stracke et al. as a motility stimulating protein. 10 In 2002, Umezu-Goto and co-workers demonstrated that ATX was the same protein as a known lysophopholipase D enzyme, which catalyzed the conversion of LPC to LPA.11 Autotaxin is a multidomain protein with two Nterminal somatomedin B-like domains, a centrally located phosphodiesterase domain, and a catalytically inactive nuclease-like domain on the C-terminal region. It is expressed in four main isoforms (ATXα−δ) with largely unknown differential functionality in vivo.7 The catalytic domain of ATX comprises two zinc ions coordinated with histidine and aspartic acid residues with a threonine alcohol serving as the nucleophile. A large hydro...
Computational assessment of the IL-17A structure identified two distinct binding pockets, the β-hairpin pocket and the α-helix pocket. The β-hairpin pocket was hypothesized to be the site of binding for peptide macrocycles. Support for this hypothesis was obtained using HDX-MS which revealed protection to exchange only within the β-hairpin pocket. This data represents the first direct structural evidence of a small molecule binding site on IL-17A that functions to disrupt the interaction with its receptor.
A synthesis of the hasubanan alkaloids hasubanonine, runanine, and aknadinine via a unified route was attempted. Construction of key phenanthrene intermediates by a Suzuki coupling-Wittig olefination-ring-closing metathesis sequence allowed a convergent and flexible approach. Conversion of the phenanthrenes into the target structures was projected to involve six steps including phenolic oxidation, ketone allylation, anionic oxy-Cope rearrangement, and acid-promoted cyclization. The final step was thwarted by a pinacol-like rearrangement that delivered the unnatural isohasubanan alkaloid skeleton. The structures of the products were established by exhaustive NMR experiments and confirmed by GIAO (13)C NMR calculations of runanine, isorunanine, and three other isomers. These computations revealed some inconsistencies with the benzene solvent correction which suggest that caution should be used in employing this algorithm. The racemic synthesis of isohasubanonine was transformed into an enantioselective synthesis by the discovery that Nakamura's chiral bisoxazoline-ligated allylzinc reagent mediates the enantioselective allylation of ketone 19 in 93% ee. This method could be extended to three other structurally related ketones (92-96% ee), and the enantioselective syntheses of two other isohasubanan alkaloids, isorunanine and isoaknadinine, were accomplished. Racemic isohasubanonine was found to be an ineffective analgesic agent.
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