42 research outputs found
An Efficient Strategy for the Synthesis of α,α′-cis and trans-Disubstituted Medium Ring Ethers
An asymmetric alkylation-ring-closing metathesis strat-egy was developed for the construction of a,a'-disubstituted medi-um ring ethers. The approach features an asymmetric alkylation of highly functionalized a-alkoxy acyl oxazolidinones followed by ring closure effected by Grubbs' ruthenium catalyst. The relation-ship between diene conformation and the rate of ring-closure was examined. Medium ring ethers are a common structural feature of many ladder ether marine toxins, as well as simpler me-tabolites from Laurencia species. This diverse collection of natural products often contains seven, eight, and nine membered ring ethers. 1 The challenge of efficient con-struction of medium ring ethers has led to the develop-ment of numerous strategies for their synthesis. 2-5 The vast majority of these approaches have focused on the a,a'-cis-disubstitution pattern rather than a,a'-trans-di-substituted medium ring ethers, despite their similar fre-quency of occurrence. trans-Isoprelaurefucin (1), 6 isolau-refucin methyl ether (2), 7 chlorofucin (3), 8 bromofucin (4), 9 isolaureatin (5), 10 and obtusenyne (6), 8 for example, all contain a,a'-trans-disubstituted medium ring ethers (Figure 1). Murai's synthesis of obtusenyne (6) 11 and our own recent syntheses of prelaureatin and laurallene 12 con-stitute the only known syntheses of medium ring ether natural products with the a,a'-trans-disubstitution ar-rangement. The investigation of a versatile, general strat-egy for the synthesis of both a,a'-cis and a,a'-trans-disubstituted medium ring ethers is described here. We recently published a total synthesis of the marine nat-ural product (+)-laurencin (9), in which the key steps were an asymmetric alkylation of the sodium enolate of substi-tuted acyl oxazolidinone 7, followed by ring-closing met-athesis of the resultant diene to give cyclic ether 8 (Scheme 1). 2 Previous work in our laboratory has demon-strated that an asymmetric aldol-ring-closing metathesis strategy for the assembly of medium ring ethers was equally adaptable to both the a,a'-cis and a,a'-trans-di-substituted medium ring ethers. 3,12 The asymmetric alky-lation-ring-closing metathesis approach to cyclic ethers also offered the potential for a similar adaptable strategy
Enantioselective Total Synthesis of Brevetoxin A: Unified Strategy for the B, E, G, and J Subunits
Brevetoxin A is a decacyclic ladder toxin that possesses five-,six-, seven-, eight-, and nine-membered oxacycles, as well as 22 tetrahedral stereocenters. Herein, we describe a unified approach to the B, E, G, and J rings predicated upon a ring-closing metathesis strategy from the corresponding dienes. The enolate technologies developed in our laboratory allowed access to the precursor acyclic dienes for the B, E, and G medium ring ethers. The strategies developed for the syntheses of these four monocycles ultimately provided multigram quantities of each of the rings, supporting our efforts toward the convergent completion of brevetoxin A
Total Synthesis of Brevetoxin A
A total synthesis of brevetoxin A is reported. Two tetracyclic coupling partners, prepared from previously reported advanced fragments, were effectively united via a Horner—Wittig olefination. The resulting octacycle was progressed to substrates that were explored for reductive etherification, the success of which led to a penultimate tetraol intermediate. The tetraol was converted to the natural product through an expeditious selective oxidative process, followed by methylenation
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Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes
Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the U.S. National Institutes of Health launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines, but also highlight the need to innovate the science of therapeutic discovery.Chemistry and Chemical Biolog
Structure–Activity Relationship Studies in a Series of Xanthine Inhibitors of SLACK Potassium Channels
Gain-of-function mutations in the KCNT1 gene, which encodes the sodium-activated potassium channel known as SLACK, are associated with the rare but devastating developmental and epileptic encephalopathy known as epilepsy of infancy with migrating focal seizures (EIMFS). The design of small molecule inhibitors of SLACK channels represents a potential therapeutic approach to the treatment of EIMFS, other childhood epilepsies, and developmental disorders. Herein, we describe a hit optimization effort centered on a xanthine SLACK inhibitor (8) discovered via a high-throughput screen. Across three distinct regions of the chemotype, we synthesized 58 new analogs and tested each one in a whole-cell automated patch-clamp assay to develop structure–activity relationships for inhibition of SLACK channels. We further evaluated selected analogs for their selectivity versus a variety of other ion channels and for their activity versus clinically relevant SLACK mutants. Selectivity within the series was quite good, including versus hERG. Analog 80 (VU0948578) was a potent inhibitor of WT, A934T, and G288S SLACK, with IC50 values between 0.59 and 0.71 µM across these variants. VU0948578 represents a useful in vitro tool compound from a chemotype that is distinct from previously reported small molecule inhibitors of SLACK channels
A Novel Class of Succinimide-Derived Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 1 Provides Insight into a Disconnect in Activity between the Rat and Human Receptors
Recent
progress in the discovery of mGlu<sub>1</sub> allosteric
modulators has suggested the modulation of mGlu<sub>1</sub> could
offer possible treatment for a number of central nervous system disorders;
however, the available chemotypes are inadequate to fully investigate
the therapeutic potential of mGlu<sub>1</sub> modulation. To address
this issue, we used a fluorescence-based high-throughput screening
assay to screen an allosteric modulator-biased library of compounds
to generate structurally diverse mGlu<sub>1</sub> negative allosteric
modulator hits for chemical optimization. Herein, we describe the
discovery and characterization of a novel mGlu<sub>1</sub> chemotype.
This series of succinimide negative allosteric modulators, exemplified
by VU0410425, exhibited potent inhibitory activity at rat mGlu<sub>1</sub> but was, surprisingly, inactive at human mGlu<sub>1</sub>. VU0410425 and a set of chemically diverse mGlu<sub>1</sub> negative
allosteric modulators previously reported in the literature were utilized
to examine this species disconnect between rat and human mGlu<sub>1</sub> activity. Mutation of the key transmembrane domain residue
757 and functional screening of VU0410425 and the literature compounds
suggests that amino acid 757 plays a role in the activity of these
compounds, but the contribution of the residue is scaffold specific,
ranging from critical to minor. The operational model of allosterism
was used to estimate the binding affinities of each compound to compare
to functional data. This novel series of mGlu<sub>1</sub> negative
allosteric modulators provides valuable insight into the pharmacology
underlying the disconnect between rat and human mGlu<sub>1</sub> activity,
an issue that must be understood to progress the therapeutic potential
of allosteric modulators of mGlu<sub>1</sub>
Discovery of (<i>R</i>)‑(2-Fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-Hydroxypiperidin-1-yl)methanone (ML337), An mGlu<sub>3</sub> Selective and CNS Penetrant Negative Allosteric Modulator (NAM)
A multidimensional,
iterative parallel synthesis effort identified a series of highly
selective mGlu<sub>3</sub> NAMs with submicromolar potency and good CNS penetration.
Of these, ML337 resulted (mGlu<sub>3</sub> IC<sub>50</sub> = 593 nM,
mGlu<sub>2</sub> IC<sub>50</sub> >30 μM) with B:P ratios
of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to
the incorporation of deuterium atoms to address a metabolic soft spot,
which subsequently lowered both in vitro and in vivo clearance by
>50%