5‑Hydroxyindoles by Intramolecular Alkynol–Furan Diels–Alder Cycloaddition

A convergent approach provides a convenient access to synthetically and biologically useful 3,4-disubstituted 5-hydroxyindoles. The one-pot procedure uses microwave heating to initiate an intramolecular [4 + 2]-cycloaddition of an alkynol segment onto a furan followed by a fragmentation, aromatization, and <i>N</i>-Boc deprotection cascade. Yields range from 15 to 74%, with aromatic substituents providing better conversions. 4-Trimethylsilylated analogues undergo a 1,3-silatropic rearrangement to give the <i>O</i>-TMS ethers

Hydrophosphination of Bicyclo[1.1.0]butane-1-carbonitriles

Hydrophosphination of bicyclo[1.1.0]­butyl nitriles with phosphine boranes and phosphites provided novel cyclobutyl-P derivatives. The reaction generally favors the <i>syn</i>-diastereomer, and the nitrile can be reduced and converted to other functional groups, thus enabling the preparation of bidentate ligands that access new conformational space by virtue of their attachment to the torsionally malleable but sterically restrictive cyclobutane scaffold. The enantioselective hydrogenation of dehydrophenylalanine using a bidentate phosphine–phosphite ligand illustrates the synthetic utility of the newly prepared scaffold

Influence of Base and Structure in the Reversible Covalent Conjugate Addition of Thiol to Polycyclic Enone Scaffolds

The energetics of thiol addition and elimination reactions to bicyclic enones derived from an indole core structure were explored using ¹H NMR and density functional theory (DFT) calculations. The agreement between experiment and theory is excellent, and the combined results reveal that even minor changes in the conformation of the enone, substituents on the scaffold, and the use of different bases have a signficant influence on product distribution. A potential application of these principles is in the rational design of new reversible covalent enzyme inhibitors

Synthesis of Heterocyclic Triads by Pd-Catalyzed Cross-Couplings and Evaluation of Their Cell-Specific Toxicity Profile

Two complementary approaches for the preparation of linked 5-membered heterocycles were developed. The Pd-catalyzed Suzuki–Miyaura cross-coupling with halogenated furan, thiophene, and selenophene led to higher overall yields, but C,H-bond activation was a more efficient strategy for the coupling at C(2) of oxazoles. Potency and selectivity of the final hydroxymethyl products in renal (A498), lung (NCI-H226), kidney (CAKI-1), and breast (MDA-MB-468, MCF7) carcinoma cell lines were determined

Stochastic Voyages into Uncharted Chemical Space Produce a Representative Library of All Possible Drug-Like Compounds

The “small molecule universe” (SMU), the set of all synthetically feasible organic molecules of 500 Da molecular weight or less, is estimated to contain over 10⁶⁰ structures, making exhaustive searches for structures of interest impractical. Here, we describe the construction of a “representative universal library” spanning the SMU that samples the full extent of feasible small molecule chemistries. This library was generated using the newly developed Algorithm for Chemical Space Exploration with Stochastic Search (ACSESS). ACSESS makes two important contributions to chemical space exploration: it allows the systematic search of the unexplored regions of the small molecule universe, and it facilitates the mining of chemical libraries that do not yet exist, providing a near-infinite source of diverse novel compounds

Screen of a kinase inhibitor library for PKD1 activity.

<p>A targeted library of 235 compounds was screened for PKD1 activity at 1 µM using an <i>in vitro</i> radiometric PKD1 kinase assay. The representative graphs show % residual PKD1 kinase activity calculated based on the total kinase activity measured in the absence of inhibitors (DMSO). Kb-NB142-70, a previously known PKD inhibitor, was used as a positive control. Experiments were performed with triplicate determinations at 1 µM for each compound.</p

Stochastic Voyages into Uncharted Chemical Space Produce a Representative Library of All Possible Drug-Like Compounds

The “small molecule universe” (SMU), the set of all synthetically feasible organic molecules of 500 Da molecular weight or less, is estimated to contain over 10⁶⁰ structures, making exhaustive searches for structures of interest impractical. Here, we describe the construction of a “representative universal library” spanning the SMU that samples the full extent of feasible small molecule chemistries. This library was generated using the newly developed Algorithm for Chemical Space Exploration with Stochastic Search (ACSESS). ACSESS makes two important contributions to chemical space exploration: it allows the systematic search of the unexplored regions of the small molecule universe, and it facilitates the mining of chemical libraries that do not yet exist, providing a near-infinite source of diverse novel compounds

New Pyrazolopyrimidine Inhibitors of Protein Kinase D as Potent Anticancer Agents for Prostate Cancer Cells

<div><p>The emergence of protein kinase D (PKD) as a potential therapeutic target for several diseases including cancer has triggered the search for potent, selective, and cell-permeable small molecule inhibitors. In this study, we describe the identification, <i>in vitro</i> characterization, structure-activity analysis, and biological evaluation of a novel PKD inhibitory scaffold exemplified by 1-naphthyl PP1 (1-NA-PP1). 1-NA-PP1 and IKK-16 were identified as pan-PKD inhibitors in a small-scale targeted kinase inhibitor library assay. Both screening hits inhibited PKD isoforms at about 100 nM and were ATP-competitive inhibitors. Analysis of several related kinases indicated that 1-NA-PP1 was highly selective for PKD as compared to IKK-16. SAR analysis showed that 1-NA-PP1 was considerably more potent and showed distinct substituent effects at the pyrazolopyrimidine core. 1-NA-PP1 was cell-active, and potently blocked prostate cancer cell proliferation by inducing G2/M arrest. It also potently blocked the migration and invasion of prostate cancer cells, demonstrating promising anticancer activities on multiple fronts. Overexpression of PKD1 or PKD3 almost completely reversed the growth arrest and the inhibition of tumor cell invasion caused by 1-NA-PP1, indicating that its anti-proliferative and anti-invasive activities were mediated through the inhibition of PKD. Interestingly, a 12-fold increase in sensitivity to 1-NA-PP1 could be achieved by engineering a gatekeeper mutation in the active site of PKD1, suggesting that 1-NA-PP1 could be paired with the analog-sensitive PKD1^M659G for dissecting PKD-specific functions and signaling pathways in various biological systems.</p></div