Stereoselective synthesis of 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as PIM kinase inhibitors inspired from marine alkaloids.

We previously demonstrated that natural product-inspired 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones derivatives delivered potent and selective PIM kinases inhibitors however with non-optimal ADME/PK properties and modest oral bioavailability. Herein, we describe a structure-based scaffold decoration and a stereoselective approach to this chemical class. The synthesis, structure-activity relationship studies, chiral analysis, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Compound 20c demonstrated excellent potency on PIM1 and PIM2 with exquisite kinases selectivity and PK properties that efficiently and dose-dependently promoted c-Myc degradation and appear to be promising lead compounds for further development.

Discovery of 2-(cyclohexylmethylamino)pyrimidines as a new class of reversible valosine containing protein inhibitors.

Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure-activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity.

Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships.

Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.

The generation of purinome-targeted libraries as a means to diversify ATP-mimetic chemical classes for lead finding.

The generation of novel chemotypes in support of our oncology research projects expanded in recent years from a canonical design of kinase-targeted compound libraries to a broader interpretation of purinome-targeted libraries (PTL) addressing the specificity of cancer relevant targets such as kinases and ATPases. Successful screening of structurally diverse ATP-binding targets requires compound libraries covering multiple design elements, which may include phosphate surrogate moieties in ATPase inhibitors or far reaching lipophilic residues stabilizing inactive kinase conformations. Here, we exemplify the design and preparation of drug-like combinatorial libraries and report significantly enhanced screening performance on purinomic targets. We compared overall hit rates of PTL with a simultaneously tested unbiased collection of 200,000 compounds and found consistent superiority of the targeted libraries in all cases. We also analyzed the performance of the largest targeted libraries in comparison with each other and often found striking differences in how a specific target responds to various chemotypes and to whole collections.

Towards aqueous chiral heptadentate lanthanide complexes as selective shift and relaxation agents for MRS.

Magnetic resonance spectroscopy (MRS) is of prime importance in diagnostics and offers a means of analyzing, in vivo, the chemical content of living tissue, as a non-invasive alternative to biopsy. Several heptadentate, lanthanide complexes have been synthesized and their potential to act as shift and relaxation agents in MRS (for lactate, in particular) has been assessed through (1)H NMR analysis. The binding affinity and enantiopurity of the complexes have been modulated by systematic variation of the lanthanide ion and ligand structure, in particular the peripheral electrostatic charge of the complex (cationic versus neutral) and the local charge and steric demand at the metal centre.

A new chiral lanthanide NMR probe for the determination of the enantiomeric purity of alpha-hydroxy acids and the absolute configuration of alpha-amino acids in water.

A water-soluble, enantiopure lanthanide complex, SSS-[Ln x L3], has been assessed as an effective chiral derivatizing agent for the determination of the enantiomeric purity of alpha-hydroxy acids in aqueous solution. The complex displays superior chemical shift non-equivalence (DeltaDeltadelta approximately 2-11 ppm) for the diastereomeric resonances of interest compared to lanthanide shift reagents reported in the literature (DeltaDeltadelta <0.1 ppm, typically). 1H NMR studies have also revealed that SSS-[Ln x L3] can be used to determine the absolute configuration of alpha-amino acids at physiological pH, in water. The ability of SSS-[Ln x L3] to signal anion binding and, in particular, to distinguish between diastereomers through optical techniques such as lanthanide luminescence and circular dichroism has also been assessed.

On the role of the counter-ion in defining water structure and dynamics: order, structure and dynamics in hydrophilic and hydrophobic gadolinium salt complexes.

The crystal structures of the hydrated salts of [Gd.DOTAM]3+ and its more hydrophobic derivative [Gd.]3+, bearing 4 alpha-phenylethyl groups, (both Gd and Yb salts) are reported and compared. The nature of the anion determines the degree of ordering in the lattice and the extent of hydration. These effects are correlated with the results of 17O and 1H NMR measurements of water exchange dynamics in solution. With [Gd.DOTAM]3+, structural ordering or the extent of hydration in the hydrated lattice follows the sequence Cl->Br->I- and this order also defines the water exchange rate in solution: 7.3, 19.5, 33.3x10(4) s-1 (298 K), respectively. For [Gd.]3+ salts, the measured relaxivity is determined purely by the outer sphere term and the water exchange rate at 298 K is very similar (typically 1x10(4) s-1) for chloride, bromide, iodide, acetate, triflate and nitrate salts, notwithstanding the different nature and extent of hydration found in the crystalline lattice.

Asymmetric catalysis by chiral lanthanide complexes in water.

The development of catalytic, asymmetric transformations in water is a challenging task. The lanthanides are becoming reagents of choice for many Lewis acid-catalyzed reactions in aqueous media as they are water tolerant. However, enantioselective reactions catalyzed by lanthanides are difficult to achieve in water due to the instability of the reported catalysts. Herein we report the development of stable, well-defined chiral lanthanide complexes and their effectiveness in the asymmetric reduction of alpha-keto acids in aqueous solution. This is the first example of asymmetric reduction by a chiral lanthanide complex in water. Although modest ees are obtained (40-50%) the ytterbium complexes offer a unique advantage as they have the ability to monitor, direct from the reaction mixture, the % ee for the reaction, by 1H NMR, through a dipolar analysis of the observed paramagnetic shift.