The canonical WNT pathway plays an
important role in cancer pathogenesis.
Inhibition of poly(ADP-ribose) polymerase catalytic activity of the
tankyrases (TNKS/TNKS2) has been reported to reduce the Wnt/β-catenin
signal by preventing poly ADP-ribosylation-dependent degradation of
AXIN, a negative regulator of Wnt/β-catenin signaling. With
the goal of investigating the effects of tankyrase and Wnt pathway
inhibition on tumor growth, we set out to find small-molecule inhibitors
of TNKS/TNKS2 with suitable drug-like properties. Starting from 1a, a high-throughput screening hit, the spiroindoline derivative 40c (RK-287107) was discovered as a potent TNKS/TNKS2 inhibitor
with >7000-fold selectivity against the PARP1 enzyme, which inhibits
WNT-responsive TCF reporter activity and proliferation of human colorectal
cancer cell line COLO-320DM. RK-287107 also demonstrated dose-dependent
tumor growth inhibition in a mouse xenograft model. These observations
suggest that RK-287107 is a promising lead compound for the development
of novel tankyrase inhibitors as anticancer agents.
A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists.
Catalytic cross double carbonylation of secondary amines and alcohols proceeds in the presence of [PdCl2(MeCN)2] and CuI under carbon monoxide (80 atm) and oxygen (5 atm). Catalytic intramolecular double carbonylation of β-amino alcohols gives morpholine-2,3-diones, which are excellent protecting compounds of amino alcohols and important precursors for biologically active nitrogen compounds. In contrast, catalytic single carbonylation of β-amino alcohols under a mixture (1 : 1) of carbon monoxide and oxygen (1.0 atm) proceeds to give oxazolidin-2-ones selectively. The reaction can be explained by assuming a mechanism which includes intramolecular nucleophilic attack of the hydroxy group of (hydroxyethyl)aminocarbonyl ligands on the CO ligand of the carbamoylpalladium(II) complexes, followed by reductive elimination to give morpholine-2,3-diones. In contrast, direct nucleophilic attack of the hydroxy group to the carbamoyl group affords oxazolidin-2-ones. As a common intermediate for the double and single carbonylations, carbamoylpalladium(II) complex has been isolated by the reaction of [PdCl2(PMe3)2] with β-amino alcohol under CO.
The present double carbonylation of amino alcohols provides a novel and convenient method for synthesis of α-oxo carboxylic acids. Thus, the morpholine-2,3-diones obtained undergo reaction with Grignard reagents chemoselectively at the ester positions to give 2-substituted 2-hydroxymorpholin-3-ones, which undergo acid hydrolysis to give α-oxo carboxylic acids.
Tankyrases
(TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase
family. Inhibition of their enzymatic activities attenuates the Wnt/β-catenin
signaling, which plays an important role in cancer pathogenesis. We
previously reported the discovery of RK-287107, a spiroindoline-based,
highly selective, potent tankyrase inhibitor. Herein we describe the
optimization process of RK-287107 leading to RK-582, which exhibits
a markedly improved robust tumor growth inhibition in a COLO-320DM
mouse xenograft model when orally administered. In addition to the
dose-dependent elevation and attenuation of the levels of biomarkers
AXIN2 and β-catenin, respectively, results of the TCF reporter
and cell proliferation studies on COLO-320DM are discussed.
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