ABSTRACT
A general and efficient catalytic approach to synthesis of the furo[2,3-c]pyridazine ring system is reported. Building on the easily accessible 2-bromo-3-aminopyridizinone skeleton, a tandem Sonogashira coupling-cycloisomerization provides ready access to functionalized furopyridazines. A wide functional group tolerance was observed in the tandem reaction, which proceeds in high yield in 1-3 h. The structure of the heterocyclic ring system was confirmed through single-crystal X-ray crystallography.
ABSTRACT
Natural products have been widely used to dissect the basic mechanisms of fundamental life science and as clinical therapeutics. Recently, there has been significant interest in discovering new chemical pharmacophores in natural products to fulfil the vast demand for novel kinase inhibitors and address critical unmet medical needs with respect to signal transduction pathways. In this review, we summarize the history of several different classes of natural product-derived kinase inhibitors, discuss their kinome-wide target profiles and examine their structural binding modes based on available 3D X-ray structures. In particular, their origin, target activity, selectivity, scope and potential therapeutic development are highlighted against the backdrop of medicinal chemistry.
Subject(s)
Biological Products , Protein Kinase Inhibitors , Androstadienes/chemistry , Androstadienes/pharmacology , Drug Design , Humans , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , WortmanninABSTRACT
An intensive recent effort to develop ATP-competitive mTOR inhibitors has resulted in several potent and selective molecules such as Torin1, PP242, KU63794, and WYE354. These inhibitors are being widely used as pharmacological probes of mTOR-dependent biology. To determine the potency and specificity of these agents, we have undertaken a systematic kinome-wide effort to profile their selectivity and potency using chemical proteomics and assays for enzymatic activity, protein binding, and disruption of cellular signaling. Enzymatic and cellular assays revealed that all four compounds are potent inhibitors of mTORC1 and mTORC2, with Torin1 exhibiting â¼20-fold greater potency for inhibition of Thr-389 phosphorylation on S6 kinases (EC(50) = 2 nM) relative to other inhibitors. In vitro biochemical profiling at 10 µM revealed binding of PP242 to numerous kinases, although WYE354 and KU63794 bound only to p38 kinases and PI3K isoforms and Torin1 to ataxia telangiectasia mutated, ATM and Rad3-related protein, and DNA-PK. Analysis of these protein targets in cellular assays did not reveal any off-target activities for Torin1, WYE354, and KU63794 at concentrations below 1 µM but did show that PP242 efficiently inhibited the RET receptor (EC(50), 42 nM) and JAK1/2/3 kinases (EC(50), 780 nM). In addition, Torin1 displayed unusually slow kinetics for inhibition of the mTORC1/2 complex, a property likely to contribute to the pharmacology of this inhibitor. Our results demonstrated that, with the exception of PP242, available ATP-competitive compounds are highly selective mTOR inhibitors when applied to cells at concentrations below 1 µM and that the compounds may represent a starting point for medicinal chemistry efforts aimed at developing inhibitors of other PI3K kinase-related kinases.
Subject(s)
Enzyme Inhibitors/pharmacokinetics , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Adenosine Triphosphate , Ataxia Telangiectasia Mutated Proteins , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Cell Line, Tumor , DNA-Binding Proteins/antagonists & inhibitors , DNA-Binding Proteins/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Humans , Kinetics , Mechanistic Target of Rapamycin Complex 1 , Multiprotein Complexes , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Phosphorylation/drug effects , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Proteins/antagonists & inhibitors , Proteins/metabolism , Proteomics/methods , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Tumor Suppressor Proteins/antagonists & inhibitors , Tumor Suppressor Proteins/metabolism , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Starting from small molecule mTOR inhibitor Torin1, replacement of the piperazine ring with a phenyl ring resulted in a new series of mTOR inhibitors (as exemplified by 10) that showed superior potency and selectivity for mTOR, along with significantly improved mouse liver microsome stability and a longer in vivo half-life.
Subject(s)
Drug Discovery , Microsomes, Liver/drug effects , Naphthyridines/chemical synthesis , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Cells, Cultured , Drug Stability , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Mice , Molecular Structure , Naphthyridines/chemistry , Naphthyridines/pharmacologyABSTRACT
Addition of in situ generated di- or trisubstituted alkenylalanes to N-acyliminium ions provides rapid access to functionalized isoindolinones. Subsequent ring closing metathesis leads to tricyclic products. These transformations proceed under mild conditions and allow for the convergent synthesis of biologically significant scaffolds from readily available starting materials.
ABSTRACT
Oxidative rearrangement of cyclic enol ethers leads to alpha-alkoxyesters. In the presence of a neighboring spiroether, this approach provides a stereoselective access to spiroketals. A modified proposal for the biosynthesis of acutumine is presented.
Subject(s)
Alkenes/chemistry , Ethers, Cyclic/chemistry , Ketones/chemical synthesis , Spiro Compounds/chemical synthesis , Alkaloids/chemical synthesis , Alkaloids/chemistry , Alkenes/metabolism , Ethers, Cyclic/metabolism , Ketones/chemistry , Molecular Structure , Oxidation-Reduction , Spiro Compounds/chemistry , StereoisomerismABSTRACT
[Chemical reaction: See text] A three-step cascade reaction involving a water-accelerated catalytic carboalumination, a Claisen rearrangement, and a nucleophilic carbonyl addition converts terminal alkynes and allyl vinyl ethers into allylic alcohols containing up to three contiguous asymmetric carbon centers. Stoichiometric quantities of water as an additive increase the rate of the [3,3] sigmatropic rearrangement as well as the diastereoselectivity of the carbonyl addition process. Reaction products contain 1,6-diene functionalities that are readily cyclized to substituted cyclopentenes. An extension of this methodology to a sequence involving a [1,3] sigmatropic shift was feasible with a cyclopropylmethyl vinyl ether substrate.