Facile Pd-catalyzed amination of imidazolin-1-yl chloroazines under microwave irradiation: Toward a new kinase-inhibitory chemotype

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The imidazolin-1-yl azine moiety, constructed using a recently developed Buchwald–Hartwig-type arylation methodology, displays excellent chemical stability under subsequent microwave-assisted Pd-catalyzed amination with a range of N-nucleophiles. This finding extends the usage of imidazolin-1-yl azines for bioactive compound library design. The latter is exemplified herein by the discovery of micromolar kinase inhibitors.

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Nitrogen-containing organic compounds, in particular, heterocycles are of high importance in numerous fields including the pharmaceutical and agrochemical industries. This review attempts to collect useful information with respect to the synthesis of nitrogen-containing compounds through the formation of CN bonds carried out under microwave irradiation. The two major fields covered are the synthesis of arylated and alkylated amines and varied ring-forming reactions. The latter part is organized in order of increasing complexity. The syntheses of simple monocyclic compounds with a single nitrogen atom through complex ring systems with numerous ring nitrogen atoms are discussed and analyzed. Detailed treatments of catalyzed and un-catalyzed processes illustrate the rich chemistry and the multitude of approaches available for the synthesis of nitrogen-containing compounds.
Series of structurally diverse 2-imidazoline derivatives have been synthesized by condensation of substituted aldehydes with ethylenediamine, Pd-catalyzed N-arylation of 2-imidazolines and by the formation of 1,2,4-oxadiazoles and benzoxazepines from 2-imidazoline-containing precursors. The 2-imidazoline derivatives were evaluated as potential inhibitors of human monoamine oxidase (MAO) A and B. Among the 2-imidazolines, good potency inhibitors were discovered with compound 9p (IC50 = 0.012 µM) being the most potent MAO-B inhibitor, while compound 9d (IC50 = 0.751 µM) was the most potent MAO-A inhibitor of the series. These potencies are in the same range as those of reference MAO inhibitors used in the clinic. Among 33 compounds evaluated, 13 exhibited IC50 values in the submicromolar range for the inhibition of an MAO isoform. It is postulated that the imidazoline moieties of some of these inhibitors may be recognized by the imidazoline I2-binding site of MAO. Good potency MAO inhibitors may be useful for the treatment of neuropsychiatric and neurodegenerative disorders such as depression and Parkinson's disease, and future application for the treatment of prostate cancer, congestive heart failure and Alzheimer's disease. In addition, high potency 2-imidazoline-derived MAO inhibitors may be used as potential probes for the imidazoline binding sites of the MAOs, as well as to determine alternative binding regions of imidazoline within the MAO active site.
The diverse biological activities of compounds containing N-(hetero)aryl-2-imidazoline moiety and methods to construct them are comprehensively reviewed for the first time. This intriguing non-flat, cyclic amidine motif clearly represents an emerging privileged structure.
A series of novel benzene sulfonamides (previously evaluated as selective cyclooxygenase-2 inhibitors) has been profiled against human carbonic anhydrases I, II, IV and VII in an attempt to observe the manifestation of the well established "tail" approach for designing potent, isoform-selective inhibitors of carbonic anhydrases (CAs, EC The compounds displayed an excellent (pKi 7-8) inhibitory profile against CA II (a cytosolic anti-glaucoma and anti-edema biological target) and CA VII (also a cytosolic target believed to be involved in epilepsy and neuropathic pain) and a marked (1-2 orders of magnitude) selectivity against cytosolic isoform CA I and membrane-bound isoform CA IV. The separation of the CA II and CA IV (both of which are catalytically active isoforms, highly sensitive to sulfonamide-type inhibitors) is particularly remarkable and is adding significantly to the global body of data on the chemical biology of carbonic anhydrases.
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A novel library based on quinolin-4-ylimidazoline core was designed to incorporate a general quinoline antimicrobial pharmacophore. A synthesis of the well-characterized library of 36 compounds was achieved using the Pd-catalyzed Buchwald-Hartwig-type imidazoline arylation chemistry developed earlier. Compounds were tested for biological activity and were found to possess no antimalarial activity. However, the library delivered two promising antitubercular leads, which are non-cytotoxic and can be further optimized with respect to antimycobacterial potency.
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The literature on alpha 2-adrenoceptors in depression is replete with seemingly contradictory findings, including reports of both hypersensitive and hyposensitive alterations. Now, with the discovery of nonadrenergic imidazoline receptors (I receptors) and an endogenous I receptor ligand (agmatine), new light is being shed on this controversy. Specifically, those studies that had utilized allegedly "alpha 2-selective" imidazoline radioligands, i.e., 3H-clonidine, could be reinterpreted in terms of increased I receptors in depression. Although the molecular identity of the I1 binding site remains unknown, an I2 receptive site has been reported to be encoded by monoamine oxidase genes (both MAO-A and MAO-B), suggesting a novel explanation for the antidepressant efficacy of idazoxan, a prototypic I2 ligand. Platelet I1 binding sites are also reported to be elevated in patients with unipolar depression and are lowered by antidepressant treatments. Furthermore, clonidine challenge and animal studies of the behavioral effects of imidazolines may be reinterpreted to support a role for I1 sites in the central control of behavior. A hypothesis for depletion of brain clonidine-displacing substance (CDS) in depression is presented. Lowered concentrations of CDS could account for an elevation of I receptors, via compensatory upregulation. Our model offers an explanation for a number of previously discrepant observations as well as testable hypotheses for the study of imidazoline receptors in depression.
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This review discusses the development and uses of imatinib mesylate, a protein tyrosine kinase inhibitor useful in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors that was recently approved by the Food and Drug Administration. Imatinib targets platelet-derived growth factor receptor, inhibits the fusion product of the Philadelphia chromosome, and targets c-kit, a protein tyrosine kinase. The drug may also be effective in the treatment of other tumors that express platelet-derived growth factor receptor or c-kit.
2-Imidazolines are well known as pharmacophores for various isoforms of adrenergic (α) and imidazoline (I) receptors. The biological activities exerted through the modulation of these targets, mostly in the central nervous system, have found utility in the development of many drug candidates - and even marketed drugs - for hypertension, diabetes and various CNS disorders. However, there is a growing evidence for the general privileged character of the 2-imidazoline scaffold, considering the documented success in the development of numerous biologically active compounds acting outside of the α/I receptor domain. In this review, we provide an overview of these, less traditional areas of medicinal applications of 2-imidazolines. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
We discovered a facile rearrangement of N-(hetero)aryl 2-imidazolines into diversely substituted imidazo[4,5-b]pyridines and benzimidazoles, under Bechamp reduction conditions. Combined with the earlier reported protocol for Pd-catalyzed (hetero)arylation of 2-imidazolines, it provides a simple two-step access to a range of compounds based on these medicinally important heterocyclic cores.
A palladium-catalyzed Buchwald–Hartwig arylation protocol has been applied to achieve high-yielding N-heteroarylation of a diverse set of privileged 2-imidazolines. The resulting compounds are of interest as a novel type of molecular tool for fragment-based drug discovery. The potential for combining two 2-imidazoline moieties in a heteroarene-linked dimer via sequential Pd-catalyzed arylation has been demonstrated.
A range of 2-substituted 4,5-dihydroimidazoles and 2-substituted 1,4,5,6-tetrahydropyrimidines when heated with an excess of substituted ethane-1,2-diamines, o-phenylenediamines, and propane-1,3-diamine underwent diamine exchange to give 2-substituted heterocycles derived from the solvent diamine. The reaction was an equilibrium process favouring six-membered rings. The synthetic scope is amplified by the ready aromatisation of these partially reduced heterocycles.
The reactions of various aldehydes and 1,2-diamines followed by NXS treatment proceed at 0 °C–rt to give the corresponding dihydroimidazoles in high yields. The reaction is mild, and many functional groups such as halogens, nitriles, and esters can exist.
Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors remains challenging. Here, we describe a structure-based de novo design approach that generates novel, hinge-binding fragments that are synthetically feasible and can be elaborated to small molecule libraries. Starting from commercially available compounds, core fragments were extracted, filtered for pharmacophoric properties compatible with hinge-region binding, and docked into a panel of protein kinases. Fragments with a high consensus score were subsequently short-listed for synthesis. Application of this strategy led to a number of core fragments with no previously reported activity against kinases. Small libraries around the core fragments were synthesized, and representative compounds were tested against a large panel of protein kinases and subjected to co-crystallization experiments. Each of the tested compounds was active against at least one kinase, but not all kinases in the panel were inhibited. A number of compounds showed high ligand efficiencies for therapeutically relevant kinases; among them were MAPKAP-K3, SRPK1, SGK1, TAK1, and GCK for which only few inhibitors are reported in the literature.
A simple and efficient methodology for regioselective alkylation of exocyclic nitrogen of cyclic amidines was developed by microwave-assisted heating in the presence of amines. Novel N-alkylated 3,4-dihydropyrazino[2,1-b]quinazolin-6-ones were prepared in good yields. The reaction occurred via a transamination (addition–elimination) process involving a first attack of the amine on the electrophilic carbon of the amidine function.
Primary amines can be converted in high yield into N,N-dibenzyl formamidines under mild conditions. The N,N-dibenzyl formamidine group was found to be effective as a protective group for primary amines as it is stable to a variety of conditions and can be removed by catalytic hydrogenation. (C) 1997 Published by Elsevier Science Ltd.
A variety of amidines have been evaluated as linkers for solid-supported synthesis. As a demonstration of its utility, an amidine linker was used to prepare a set of compounds involving amine exchange, oxidation, reduction and ether formation reactions. These compounds were successfully cleaved from the support to generate α-substituted, secondary amine derivatives, which were thoroughly characterized by spectroscopic methods.
Various imidazoline and guanidinium derivatives elicit diverse cellular responses in peripheral and nervous tissues that are often difficult to attribute to known receptor signalling systems. Biochemical, functional and clinical evidence suggests that some activities of these compounds may be related to their action on defined imidazoline binding sites, which have been recently characterized. Unexpectedly, and of particular significance, recent data indicate that two members of the family of imidazoline binding sites are identical to the A and B isoforms of monoamine oxidase. In this article, Angelo Parini and colleagues summarize the evidence for the characterization and location of imidazoline binding sites, and speculate on the clinical implications of compounds acting on these sites.
This review explores the concept of using privileged scaffolds to identify biologically active compounds through building chemical libraries. We hope to accomplish three main objectives: to provide one of the most comprehensive listings of privileged scaffolds; to reveal through four selected examples the present state of the art in privileged scaffold library synthesis (in hopes of inspiring new and even more creative approaches); and also to offer some thoughts on how new privileged scaffolds might be identified and exploited.
3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modification of the known anxiolytic benzodiazepines, these compounds provide highly potent, orally effective ligands selective for peripheral (CCK-A) receptors, with binding affinities approaching or equaling that of the natural ligand CCK-8. The distinction between CCK-A receptors on the one hand and CNS (CCK-B), gastrin, and central benzodiazepine receptors on the other is demonstrated by using the structure-activity profiles of the new compounds. Details of the binding of these agents to CCK-A receptors are examined, and the method of development of these compounds is discussed in terms of its relevance to the general problem of drug discovery.
The B-type cyclins of S. cerevisiae are diversified with respect to time of expression during the cell cycle as well as biological function. We replaced the early-expressed CLB5 coding sequence with the late-expressed CLB2 coding sequence, at the CLB5 locus. CLB5::CLB2 exhibited almost no rescue of clb5-specific replication defects, although it could rescue clb1 clb2 lethality, and in synchronized cells Clb2p-associated kinase activity from CLB5::CLB2 rose early in the cell cycle, similar to that of Clb5p. Mutagenesis of a potential substrate-targeting domain of CLB5 reduced biological activity without reducing Clb5p-associated kinase activity. Thus, Clb5p may have targeting domains required for CLB5-specific biological activity.
Signaling by insulin requires autophosphorylation of the insulin receptor kinase (IRK) at Tyr1158, Tyr1162, and Tyr1163. Earlier experiments with (32)P-gamma-ATP indicated that the nonphosphorylated IRK (IRK-0P) is relatively inactive, and crystallographic data indicated that the ATP binding site of IRK-0P is blocked by its activation loop. We now show that phosphocreatine (PCr) in combination with hydrogen peroxide serves as an alternative phosphate donor and that ATP and PCr use distinct binding sites. Whereas phosphorylation of the IRK by ATP is inhibited by the nonhydrolyzable competitor adenylyl-imidodiphosphate, phosphorylation by PCr is enhanced. The IRK mutant Tyr1158Phe showed no phosphorylation with PCr but almost normal phosphorylation with ATP, whereas Tyr1162Phe was phosphorylated well with PCr but less then normal with ATP. 3-Dimensional models of IRK-0P revealed that the conversion of any of the four cysteine residues 1056, 1138, 1234, and 1245 into sulfenic acid produces structural changes that bring Tyr1158 into close contact with Asp1083 and render the well-known catalytic site at Asp1132 and Tyr1162 accessible from a direction that differs from the known ATP binding site. The mutant Cys1138Ala, in contrast, showed relatively inaccessible catalytic sites and weak catalytic activity in functional experiments. Taken together, these findings indicate that 'redox priming' of the IRK facilitates its autophosphorylation by PCr in the activation loop.
We previously reported the cloning of the thousand and one-amino acid protein kinase 1 (TAO1), a rat homolog of the Saccharomyces cerevisiae protein kinase sterile 20 protein. Here we report the complete sequence and properties of a related rat protein kinase TAO2. Like TAO1, recombinant TAO2 selectively activated mitogen-activated protein/extracellular signal-regulated kinase kinases (MEKs) 3, 4, and 6 of the stress-responsive mitogen-activated protein kinase pathways in vitro and copurified with MEK3 endogenous to Sf9 cells. To examine TAO2 interactions with MEKs, the MEK binding domain of TAO2 was localized to an ∼135-residue sequence just C-terminal to the TAO2 catalytic domain. In vitro this MEK binding domain associated with MEKs 3 and 6 but not MEKs 1, 2, or 4. Using chimeric MEK proteins, we found that the MEK N terminus was sufficient for binding to TAO2. Catalytic activity of full-length TAO2 enhanced its binding to MEKs. However, neither the autophosphorylation of the MEK binding domain of TAO2 nor the activity of MEK itself was required for MEK binding. These results suggest that TAO proteins lie in stress-sensitive kinase cascades and define a mechanism by which these kinases may organize downstream targets.
Among the numerous tyrosine kinase receptors, those belonging to the Trk family are distinctively involved in the development of complex traits within the vertebrate nervous system. Until recently, the lack of a proper Nt/Trk system in invertebrates has lead to the belief that they were a vertebrate innovation. Recent data, however, have challenged the field, and proved that bona fide Trk receptors do exist in invertebrates. Here, we review and discuss the evolutionary history of the Trk receptor family, and draw a comprehensive scenario that situates the origin of the Nt/Trk signalling prior to the origin of vertebrates. Probably, a ProtoTrk receptor was invented by means of domain and exon shuffling from pieces of ancient genes, generating the unique combination of domains found in extant Trk receptors. It is suggestive to propose that subtle protein mutations, gene duplications, and co-options in particular territories of a primitive Nt/Trk system were instrumental to the development of a complex vertebrate nervous system.
Elevated activity of Src, the first characterized protein-tyrosine kinase, is associated with progression of many human cancers, and Src has attracted interest as a therapeutic target. Src is known to act in various receptor signaling systems to impact cell behavior, yet it remains likely that the spectrum of Src protein substrates relevant to cancer is incompletely understood. To better understand the cellular impact of deregulated Src kinase activity, we extensively applied a mass spectrometry shotgun phosphotyrosine (pTyr) proteomics strategy to obtain global pTyr profiles of Src-transformed mouse fibroblasts as well as their nontransformed counterparts. A total of 867 peptides representing 563 distinct pTyr sites on 374 different proteins were identified from the Src-transformed cells, while 514 peptides representing 275 pTyr sites on 167 proteins were identified from nontransformed cells. Distinct characteristics of the two profiles were revealed by spectral counting, indicative of pTyr site relative abundance, and by complementary quantitative analysis using stable isotope labeling with amino acids in cell culture (SILAC). While both pTyr profiles are replete with sites on signaling and adhesion/cytoskeletal regulatory proteins, the Src-transformed profile is more diverse with enrichment in sites on metabolic enzymes and RNA and protein synthesis and processing machinery. Forty-three pTyr sites (32 proteins) are predicted as major biologically relevant Src targets on the basis of frequent identification in both cell populations. This select group, of particular interest as diagnostic biomarkers, includes well-established Src sites on signaling/adhesion/cytoskeletal proteins, but also uncharacterized sites of potential relevance to the transformed cell phenotype.
  • R Urich
  • G Wishart
  • M Kiczun
  • A Richters
  • N Tidten-Luksch
  • D Rauh
  • B Sherborne
  • P G Wyatt
  • R Brenk
Urich, R.; Wishart, G.; Kiczun, M.; Richters, A.; Tidten-Luksch, N.; Rauh, D.; Sherborne, B.; Wyatt, P. G.; Brenk, R. ACS Chem. Biol. 2013, 8, 1044-1052.
  • B E Evans
  • K E Rittle
  • M G Bock
  • R M Dipardo
  • R M Freidinger
  • W L Whitter
  • G F Lundell
  • D F Veber
  • P S Anderson
Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S. J. Med. Chem. 1988, 31, 2235-2246.
  • A Parini
  • C G Moudanos
  • N Pizzinat
  • S M Lanier
Parini, A.; Moudanos, C. G.; Pizzinat, N.; Lanier, S. M. Trends Pharmacol. Sci. 1996, 17, 13-16.
  • W Luo
  • R J Slebos
  • S Hill
  • M Li
  • J Brábek
  • R Amanchy
  • R Chaerkady
  • A Pandey
  • A L Ham
  • S K Hanks
Luo, W.; Slebos, R. J.; Hill, S.; Li, M.; Brábek, J.; Amanchy, R.; Chaerkady, R.; Pandey, A.; Ham, A. L.; Hanks, S. K. J. Proteome Res. 2008, 7, 3447-3460.
  • D G Savage
  • K H N Antman
  • Eng
Savage, D. G.; Antman, K. H. N. Eng. J. Med. 2002, 346, 683-693.
  • M Krasavin
Krasavin, M. Eur. J. Med. Chem. 2015. j.ejmech.2014.11.028.
  • Z Chen
  • M Hutchison
  • M H Cobb
Chen, Z.; Hutchison, M.; Cobb, M. H. J. Biol. Chem. 1999, 274, 28803–28807.
  • P Sarnpitak
  • P Mujumdar
  • C Morisseau
  • S H Hwang
  • B Hammock
  • V Iurchenko
  • S Zozulya
  • A Gavalas
  • A Geronikaki
  • Y Ivanenkov
  • M Krasavin
Sarnpitak, P.; Mujumdar, P.; Morisseau, C.; Hwang, S. H.; Hammock, B.; Iurchenko, V.; Zozulya, S.; Gavalas, A.; Geronikaki, A.; Ivanenkov, Y.; Krasavin, M. Eur. J. Med. Chem. 2014, 84, 160-172.
  • P Mujumdar
  • T Grkovic
  • M Krasavin
Mujumdar, P.; Grkovic, T.; Krasavin, M. Tetrahedron Lett. 2013, 54, 3336-3340.
  • R N Butler
  • K J Fitzgeraldm
Butler, R. N.; Fitzgeraldm, K. J. J. Chem. Soc., Perkin Trans. 1 1989, 155-157.
  • L Aguado
  • M.-D Canela
  • H J Thibaut
  • E.-M Priego
  • M.-J Camarasa
  • P Leyssen
  • J Neyts
  • M J Perez-Perez
Aguado, L.; Canela, M.-D.; Thibaut, H. J.; Priego, E.-M.; Camarasa, M.-J.; Leyssen, P.; Neyts, J.; Perez-Perez, M. J. Eur. J. Med. Chem. 2012, 49, 279-288.
  • M.-F Pereira
  • V Thiery
  • T Besson
Pereira, M.-F.; Thiery, V.; Besson, T. Tetrahedron Lett. 2007, 48, 7657-7659.
  • H Fujioka
  • K Murai
  • Y Ohba
  • A Hiramatsu
  • Y Kita
Fujioka, H.; Murai, K.; Ohba, Y.; Hiramatsu, A.; Kita, Y. Tetrahedron Lett. 2005, 46, 2197-2199.
  • M E Welsch
  • S A Snyder
  • B R Stockwell
Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347-361.
  • F R Cross
  • M Yuste-Rojas
  • S Gray
  • M D Jacobson
Cross, F. R.; Yuste-Rojas, M.; Gray, S.; Jacobson, M. D. Mol. Cell. 1999, 4, 11-19.