- An efficient microwave assisted synthesis of N′-aryl/(alkyl)-substituted N-(4-hydroxy-6-phenylpyrimidin-2-yl)guanidines: Scope and limitations
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Treatment of N-[(4-hydroxy-6-phenyl)pyrimidin-2-yl]cyanamide with 1° alkyl or arylamines in isopropyl alcohol for only 10?min at 110–120?°C under microwave conditions gave the corresponding N′-alkyl(aryl)guanidine derivatives in excellent yields (65–84%). Isolated yields were greatest when >1.0?equiv. of amines were employed, but excellent results were also obtained when aryl and alkylamines were reacted with a more atom-economical loading (1.0?equiv.; 70% and 72% ave. yields, respectively). Arylamines with either highly electron withdrawing substituents (e.g. CO2H) or pi-deficient heterocycles (e.g. variously substituted aminopyridines) did not work well under these conditions, and reaction with ureas and/or amino acids did not give detectable products. Work-up was exceedingly simple, and involved simple collection and washing of product on a sintered glass funnel. Products were obtained in analytically pure form and required approximately 1?h to prepare, start to finish.
- Machicao, Paulo A.,Burt, Scott R.,Christensen, Ryan K.,Lohner, Nathan B.,Singleton,Peterson, Matt A.
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- High-Performance Liquid Chromatographic Determination of 5-Halopyrimidinone Interferon Inducers
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High-performance liquid chromatography with microparticulate, bonded, reversed-phase columns separates closely related 5-halopyrimidinones that are interferon inducers.A method was developed to a quantitate serum levels of 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone, an important analogue of this new series.The method is, with minor modifications, suitable to measure other 5-halophenylpyrimidinone analoques.Results show that the quantitation of serum levels as low as 2 μg mL-1 is possible with ultraviolet detection at 235 nm.Protein precipitation and extraction prior to chromatography improve the daily sample throughput by removing interfering peaks with capacity factors greater than 45.Preliminary results indicate a species-dependent variation in the half-lives of elimination of the free compound after its administration, orally, to experimental animals.Rats clear the drug with a half-life of 4.5 h; cats clear the drug with half-lives ranging from 10 to 18 h depending on the dose administered.The differences in metabolic clearance may be relevant to observed toxicity differences between these species.
- Wynalda, M. A.,Fitzpatrick, F. A.
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- Controlling Keto-Enol Tautomerism of Ureidopyrimidinone to Generate a Single-Quadruple AADD-DDAA Dimeric Array
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Units of ureidopyrimidinone (UPy) which dimerize via strong quadruple hydrogen bonding are widely used for the construction of supramolecular systems. This self-complementary system exists in the tautomerism equilibrium of 4[1H]-pyrimidinone dimer and pyrimidin-4-ol dimer, making generated supramolecular assembly systems essentially complicated. In this contribution, a rational but simple design concept is described for preorganizing the self-complementary quadruple hydrogen bonding of UPy via supramolecular strategy into a single-quadruple DDAA-AADD dimeric array. With this concept, the designed UPy derivatives form only 4[1H]-pyrimidinone dimer with a ketone configuration via intermolecular hydrogen-bonding interactions, both in the solid state as well as in solution, as is evident from single-crystal X-ray diffraction and 1H NMR spectroscopy. The single DDAA-AADD dimeric array provides defined noncovalent driving forces that can be used to generate constitutionally clear supramolecular structures that are vitally important in the fields of supramolecular chemistry and materials.
- Ding, Qinwen,Dong, Zeyuan,Fan, Zengming,Mao, Shizhong,Qi, Shuaiwei,Zhang, Chenyang,Zhang, Jing
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supporting information
p. 7305 - 7309
(2020/10/05)
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- Screening of focused compound library targeting liver X receptors in pancreatic cancer identified ligands with inverse agonist and degrader activity
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Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer. PDACs harbor oncogenic mutations in the KRAS gene, and ongoing efforts to directly target its mutant protein product to inhibit tumor growth are a priority not only in pancreatic cancer but in other malignancies such as lung and colorectal cancers where KRAS is also commonly mutated. An alternative strategy to directly targeting KRAS is to identify and target druggable receptors involved in dysregulated cancer hallmarks downstream of KRAS dysregulation. Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-modulated transcription factors and are involved in the regulation of genes which function in key cancer-related processes, including cholesterol transport, lipid and glucose metabolism, and inflammatory and immune responses. Modulation of LXRs via small molecule ligands has emerged as a promising approach for directly targeting tumor cells or the stromal and immune cells within the tumor microenvironment. We have previously shown that only one of the two LXR subtypes (LXRβ) is expressed in pancreatic cancer cells, and targeting LXR with available synthetic ligands blocked the proliferation of PDAC cells and tumor formation. In a screen of a focused library of drug-like small molecules predicted to dock in the ligand-binding pocket of LXRβ, we identified two novel LXR ligands with more potent antitumor activity than current LXR agonists used in our published studies. Characterization of the two lead compounds (GAC0001E5 and GAC0003A4) indicates that they function as LXR inverse agonists which inhibit their transcriptional activity. Prolonged treatments with novel ligands further revealed their function as LXR “degraders” which significantly reduced LXR protein levels in all three PDAC cell lines tested. These findings support the utility of these novel inhibitors in basic research on ligand design, allosteric mechanisms, and LXR functions and their potential application as treatments for advanced pancreatic cancer and other recalcitrant malignancies.
- Karaboga, Husna,Huang, Wentao,Srivastava, Shivangi,Widmann, Scott,Addanki, Sridevi,Gamage, Kasuni Thawalama,Mazhar, Zahra,Ebalunode, Jerry O.,Briggs, James M.,Gustafsson, Jan-?ke,Filgueira, Carly S.,Gilbertson, Scott R.,Lin, Chin-Yo
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p. 2916 - 2928
(2020/11/18)
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- Synthesis and Investigation of Phthalazinones as Antitubercular Agents
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A series of 2- and 7-substituted phthalazinones was synthesised and their potential as anti-tubercular drugs assessed via Mycobacterium tuberculosis (mc26230) growth inhibition assays. All phthalazinones tested showed growth inhibitory activity (MIC 100 μm), and those compounds containing lipophilic and electron-withdrawing groups generally exhibited better anti-tubercular activity. Several lead compounds were identified, including 7-((2-amino-6-(4-fluorophenyl)pyrimidin-4-yl)amino)-2-heptylphthalazin-1(2H)-one (MIC=1.6 μm), 4-tertbutylphthalazin-2(1H)-one (MIC=3 μm), and 7-nitro-phthalazin-1(2H)-one (MIC=3 μm). Mode of action studies indicated that selected pyrimidinyl-phthalazinones may interfere with NADH oxidation, however, the mode of action of the lead compound is independent of this enzyme. MIC=minimum inhibitory concentration.
- Santoso, Kristiana T.,Cheung, Chen-Yi,Hards, Kiel,Cook, Gregory M.,Stocker, Bridget L.,Timmer, Mattie S. M.
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supporting information
p. 1278 - 1285
(2019/02/24)
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- Synthesis of 6-arylisocytosines and their potential for hydrogen bonding interactions
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Abstract The synthesis of a number of 6-arylisocytosines, including linked bis-isocytosines, from the reaction of guanidine with β-ketoesters is described. The compounds were investigated for their ability to form hydrogen-bonded structural networks, and for their potential interactions with the telomeric quadruplex forming sequence AGGG(TTAGGG)3.
- Patel, Alpa,Lewis, William,Searle, Mark S.,Stevens, Malcolm F.G.,Moody, Christopher J.
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supporting information
p. 7339 - 7343
(2015/08/24)
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- Direct synthesis of 5- and 6-substituted 2-aminopyrimidines as potential non-natural nucleobase analogues
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A series of 2-aminopyrimidine derivatives, substituted at 5- and 6-positions, were synthesized. The reaction was carried out in a single step by treatment of the corresponding β-ketoester or β-aldehydoester with guanidine hydrochloride in the presence of K2CO3, in a microwave-assisted method without the requirement of solvent. A unique 1:1 co-crystal structure was obtained which shows that a 6-phenyl-2- aminopyrimidinone forms a strong nucleobase-pair with cytosine, involving three hydrogen bonds. The base-pair was found to be as strong as that of natural guanine:cytosine (G:C), signifying the potential application of the synthesized derivatives. Additionally, we also report a second co-crystal involving 5-isopropyl-6-methyl-2-aminopyrimidinone and cytosine in a 1:1 ratio, which also shows strong base-pairing properties. the Partner Organisations 2014.
- Radhakrishnan,Sharma, Namita,Kundu, Lal Mohan
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p. 15087 - 15090
(2014/04/17)
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- HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase
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The identification of novel, non-purine based inhibitors of xanthine oxidase is described. After a high-throughput screening campaign, an NMR based counterscreen was used to distinguish actives, which interact with XO in a reversible manner, from assay artefacts. This approach identified pyrimidone 1 as a reversible and competitive inhibitor with good lead-like properties. A hit to lead campaign gave compound 41, a nanomolar inhibitor of hXO with efficacy in the hyperuricemic rat model after oral dosing.
- Even?s, Johan,Edfeldt, Fredrik,Lepist?, Matti,Svitacheva, Naila,Synnergren, Anna,Lundquist, Britta,Gr?nse, Mia,R?nnholm, Anna,Varga, Mikael,Wright, John,Wei, Min,Yue, Sherrie,Wang, Junfeng,Li, Chong,Li, Xuan,Chen, Gang,Liao, Yong,Lv, Gang,Tj?rnebo, Ann,Narjes, Frank
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p. 1315 - 1321
(2014/03/21)
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- Quinolinyl pyrimidines: Potent inhibitors of NDH-2 as a novel class of anti-TB agents
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NDH-2 is an essential respiratory enzyme in Mycobacterium tuberculosis (Mtb), which plays an important role in the physiology of Mtb. Herein, we present a target-based effort to identify a new structural class of inhibitors for NDH-2. High-throughput screening of the AstraZeneca corporate collection resulted in the identification of quinolinyl pyrimidines as the most promising class of NDH-2 inhibitors. Structure-activity relationship studies showed improved enzyme inhibition (IC50) against the NDH-2 target, which in turn translated into cellular activity against Mtb. Thus, the compounds in this class show a good correlation between enzyme inhibition and cellular potency. Furthermore, early ADME profiling of the best compounds showed promising results and highlighted the quinolinyl pyrimidine class as a potential lead for further development.
- Shirude, Pravin S.,Paul, Beena,Roy Choudhury, Nilanjana,Kedari, Chaitanya,Bandodkar, Balachandra,Ugarkar, Bheemarao G.
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supporting information
p. 736 - 740
(2012/10/29)
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- Identification of an anti-MRSA dihydrofolate reductase inhibitor from a diversity-oriented synthesis
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The screening of a diversity-oriented synthesis library followed by structure-activity relationship investigations have led to the discovery of an anti-MRSA agent which operates as an inhibitor of Staphylococcus aureus dihydrofolate reductase. The Royal Society of Chemistry.
- Wyatt, Emma E.,Galloway, Warren R. J. D.,Thomas, Gemma L.,Welch, Martin,Loiseleur, Olivier,Plowright, Alleyn T.,Spring, David R.
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supporting information; experimental part
p. 4962 - 4964
(2009/06/06)
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- Skeletal diversity construction via a branching synthetic strategy
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A branching synthetic strategy was used to efficiently generate structurally diverse scaffolds, which span a broad area of chemical descriptor space, and their biological activity against MRSA was demonstrated. The Royal Society of Chemistry 2006.
- Wyatt, Emma E.,Fergus, Suzanne,Galloway, Warren R. J. D.,Bender, Andreas,Fox, David J.,Plowright, Alleyn T.,Jessiman, Alan S.,Welch, Martin,Spring, David R.
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p. 3296 - 3298
(2008/09/19)
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- NOVEL PYRIMIDINE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM
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The present invention provides new heterocyclic compounds, particularly substituted pyrimidines, methods and compositions for making and using these heterocyclic compounds, and methods for treating a variety of diseases and disease states, including atherosclerosis, arthritis, restenosis, diabetic nephropathy, or dyslipidemia, or disease states mediated by the low expression of Perlecan.
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Page/Page column 283-284
(2008/06/13)
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- PYRIMIDINE DERIVATIVES FOR TREATMENT OF HYPERPROLIFERATIVE DISORDERS
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Pyrimidine derivatives of formula (I), pharmaceutical compositions containing these compounds, and methods of using these compounds in treatment of hyperproliferative diseases such as cancer are disclosed and claimed.
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(2010/11/23)
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- SUBSTITUTED AMINO-PYRIMIDONES AND USES THEREOF
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This invention relates to novel compounds having the structural formula Ia or formula Ib below: (Ia,Ib), and their phatmaceutically acceptable salts, tautomers or in vivo hydrolysable precursors, compositions and methods of use thereof. These novel compounds provide a treatment or prophylaxis of Abeta related pathologies such as cognitive impairment, Alzheimer Disease, neurodegeneration and dementia.
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- PYRIMIDINE DERIVATIVES FOR TREATMENT OF HYPERPROLIFERATIVE DISORDERS
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Pyrimidine derivatives of formula (I) in which J and Y represent aromatic or heteroaromatic rings; R2, G, G', and G" represent substituent groups and R2a represents H or halogen; L represents a linking group; and M represents CH or N. Pharmaceutical compositions containing these compounds, and methods of using these compounds in treatment of hyperproliferative diseases such as cancer are also disclosed and claimed.
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- SUPRAMOLECULAR POLYMER
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A polymer comprising monomeric units linked via 4 H-bridges and bound within said polymer via a different bond. The bond via the H-bridges is much stronger than with known supramolecular polymers.
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- Adenosine receptor ligands and their use in the treatment of disease
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The invention relates to cyclic heteroaromatic compounds, containing at least one nitrogen atom, and to their use in the manufacture of medicaments for the treatment of diseases, related to adenosine receptor modulators, such as Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma, allergic responses, hypoxia, ischaemia, seizure, substance abuse, sedation and they may be active as muscle relaxants, antipsychotics, anti epileptics, anticonvulsants and cardiaprotective agents.
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- Structural studies on bioactive compounds. Part 29: Palladium catalysed arylations and alkynylations of sterically hindered immunomodulatory 2-amino- 5-halo-4,6-(disubstituted)pyrimidines
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The immunological agent bropirimine 5 is a tetra-substituted pyrimidine with anticancer and interferon-inducing properties. Synthetic routes to novel 5-aryl analogues of bropirimine have been developed and their potential molecular recognition properties analysed by molecular modelling methods. Sterically challenged 2-amino-5-halo-6-phenylpyrimidin-4-ones (halo=Br or I) are poor substrates for palladium catalysed Suzuki cross-coupling reactions with benzeneboronic acid because the basic conditions of the reaction converts the amphoteric pyrimidinones to their unreactive enolic forms. Palladium-mediated reductive dehalogenation of the pyrimidinone substrates effectively competes with cross-coupling. 2-Amino-5-halo-4-methoxy-6- phenylpyrimidines can be converted to a range of 5-aryl derivatives with the 5-iodopyrimidines being the most efficient substrates. Hydrolysis of the 2- amino-5-aryl-4-methoxy-6-phenylpyrimidines affords the required pyrimidin-4- ones in high yields. Semi-empirical quantum mechanical calculations show how the nature of the 5-substituent influences the equilibrium between the 1H- and 3H-tautomeric forms, and the rotational freedom about the bond connecting the 6-phenyl group and the pyrimidine ring. Both of these factors may influence the biological properties of these compounds. (C) 2000 Elsevier Science Ltd.
- Hannah, Duncan R.,Sherer, Edward C.,Davies, Roy V.,Titman, Roger B.,Laughton, Charles A.,Stevens, Malcolm F. G.
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p. 739 - 750
(2007/10/03)
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- Strong dimerization of ureidopyrimidones via quadruple hydrogen bonding
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6-Methyl-2-butylureidopyrimidone dimerizes via four hydrogen bonds in the solid state as well as in CHCl3 solution via a donor-donor-acceptor-acceptor (DDAA) array of hydrogen bonding sites in the 4[1H]-pyrimidinone tautomer. An intramolecular hydrogen bond from the pyrimidine NH group to the urea oxygen atom preorganizes the molecules for dimerization. The dimerization constant of the dimer in CHCl3 exceeds 106 M-1. In CHCl3 containing DMSO, the dimer is in equilibrium with the monomeric G[1H]-pyrimidinone tautomer. In 6-phenyl-2-butylureidopyrimidone, the 4[1H]-pyrimidinone tautomer coexists with the pyrimidin-4-ol form, which dimerizes with similar high dimerization constants via four hydrogen bonds in a DADA array. The latter tautomer predominates in derivatives with electronegative 6-substituents, like 6-nitrophenyl- and 6-trifluoromethyl-2-butylureidopyrimidone Due to its simple preparation and high dimerization constant, the ureidopyrimidone functionality is a useful building block for supramolecular chemistry.
- Beijer, Felix H.,Sijbesma, Rint P.,Kooijman, Huub,Spek, Anthony L.,Meijer
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p. 6761 - 6769
(2007/10/03)
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