Pyrimidine Core Research Articles

New manganese-scaffolded organic triple-deckers based on quinoxaline, pyrazine and pyrimidine cores

The thermolytic coupling of Ph(2)CN(2) and (t-Bu)(Ph)CN(2) with doubly cyclomanganated 2,5-diphenylpyrazine and 4,6-diphenylpyrimidine afforded substantial amounts of new triple decker compounds of either C(i) and C(2) symmetry respectively containing, in both series, two eta(3)-bonded Mn(CO)(3) fragments which intervene as scaffolds sustaining the helical non-conjugated triaryl backbone. The molecular structures of two pyrazine derivatives show a typical non-parallel stacking of the aromatic rings and the encapsulation of the central pyrazyl fragment with interplanar centroid-to-centroid distances of ca. 3.5 A. The stacking of the aromatics in the triple-decker pyrimidine derivatives has been assessed by (1)H NMR experiments at low temperature. All the triple-decker-type compounds are electroactive. Pyrimidine triple-deckers can reversibly be electrochemically reduced to the corresponding anions.

Design and synthesis of pyrazolo[3,4- d]pyrimidine core based dissymmetrical ‘Leonard linker’ compounds: 1H NMR and crystallographic evidence for folded conformation due to arene interactions

Proton NMR analysis of two newly synthesized ‘Leonard/trimethylene linker’ dissymmetrical compounds 1-(4,6-dimethylsulfanyl-1 H-pyrazolo[3,4- d]pyrimidin-1-yl)-3-(5-methyl-6-methylsulfanyl-4-oxo-1,5-dihydropyrazolo[3,4- d]pyrimidin-1-yl)propane (8) and 1-(4-methoxy-6-methylsulfanyl-1 H-pyrazolo[3,4- d]pyrimidin-1-yl)-3-(6-methoxy-5-methyl-4-oxo-1,5-dihydropyrazolo[3,4- d]pyrimidin-1-yl)propane (10) show intramolecularly stacked conformation in solution. X-Ray crystallography of dissymmetrical ‘Leonard/trimethylene linker’ compound (8) based on pyrazolo[3,4- d]pyrimidine core, for the first time, shows unusual U-motif formed due to intramolecular π–π stacking interactions, which is similar to earlier related symmetrical compounds 1 & 2. Supramolecular structures of new compound (8) show additional CH…O, CH…N, CH…S and S…S interactions.

Synthesis of [1,2,4]triazolo[1,5- a]pyrazines as adenosine A 2A receptor antagonists

Potent and selective antagonists of the adenosine A 2A receptor often contain a nitrogen-rich fused-ring heterocyclic core. Replacement of the core with an isomeric ring system has previously been shown to improve target affinity, selectivity, and in vivo activity. This paper describes the preparation, by a novel route, of A 2A receptor antagonists containing the [1,2,4]triazolo[1,5- a]pyrazine nucleus, which is isomeric with the [1,2,4]triazolo[1,5- c]pyrimidine core of a series of known A 2A antagonists with in vivo activity in animal models of Parkinson’s disease.

Fine tuning of folded conformation by change of substituents: 1H NMR and crystallographic evidence for folded conformation due to arene interactions in pyrazolo[3,4-d]pyrimidine core based ‘propylene linker’ compounds

Proton NMR and X-ray crystallographic analysis of two newly synthesized ‘trimethylene linker,’ (Leonard linker) compounds 1,3-bis(4-ethoxy-6-methylsulfanyl-lH-pyrazolo[3,4-d]pyrimidin-1-yl)propane (4c) and 1,3-bis(4-isopropoxy-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propane (4d) show intramolecularly stacked conformations both in solution and solid state. Robustness of the unusual U-motif formed due to intramolecular stacking in earlier related compounds (1, n=3 and 3, n=3) is not only confirmed but additional fine tuning is also achieved in new compounds (4) formed by replacement of remote 4-alkylsulfanyl group in 1a by 4-alkoxy substituents.

Design and Synthesis of the First Generation of Novel Potent, Selective, and in Vivo Active (Benzothiazol-2-yl)acetonitrile Inhibitors of the c-Jun N-Terminal Kinase

Several lines of evidence support the hypothesis that c-Jun N-terminal kinase (JNKs) plays a critical role in a wide range of diseases including cell death (apoptosis)-related disorders (neurodegenerative diseases, brain, heart, and renal ischemia, epilepsy) and inflammatory disorders (multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases). Screening of our internal compound collection for inhibitors of JNK3 led to the identification of (benzothiazol-2-yl)acetonitrile derivatives as potent and selective JNK1, -2, -3 inhibitors. Starting from initial hit 1 (AS007149), the chemistry and initial structure-activity relationship (SAR) of this novel and unique kinase inhibitor template were explored. Investigation of the SAR rapidly revealed that the benzothiazol-2-ylacetonitrile pyrimidine core was crucial to retain a good level of potency on rat JNK3. Therefore, compound 6 was further optimized by exploring a number of distal combinations in place of the chlorine atom. This led to the observation that the presence of an aromatic group, two carbons away from the aminopyrimidine moiety and bearing substituents conferring hydrogen bond acceptor (HBA) properties, could improve the potency. Further improvements to the biological and biopharmaceutical profile of the most promising compounds were performed, resulting in the discovery of compound 59 (AS601245). The in vitro and in vivo anti-inflammatory potential of this new JNK inhibitor was investigated and found to demonstrate efficacy per oral route in an experimental model of rheumatoid arthritis (RA).

Pyrimidine‐Core Extended π‐Systems: General Synthesis and Interesting Fluorescent Properties.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Pyrimidine-Core Extended π-Systems: General Synthesis and Interesting Fluorescent Properties

We have developed a simple but powerful synthetic strategy that permits the assembly of pi-systems onto a pyrimidine core in a programmable and diversity-oriented format. The nucleophilic addition of ArLi to 2-methylthiopyrimidine, followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) oxidation, resulted in the production of 4-aryl-2-methylthiopyrimidines. The iterative reaction sequence then gave 4,6-diaryl-2-methylthiopyrimidines. The resulting adduct was further allowed to react with ArMgBr under the catalytic influence of NiCl2(dppe) to afford 2,4,6-triarylpyrimidines. By following this synthetic scheme, interesting pyrimidine-core pi-systems were rapidly constructed in a programmable fashion. The successful discovery of a number of interesting fluorescent materials and properties (e.g., solvatofluorochromism) speaks well for the potential of our platform strategy in the development of functional organic materials.

Pyrazolo[1,5-a]pyrimidines: Estrogen Receptor Ligands Possessing Estrogen Receptor β Antagonist Activity

In our search for novel subtype-selective estrogen receptor (ER) ligands, we have examined various heterocyclic units as core structural elements. Here, we have investigated the fused, bicyclic pyrazolo[1,5-a]pyrimidine core, which is a system that allows for analogues to be readily assembled in a library-like fashion. This series of pyrazolo[1,5-a]pyrimidine ER ligands provided us with a new pharmacological profile for an ER ligand: compounds that are passive on both ERs, with a distinct potency selectivity in favor of ERbeta. The most distinctive ligand in this series, 2-phenyl-3-(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine, was 36-fold selective for ERbeta in binding. Curiously, on the basis of molecular modeling, the ERbeta binding selectivity of compounds in this series appears to be derived from differing orientations that they adapt in the ligand binding pockets of ERalpha vs ERbeta. In transcription assays this pyrazolopyrimidine was fully effective as an ERbeta antagonist while exhibiting no significant activity on ERalpha. Thus, this ligand functions as a potency- and efficacy-selective ERbeta antagonist that would abrogate estrogen action through ERbeta with minimal effects on its activity through ERalpha; as such, it could be used to study the biological function of ERbeta.

Synthesis, characterization and H 2O 2-sensing properties of pyrimidine-based hyperbranched polyimides

A series of hyperbranched polyimides having pyrimidine core in the backbone was prepared by solution polycondensation of pyromellitic dianhydride (A 2 type) and 2,4,6-triaminopyrimidine (B 3 type). The resulting polyimides were characterized by IR, GPC, DTA, DSC, TGA, density and viscosity measurement. The results showed that polyimides were obtained in 82–86% yield, had inherent viscosities of 1.58–1.87 dL/g and highly thermal stability. From the solubility tests, it was found that all the polyimides were soluble in NMP, DMAc and DMSO at room temperature. In addition, because of their interesting film properties, attempts were made to prepare H 2O 2-sensing polyimide material. For this reason, selectivity of film-coated electrodes obtained from the chemically prepared hyperbranched polyimides toward electroactive (ascorbic acid, oxalic acid and hydrogen peroxide) and non-electroactive (lactose, sucrose and urea) species was examined by means of CV, DPV and TB techniques. From the electrochemical data obtained, it has been demonstrated that polyimide (HPI-2) film responded to only hydrogen peroxide among the species examined. In other words, it has been claimed that the mentioned polyimide-coated electrode can be used as H 2O 2-selective membrane in the presence of the electroactive and non-electroactive interferents.

Heterocyclic columnar pyrimidines: synthesis, characterization and mesomorphic properties

The synthesis, characterization, and mesomorphic properties of two series of heterocyclic compounds derived from a pyrimidine core are reported. These series, 1a and 1b, are substituted with a variety of functional groups (X=NHSO2CF3, F, Cl, Br, I, OCH3, CH3, C2H5) at the C3′ (meta)- or C4′ (para)-position of the terminal phenyl ring, and the substituent effect on mesophase formation was studied. The compounds were characterized by 1H and 13C NMR spectroscopy and elemental analysis, and the mesomorphic behavior of the compounds was characterized and studied by differential scanning calorimetry, polarizing optical microscopy and powder X-ray diffraction. Most of the compounds were mesogenic at room temperature, and the mesophases were assigned as lamellar columnar (ColL) phases, as expected for disk-like molecules. The results also revealed that compounds with a para-substituent (1a; except for –OCH3) at the C4′-position, exhibited higher clearing temperatures and wider temperature mesophase ranges than those of compounds with a meta-substituent (1b) at the C3′-position. The higher clearing temperatures may be attributed to stronger dipolar interactions resulting from a greater resonance effect with the central core for para-substitution than for meta-substitution. The results also indicated that the columnar mesophases observed show a correlation with the electronic properties of the substituents; compounds containing electron-withdrawing substituents (X=F, Cl, Br, I, NHSO2CF3) also have higher clearing temperatures than compounds containing electron-donating substituents (X=Me, Et, OMe).

Synthesis of Pyrimidines via Base-induced Condensation of α-Chloro Oxime Derivatives

Abstract A facile synthesis of 2,4,6-trisubstituted pyrimidines from the reaction of α-chloro oxime ethers with Grignard reagents has been developed. Alkyl and aryl groups can be easily introduced at the 2-position of the pyrimidine core. In addition, a synthesis of unsymmetrical pyrimidines has been examined.

Reaction of alpha,alpha-dibromo oxime ethers with Grignard reagents: alkylative annulation providing a pyrimidine core.

A convergent synthesis of a pyrimidine core has been achieved. Treatment of alpha,alpha-dibromo oxime ethers, which are easily derived from the corresponding esters, with a variety of Grignard reagents provides trisubstituted pyrimidines in good yields. This new method offers an easy access to functionalized pyrimidines.

Solid-Phase Catalytic Hydrogenation of Uracil with Tritium: Synthesis of Tritium-Labeled β-Alanine

Solid-phase catalytic hydrogenation of uracil with gaseous tritium was studied. Isotope exchange of protons at C5 and C6 is accompanied by hydrogenation of the 5,6-double bond in the pyrimidine core; as a result, a mixture of tritium-labeled uracil and 5,6-dihydrouracil is formed. The influence of the reaction temperature and time on the yield and molar radioactivity of these compounds was examined. The best conditions for cleavage of 5,6-dihydrouracil into β-alanine were found. [5,6-3H2]Uracil (49 Ci mmol-1), [5,5,6,6-3H4]5,6-dihydrouracil (100 Ci mmol-1), and [2,2,3,3-3H4]β-alanine (100 Ci mmol-1) were prepared.

Synthesis of pyrimidine based metal ligands

A convenient synthesis of a pyrimidine based bis-tridentate metal ligand is presented. The pyrimidine core is constructed via cyclization of an amidine and a substituted propenone. A Stille coupling appends the terminal pyridyl units. The general methodology presented is amenable to functionality at several positions on the ligand framework.

Studies toward the total synthesis of the variolins: rapid entry to the core structure

The pyrido[3′,2′:4,5]pyrrolo[1,2- c]pyrimidine core structure of the variolins has been synthesized in three steps from commercially available materials. The key reaction involves the deoxygenation and concomitant cyclization of a triarylmethanol using the combination of triethylsilane and trifluoroacetic acid. Introduction of amine functionality as required for the natural products has been achieved in two steps.

Reaction of 2-Bromomethylazoles and TosMIC: A Domino Process to Azolopyrimidines. Synthesis of Core Tricycle of the Variolins Alkaloids

A new reaction of N-protected 2-bromomethylazoles and tosylmethyl isocyanide (TosMIC) leading to the preparation of azolopyrimidines is described. This domino sequence was used to synthesize the pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine core of alkaloids variolins from 4-methoxy-2-methylpyrrolo[2,3-b]pyrimidine in two steps.

Binding of AR-1-144, a tri-imidazole DNA minor groove binder, to CCGG sequence analyzed by NMR spectroscopy.

The interactions of N-[2-(dimethylamino)ethyl]-1-methyl-4-[1-methyl-4-[4-formamido-1-meth ylimidazole-2-carboxamido]imidazole-2-carboxamido]imidazole-2-c arboxa mide (AR-1-144), a tri-imidazole polyamide minor groove binder, with DNA have been investigated by NMR and CD spectroscopy. A series of DNA oligonucleotides with a C/G-containing four-bp core, i.e. CCGG, CGCG, GGCC, and GCGC, have been titrated with AR-1-144 at different ratios. AR-1-144 favors the CCGG sequence. The flanking sequence of the CCGG core also influences the binding preference, with a C or T being favored on the 3'-side of the CCGG core. The three-dimensional structure of the symmetric 2:1 side-by-side complex of AR-1-144 and GAACCGGTTC, determined by NOE-constrained NMR refinement, reveals that each AR-1-144 binds to four base pairs, i.e. at C5-G6-G7-T8, with every amide-imidazole unit forming two potential hydrogen bonds with DNA. The same DNA binding preference of AR-1-144 was also confirmed by circular dichroism spectroscopy, indicating that the DNA binding preference of AR-1-144 is independent of concentration. The cooperative binding of an AR-1-144 homodimer to the (purine)CCGG(pyrimidine) core sequence appears to be weaker than that of the distamycin A homodimer to A/T sequences, most likely due to the diminished hydrophobic interactions between AR-1-144 and DNA. Our results are consistent with previous footprinting data and explain the binding pattern found in the crystal structure of a di-imidazole drug bound to CATGGCCATG.

Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain.

Angiogenesis, the sprouting of new blood vessels from pre-existing ones, is an essential physiological process in development, yet also plays a major role in the progression of human diseases such as diabetic retinopathy, atherosclerosis and cancer. The effects of the most potent angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin and fibroblast growth factor (FGF) are mediated through cell surface receptors that possess intrinsic protein tyrosine kinase activity. In this report, we describe a synthetic compound of the pyrido[2,3-d]pyrimidine class, designated PD 173074, that selectively inhibits the tyrosine kinase activities of the FGF and VEGF receptors. We show that systemic administration of PD 173074 in mice can effectively block angiogenesis induced by either FGF or VEGF with no apparent toxicity. To elucidate the determinants of selectivity, we have determined the crystal structure of PD 173074 in complex with the tyrosine kinase domain of FGF receptor 1 at 2.5 A resolution. A high degree of surface complementarity between PD 173074 and the hydrophobic, ATP-binding pocket of FGF receptor 1 underlies the potency and selectivity of this inhibitor. PD 173074 is thus a promising candidate for a therapeutic angiogenesis inhibitor to be used in the treatment of cancer and other diseases whose progression is dependent upon new blood vessel formation.

Synthesis and tyrosine kinase inhibitory activity of a series of 2-amino-8H-pyrido[2,3-d]pyrimidines: identification of potent, selective platelet-derived growth factor receptor tyrosine kinase inhibitors.

Screening of a compound library led to the identification of 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidine (1) as a inhibitor of the platelet-derived growth factor receptor (PDGFr), fibroblast growth factor receptor (FGFr), and c-src tyrosine kinases (TKs). Replacement of the primary amino group at C-2 of 1 with a 4-(N,N-diethylaminoethoxy)phenylamino group yielded 2a, which had greatly increased activity against all three TKs. In the present work, variation of the aromatic group at C-6 and of the alkyl group at N-8 of the pyrido[2,3-d]pyrimidine core provided several analogues that retained potency, including derivatives that were biased toward inhibition of the TK activity of PDGFr. Analogues of 2a with a 3-thiophene or an unsubstituted phenyl group at C-6 were the most potent inhibitors. Compound 54, which had IC50 values of 31, 88, and 31 nM against PDGFr, FGFr, and c-src TK activity, respectively, was active in a variety of PDGF-dependent cellular assays and blocked the in vivo growth of three PDGF-dependent tumor lines.

Development of a binding model to protein tyrosine kinases for substituted pyrido[2,3-d]pyrimidine inhibitors.

Previously, our laboratories have reported on a new class of highly potent tyrosine kinase inhibitors based on the pyrido[2, 3-d]pyrimidine core template. To understand the structural basis for the potency and specificity, a model for the binding mode of this class of inhibitors to the tyrosine kinase domains of c-Src, PDGFr, FGFr, and EGFr tyrosine kinases was developed from structural information (principally utilizing the catalytic domain of c-AMP-dependent protein kinase as template) and structure-activity relationship (SAR) information. In the resulting docking mode, the pyrido[2,3-d]pyrimidine template shows a hydrogen-bonding pattern identical to that of olomoucine. The 6-aryl substituent of the heterocycle is located deep in the binding cleft in a pocket not used by ATP, which helps to confer high-affinity binding as well as specificity. The 2-anilino and 2-(dialkylamino)alkylamino substituents as well as the 7-urea substituent of inhibitors within this class are located at the entrance of the binding cleft and make contact with residues in the hinge region between the two kinase lobes. This allows considerable variability and bulk tolerance for C-2 and N-7 substituents. The models presented here are consistent with the SAR seen for the inhibition of a number of isolated enzymes and provide a structural basis to explain their specificity. They have been used successfully to design new highly potent protein kinase inhibitors.