Selectivities in the formation of pyridines and pyrimidines by ammonia-induced cyclocondensations of vinamidiniums

Arylvinamidines (2-, 3- or 4-aryl-4-(N,N-dimethyl)amino-1-azabuta-1,3-dienes), generated from 1,1,5,5-tetramethyl-2- or -3-phenyl-1,5-diazapentadienium salts, cyclocondense orientation-specifically under two regioselections forming 1-4' + 4-3' and 1-2' + 4-1' bonds on exposure to ammonia. The initial cyclates aromatise eliminatively to give mixtures of diarylpyridines and arylpyrimidines. The 2-arylvinamidines do not participate as 2-centre reactants and their 4-aryl isomers not as 4-centre reactants in the cyclocondensations which appear to be stepwise and not concerted. Reasons for the selective participation appear to be that the required eliminations from the initial cyclates are disfavoured in the first case and that a geometric factor prevents cyclate-formation in the second.

Convergent synthesis and cruzain inhibitory activity of novel 2-(N `-benzylidenehydrazino)-4-trifluoromethyl-pyrimidines

To search for new cruzain inhibitors, the synthesis of a series of novel 2-(N`-benzylidenehydrazino)-4-trifluoromethyl-pyrimidines in a convergent manner is presented. The cruzain inhibitory activity of some of these compounds was evaluated and a binding model was proposed. All derivatives tested were active and the most significant inhibitory effect (80% at 100 mu M) and IC(50) value (85 mu M) were obtained from the 2-(N`-4-chloro-benzylidenehydrazino)-4-trifluoromethyl-pyrimidine. Although further structural optimization to improve solubility is necessary, the molecular docking studies suggest that these inhibitors occupy the S2 pocket without irreversible enzyme inactivation, through hydrophobic interactions, thus, indicating a desirable mode of interaction for the design of novel inhibitors. (C) 2008 Elsevier Ltd. All rights reserved.

Radiation metabolomics. 2. Dose- and time-dependent urinary excretion of deaminated purines and pyrimidines after sublethal gamma-radiation exposure in mice

Gamma-radiation exposure of humans is a major public health concern as the threat of terrorism and potential hostile use of radiological devices increases worldwide. We report here the effects of sublethal gamma-radiation exposure on the mouse urinary metabolome determined using ultra-performance liquid chromatography-coupled time-of-flight mass spectrometry-based metabolomics. Five urinary biomarkers of sublethal radiation exposure that were statistically significantly elevated during the first 24 h after exposure to doses ranging from 1 to 3 Gy were unequivocally identified by tandem mass spectrometry. These are deaminated purine and pyrimidine derivatives, namely, thymidine, 2'-deoxyuridine, 2'-deoxyxanthosine, xanthine and xanthosine. Furthermore, the aminopyrimidine 2'-deoxycytidine appeared to display reduced urinary excretion at 2 and 3 Gy. The elevated biomarkers displayed a time-dependent excretion, peaking in urine at 8-12 h but returning to baseline by 36 h after exposure. It is proposed that 2'-deoxyuridine and 2'-deoxyxanthosine arise as a result of gamma irradiation by nitrosative deamination of 2'-deoxycytidine and 2'-deoxyguanosine, respectively, and that this further leads to increased synthesis of thymidine, xanthine and xanthosine. The urinary excretion of deaminated purines and pyrimidines, at the expense of aminopurines and aminopyrimidines, appears to form the core of the urinary radiation metabolomic signature of mice exposed to sublethal doses of ionizing radiation.

An efficient substituent dependent synthesis of congested pyridines and pyrimidines

An efficient and versatile synthesis of various congested pyridines 3a-h, 6a,b, 8a-n, lOa-g, and 16a,b, and (pyrimidin-4-yl)acetonitriles 13a-g has been delineated by base catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones la-h, 5, 7, and 15 by formamidine acetate 2a,acetamidine hydrochloride 2b, S-methylisothiourea 9a, pyrazol-I-yl-carboxamidine 9b, and arylamidine hydrochloride 12 separately in the presence of powdered KOH in dry DMF.

Hypervalent iodine in synthesis 93. A facile synthesis of 2-substituted imidazo[1,2-a]pyrimidines by cyclocondensation of alkynyl(phenyl)iodonium salts and 2-aminopyrimidine

Simple stirring of a mixture of the alkynyl(phenyl)iodonium salts 1 with 2-aminopyrimidine 2 in chloroform under reflux for two hours in the presence of K2CO3 gave, after workup, the 2-substituted imidazo[1,2-]pyrimidines 3 in moderate to good yields. A possible mechanism for the formation of 3 involves the intramolecular cyclization of the intermediate alkylidenecarbene 6.

Novel biological roles for pyrimidines

The development of classical and lipophilic inhibitors of dihydrofolate reductase (DHFR) as antitumour agents is reviewed and the advantages and problems associated with each class are discussed. The antitumour activity, pharmacokinetics and metabolism of m-azido-pyrimethamine (MZP), a novel lipophilic inhibitor, are considered and compared with metoprine, the prototype lipophilic antifolate. Evidence for a folate-independent target for lipophilic DHFR inhibitors is presented. Synthetic studies centred on three principal objectives. Firstly a series of structural analogues of MZP were prepared encompassing alkoxy, chloro and alkylamino substituents and evaluated, as the ethanesulphonate salts, for activity against mammalian DHFR. Inhibitory constant (KI) determinations were conducted by a Zone B analysis, the corresponding 4'-azido isomer of MZP proving more potent than the parent compound. Secondly, to facilitate metabolism and stability studies on MZP, a range of possible reference compounds were synthesised and characterised. Finally, a series of diaminopyrimidine derivatives were synthesised embracing structural features incompatible with DHFR inhibitory activity, in order that such compounds may serve as biochemical probes for the unidentified folate-independent target for lipophilic diaminopyrimidines discussed previously. Inactivity against DHFR was achieved via introduction of an ionic or basic group into a normally hydrophobic region of the molecule and compounds were screened against a mammalian DHFR and thymidylate synthase to confirm the abolition of activity. Several derivatives surprisingly proved potent inhibitors of DHFR exhibiting KI values comparable to that of methotrexate. Analogues were screened for antitumour activity in vitro and in vivo against murine leukaemia cell lines in order to identify potential lead compounds. Several derivatives virtually inactive against DHFR exhibited a disparate cytotoxicity and further biochemical studies are warranted. The nobreak hitherto unreported debenzylation of 2,4-diamino-5-(N-alkyl-benzylaminophenyl) pyrimidines was discovered during the course of the synthetic studies, treatment of these compounds with nitrous acid affording the corresponding benzotriazoles.

Synthesis and antimicrobial activity of some 2- Piperidinomethylamino-4-(7-H/substituted coumarin-3-yl)- 6-chlorosubstitutedphenyl pyrimidines

Purpose: To prepare and evaluate some 2-piperidinomethylamino-4-(7-H/substitutedcoumarin-3-yl)-6- chlorosubstitutedphenyl pyrimidines as antimicrobial agents. Methods: Some 2-piperidinomethylamino-4-(7-H/substitutedcoumarin-3-yl)-6-chlorosubstitutedphenyl pyrimidines were prepared by reacting 2-amino-4-(7-H/substitutedcoumarin-3-yl)-6- (chlorosubstitutedphenyl) pyrimidines with piperidine and formaldehyde. The chemical structures of the synthesized compounds were elucidated by Fourier transform infrared (FTIR), 1H-nuclear magnetic resonance (1H-NMR), mass spectrometry and elemental analysis. These compounds were investigated for their antimicrobial activity against ten bacteria and five fungi by serial plate dilution method using standard drugs, namely, ofloxacin and ketoconazole, respectively, and their minimum inhibitory concentrations (MICs) were also determined. Results: A total of eighteen new compounds (1a-18a) were synthesized. Compound 6a (MIC = 50 μg/mL; p < 0.05 or less) displayed the highest activity against S. aureus , E. faecalis , Staphylococcus epidermidis , B. subtilis , and B. cereus . Compound 6a further showed good activity (MIC = 25 μg/mL; p < 0.05 or less) against E. coli ; P. aeruginosa K. pneumonia , B. bronchiseptica , and P. vulgaris . Compounds 6a (MIC = 25 μg/mL; p < 0.0001) and 17a (MIC = 25 μg/mL; p < 0.0001) displayed very good activity against C. albicans , A. niger , A. flavus , M. purpureous , and P. citrinum , respectively. Analysis of structure-activity relationship revealed that the presence of bromo group at 7-postion of the coumarin moiety along with the 4-chlorophenyl group at position-6 of the pyrimidine ring is critical for antimicrobial activity against Gram-positive bacteria, Gram negative bacteria and fungi. Conclusion: The synthesized 2-piperidino derivatives are better antifungal and antibacterial agents than the earlier reported 2-morpholino derivatives, but require further investigations against other microbial strains to ascertain their broad spectrum antimicrobial activity.

FGFR2 as a molecular target in endometrial cancer

Although molecularly targeted therapies have been effective in some cancer types, no targeted therapy is approved for use in endometrial cancer. The recent identification of activating mutations in fibroblast growth factor receptor 2 (FGFR2) in endometrial tumors has generated a new avenue for the development of targeted therapeutic agents. The majority of the mutations identified are identical to germline mutations in FGFR2 and FGFR3 that cause craniosynostosis and hypochondroplasia syndromes and result in both ligand-independent and ligand-dependent receptor activation. Mutations that predominantly occur in the endometrioid subtype of endometrial cancer, are mutually exclusive with KRAS mutation, but occur in the presence of PTEN abrogation. In vitro studies have shown that endometrial cancer cell lines with activating FGFR2 mutations are selectively sensitive to a pan-FGFR inhibitor, PD173074. Several agents with activity against FGFRs are currently in clinical trials. Investigation of these agents in endometrial cancer patients with activating FGFR2 mutations is warranted.

Genome-scale phylogeny and the detection of systematic biases

Phylogenetic inference from sequences can be misled by both sampling (stochastic) error and systematic error (nonhistorical signals where reality differs from our simplified models). A recent study of eight yeast species using 106 concatenated genes from complete genomes showed that even small internal edges of a tree received 100% bootstrap support. This effective negation of stochastic error from large data sets is important, but longer sequences exacerbate the potential for biases (systematic error) to be positively misleading. Indeed, when we analyzed the same data set using minimum evolution optimality criteria, an alternative tree received 100% bootstrap support. We identified a compositional bias as responsible for this inconsistency and showed that it is reduced effectively by coding the nucleotides as purines and pyrimidines (RY-coding), reinforcing the original tree. Thus, a comprehensive exploration of potential systematic biases is still required, even though genome-scale data sets greatly reduce sampling error.