RESUMO
PURPOSE: The aim of this study was to show preclinical efficacy and clinical development potential of PKI-587, a dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor. EXPERIMENTAL DESIGN: In vitro class 1 PI3K enzyme and human tumor cell growth inhibition assays and in vivo five tumor xenograft models were used to show efficacy. RESULTS: In vitro, PKI-587 potently inhibited class I PI3Ks (IC(50) vs. PI3K-α = 0.4 nmol/L), PI3K-α mutants, and mTOR. PKI-587 inhibited growth of 50 diverse human tumor cell lines at IC(50) values of less than 100 nmol/L. PKI-587 suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2(+), PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nmol/L PKI-587 at 4 hours. In vivo, PKI-587 inhibited tumor growth in breast (MDA-MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models. In MDA-MB-361 tumors, PKI-587 (25 mg/kg, single dose i.v.) suppressed Akt phosphorylation [at threonine(T)308 and serine(S)473] for up to 36 hours, with cleaved PARP (cPARP) evident up to 18 hours. PKI-587 at 25 mg/kg (once weekly) shrank large (â¼1,000 mm(3)) MDA-MB-361 tumors and suppressed tumor regrowth. Tumor regression correlated with suppression of phosphorylated Akt in the MDA-MB-361 model. PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 (MEK 1/2 inhibitor), irinotecan (topoisomerase I inhibitor), or HKI-272 (neratinib, HER2 inhibitor). CONCLUSION: Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified phase 1 clinical evaluation of PKI-587.
Assuntos
Morfolinas/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Serina-Treonina Quinases TOR/antagonistas & inibidores , Triazinas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Feminino , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Morfolinas/farmacologia , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento , Triazinas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of mono-morpholino 1,3,5-triazine derivatives (8a-8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed.
Assuntos
Morfolinas/química , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Triazinas/química , Ureia/análogos & derivados , Administração Oral , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Morfolinas/síntese química , Morfolinas/farmacocinética , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo , Triazinas/síntese química , Triazinas/farmacocinética , Tropanos/química , Ureia/síntese química , Ureia/química , Ureia/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PKI-402 is a selective, reversible, ATP-competitive, equipotent inhibitor of class I phosphatidylinositol 3-kinases (PI3K), including PI3K-alpha mutants, and mammalian target of rapamycin (mTOR; IC(50) versus PI3K-alpha = 2 nmol/L). PKI-402 inhibited growth of human tumor cell lines derived from breast, brain (glioma), pancreas, and non-small cell lung cancer tissue and suppressed phosphorylation of PI3K and mTOR effector proteins (e.g., Akt at T308) at concentrations that matched those that inhibited cell growth. In MDA-MB-361 [breast: Her2(+) and PIK3CA mutant (E545K)], 30 nmol/L PKI-402 induced cleaved poly(ADP-ribose) polymerase (PARP), a marker for apoptosis. In vivo, PKI-402 inhibited tumor growth in MDA-MB-361, glioma (U87MG), and lung (A549) xenograft models. In MDA-MB-361, PKI-402 at 100 mg/kg (daily for 5 days, one round) reduced initial tumor volume of 260 mm(3) to 129 mm(3) and prevented tumor regrowth for 70 days. In MDA-MB-361 tumors, PKI-402 (100 mg/kg, single dose) suppressed Akt phosphorylation (at T308) and induced cleaved PARP. Suppression of phosphorylated Akt (p-Akt) was complete at 8 hours and still evident at 24 hours. Cleaved PARP was evident at 8 and 24 hours. In normal tissue (heart and lung), PKI-402 (100 mg/kg) had minimal effect on p-Akt, with no detectable cleaved PARP. Preferential accumulation of PKI-402 in tumor tissue was observed. Complete, sustained suppression of Akt phosphorylation may cause tumor regression in MDA-MB-361 and other xenograft models. We are testing whether dual PI3K/mTOR inhibitors can durably suppress p-Akt, induce cleaved PARP, and cause tumor regression in a diverse set of human tumor xenograft models. Mol Cancer Ther; 9(4); 976-84. (c)2010 AACR.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Compostos de Fenilureia/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Biomarcadores Tumorais/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Ensaios Enzimáticos , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Humanos , Concentração Inibidora 50 , Camundongos , Compostos de Fenilureia/sangue , Compostos de Fenilureia/química , Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/sangue , Pirimidinas/química , Serina-Treonina Quinases TORRESUMO
The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Triazinas/farmacologia , Trifosfato de Adenosina/química , Trifosfato de Adenosina/farmacologia , Animais , Área Sob a Curva , Ligação Competitiva , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Nus , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Morfolinas/química , Morfolinas/farmacocinética , Morfolinas/farmacologia , Mutação , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/prevenção & controle , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Análise de Sobrevida , Serina-Treonina Quinases TOR , Triazinas/química , Triazinas/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The synthesis and stereochemical determination of 1-(4-(4-((1R,5R,6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea (2), an active metabolite of the potent PI3 kinase inhibitor PKI-179 (1), is described. Stereospecific hydroboration of the double bond of 2,5-dihydro-1H-pyrrole 8 gave the 2,3-trans alcohol 9 exclusively. The configuration of the 3-hydroxyl group in 9 was inverted by an oxidation and stereoselective reduction sequence to give the corresponding 2,3-cis isomer 23. Both exo (21) and endo (27) isomers of the metabolite 2 were prepared via a practical synthetic route from 9 and 23, respectively, and the stereochemistry of 2 was determined to be endo. The endo isomer (27) was separated into two enantiomers 28 and 29 by chiral HPLC. Compound 2 was found to be enantiomerically pure and identical to the enantiomer 28. The absolute stereochemistry of the enantiomer 28 was determined by Mosher's method, thus establishing the stereochemistry of the active metabolite 2.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Morfolinas/síntese química , Inibidores de Fosfoinositídeo-3 Quinase , Ureia/análogos & derivados , Sítios de Ligação , Hidrocarbonetos Aromáticos com Pontes/química , Inibidores Enzimáticos/farmacologia , Estrutura Molecular , Morfolinas/química , Morfolinas/farmacologia , Oxirredução , Fosfatidilinositol 3-Quinases/química , Estereoisomerismo , Ureia/síntese química , Ureia/química , Ureia/farmacologiaRESUMO
We are introducing a novel series of 2,4-diaminoquinazolines as beta-catenin/Tcf4 inhibitors which were identified by ligand-based design. Here we elucidate the SAR of this series and explain how we were able to improve key molecular properties such as solubility and cLogP leading to compound 9. Analogue 9 exhibited better biological activity and improved physical and pharmacological properties relative to the HTS hit 49. Furthermore, 9 demonstrated good cell growth inhibition against several human colorectal cancer lines such as LoVo and HT29. In addition, treatment with compound 9 led to gene expression changes that overlapped significantly with the transcriptional profile resulting from the pathway inhibition by siRNA knockdown of beta-catenin or Tcf4. Subsequently, 9 was tested for efficacy in a beta-catenin/RKE-mouse xenograft, where it led to more then 50% decrease in tumor volume.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Quinazolinas/síntese química , Fatores de Transcrição TCF/efeitos dos fármacos , beta Catenina/efeitos dos fármacos , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Desenho de Fármacos , Humanos , Camundongos , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Relação Estrutura-Atividade , Fator de Transcrição 4 , Fatores de Transcrição/efeitos dos fármacos , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This article describes the syntheses and SAR of a series of imidazolopyrimidine derivatives, which are evaluated as inhibitors of PI3-Kinase (PI3K) and mTOR. These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of Akt at T308.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Ligação Competitiva , Linhagem Celular Tumoral , Simulação por Computador , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacologia , Serina-Treonina Quinases TORRESUMO
The synthesis and SAR of a series of 2,4-diamino-quinazoline derivatives as beta-catenin/Tcf-4 inhibitors are described. This series was developed by modifying the initial lead 1, which was identified by screening of our compound library and found to inhibit the beta-catenin/Tcf-4 pathway. Replacement of the biphenyl moiety in compound 1 with the N-phenylpiperidine-4-carboxamide chain as in 2, resulted in a number of new analogues, which are potent inhibitors of the beta-catenin/Tcf-4 pathway. Compound such as 16k exhibited good cellular potency, solubility, metabolic stability and oral bioavailability.
Assuntos
Anilidas/química , Antineoplásicos/química , Neoplasias Colorretais/tratamento farmacológico , Quinazolinas/química , Fatores de Transcrição TCF/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Anilidas/síntese química , Anilidas/farmacocinética , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Relação Estrutura-Atividade , Fatores de Transcrição TCF/metabolismo , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismoRESUMO
Botryosphaeran (EPS(FRU)), an exopolysaccharide of the beta-(1-->3,1-->6)-d-glucan type with 31% branching at C-6, is produced by the fungus Botryosphaeria rhodina MAMB-05 when grown on fructose as carbon source. Botryosphaeran was derivatized by sulfonation to induce anticoagulant activity. The effectiveness of the sulfonation reaction by chlorosulfonic acid in pyridine was monitored by the degree of substitution and FT-IR analysis of the sulfonated EPS(FRU) (once sulfonated, EPS(FRUSULF); and re-sulfonated, EPS(FRURESULF)). Activated partial thromboplastin time (APTT) and thrombin time (TT) tests of EPS(FRURESULF) indicated significant in vitro anticoagulant activity that was dose-dependent. EPS(FRU) did not inhibit any of the coagulation tests.
Assuntos
Anticoagulantes/farmacologia , Ascomicetos/crescimento & desenvolvimento , Ascomicetos/metabolismo , Frutose/metabolismo , Glucanos/química , Glucanos/farmacologia , Ácidos Sulfônicos/metabolismo , Anticoagulantes/química , Anticoagulantes/metabolismo , Coagulação Sanguínea/efeitos dos fármacos , Glucanos/metabolismo , Heparina/farmacologia , Humanos , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Beta-lactamases are serine- and metal-dependent hydrolases, produced by the bacteria as defense against beta-lactam antibiotics. Commercially available inhibitors such as clavulanic acid, sulbactam, and tazobactam, which are currently used in the hospital settings, have reduced activity against newly emerging beta-lactamases. Bacterial production of diverse beta-lactamases including class-A, class-C, and ESBLs has motivated several research groups to search for inhibitors with a broader spectrum of activity. Previously, several novel 6-methylidene penems bearing, [5,5] [5,6] and [5,5,5] heterocycles have been synthesized in our laboratory and were shown to be potent and broad-spectrum beta-lactamase inhibitors. As a continuation of our previous work and in order to extend the structure-activity relationships, in this paper, we describe herein the synthesis and in vitro, in vivo activities of several novel 5,5,6-fused tricyclic heterocycles attached to the 6-methylidene penem core. The compounds presented in the current paper are potent and broad-spectrum inhibitors of the TEM-1 and AmpC beta-lactamases. In combination with piperacillin, their in vitro activities showed enhanced susceptibility to class A- and C-resistant strains studied in various bacteria. Some of the newly synthesized compounds such as 12a-c were shown to have in vivo activity in the acute lethal infection model against TEM-1 producing organisms. The 5,5,6-fused heterocyclic ring cores such as 21, 25, and 35 reported here are hitherto unknown in the literature.
Assuntos
Antibacterianos/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Lactamas/farmacologia , Inibidores de beta-Lactamases , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Compostos Heterocíclicos com 3 Anéis/química , Imidazóis/química , Imidazóis/farmacologia , Lactamas/química , Testes de Sensibilidade Microbiana , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-Atividade , beta-LactamasesRESUMO
The design and synthesis of a series of 6-methylidene penems containing [6,5]-fused bicycles (thiophene, imidazole, or pyrazle-fused system) as novel class A, B, and C beta-lactamase inhibitors is described. These penems proved to be potent inhibitors of the TEM-1 (class A) and AmpC (class C) beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. Their in vitro and in vivo activities in combination with piperacillin are discussed. On the basis of the crystallographic structures of a serine-bound reaction intermediate of 2 with SHV-1 (class A) and GC1 (class C) enzymes, compounds 14a-l were designed and synthesized. Penems are proposed to form a seven-membered 1,4 thiazepine ring in both class A and C beta-lactamases. The interaction energy calculation for the enzyme-bound intermediates favor the formation of the C7 R enantiomer over the S enantiomer of the 1,4-thiazepine in both beta-lactamases, which is consistent with those obtained from the crystal structure of 2 with SHV-1 and GC1.
Assuntos
Antibacterianos/química , Compostos Heterocíclicos com 2 Anéis/química , Modelos Moleculares , Tiazepinas/química , Inibidores de beta-Lactamases , Aldeídos/química , Animais , Antibacterianos/síntese química , Antibacterianos/farmacologia , Enterobacter aerogenes , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/mortalidade , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/mortalidade , Bactérias Gram-Negativas/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia , Resistência beta-Lactâmica , beta-Lactamases/químicaRESUMO
The design and synthesis of a series of seven tricyclic 6-methylidene penems as novel class A and C serine beta-lactamase inhibitors is described. These compounds proved to be very potent inhibitors of the TEM-1 and AmpC beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. In combination with piperacillin, their in vitro activities enhanced susceptibility of all class C resistant strains from various bacteria. Crystallographic structures of a serine-bound reaction intermediate of 17 with the class A SHV-1 and class C GC1 enzymes have been established to resolutions of 2.0 and 1.4 A, respectively, and refined to R-factors equal 0.163 and 0.145. In both beta-lactamases, a seven-membered 1,4-thiazepine ring has formed. The stereogenic C7 atom in the ring has the R configuration in the SHV-1 intermediate and has both R and S configurations in the GC1 intermediate. Hydrophobic stacking interactions between the tricyclic C7 substituent and a tyrosine side chain, rather than electrostatic or hydrogen bonding by the C3 carboxylic acid group, dominate in both complexes. The formation of the 1,4- thiazepine ring structures is proposed based on a 7-endo-trig cyclization.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Tiazepinas/química , Inibidores de beta-Lactamases , beta-Lactamases/química , beta-Lactamas/química , Sítios de Ligação , Cristalografia por Raios X , Enterobacter cloacae/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Hidrólise , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Ligação Proteica , Pseudomonas aeruginosa/efeitos dos fármacos , Serratia marcescens/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Tiazepinas/síntese química , Tiazepinas/farmacologia , beta-Lactamas/síntese química , beta-Lactamas/farmacologiaRESUMO
Two isomeric binuclear ligands PBTPA and MBTPA and their copper(II) complexes were prepared and examined for hydrolysis of a model phosphodiester substrate: bis(p-nitrophenyl)phosphate. A bell-shaped pH vs rate profile, which is in agreement with one mechanism proposed for bimetallonucleases/phosphatases, was observed for the binuclear complex of copper(II) and PBTPA. At pH 8.4, a maximum rate of 1.14 x 10(-6) s(-1)--more than 10(4)-fold over uncatalyzed reactions--was achieved. However, the analogous complex of MBTPA did not show significant rate enhancement. The binuclear complex of copper(II) and PBTPA also showed 10-fold acceleration over mononuclear complex of copper(II) and tris(2-pyridylmethyl)amine (TPA) catalyzed reaction. A phage phiX174 DNA assay showed that the complex of copper(II) and PBTPA promoted supercoiled phage phiX174 DNA relaxation under both aerobic and anaerobic conditions, in contrast to the hydrolytic inactivity of the mononuclear complex of copper(II) and TPA.
Assuntos
Cobre/química , DNA/química , Organofosfatos/química , Catálise , Cristalografia por Raios X , Eletroforese em Gel de Ágar , Hidrólise , Cinética , Ligantes , Modelos Moleculares , Estrutura Molecular , Nitrofenóis/química , Diester Fosfórico Hidrolases/química , Piridinas/químicaRESUMO
The compound N3-benzoyl-3',5'-O-(di-tert-butylsilanediyl)uridine 2 was alkylated with various alkyl iodides in CH3CN in the presence of base. Normal 2'-O-alkylated products were obtained with methyl or benzyl iodide. If hindered alkyl iodides with beta-branching such as 2-ethylbutyl iodide were used as electrophiles under the same conditions, N3-alkyl-2'-O-benzoyl uridine derivatives were produced. This unexpected transformation is usually dormant with reactive alkylating agents, but expressed with sterically hindered, less reactive electrophiles. This unwanted reaction gives isomeric products whose spectra differ in only subtle ways from target compounds.
Assuntos
Derivados de Benzeno/química , Uridina/análogos & derivados , Alquilação , Hidrocarbonetos Iodados/química , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Estereoisomerismo , Uridina/químicaRESUMO
A combination of host-guest chemistry and coordination chemistry in the design of electrochemical sensors for alkali metal and ammonium ions is described. The sensor molecules are coordination complexes between a copper ion and a functionalized tripodal ligand. Upon presentation of the ion to the sensor molecule, a shift in the redox potential of the copper ion occurs. In the course of the study, three new alkoxyphenyl-substituted derivatives of the ligand tris(2-pyridylmethyl)amine (TPA) were prepared and characterized. The synthesis of the new ligands involved the preparation of bromopyridyl-TPA derivatives followed by Suzuki coupling with substituted phenylboronic acids. Cyclic voltammetry studies of copper complexes of the ligands indicated that steric effects played a dominant role in the overall determination of the copper redox couple. Studies of the alkoxyphenyl ligands indicated that small but reproducible changes in the copper redox couple occurred upon presentation of a guest cation that would be expected to form a complex with the copper-ligand complex.