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2.
Cancer Cell ; 27(1): 85-96, 2015 Jan 12.
Article in English | MEDLINE | ID: mdl-25500121

ABSTRACT

BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Melanoma/drug therapy , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazines/pharmacology , src-Family Kinases/antagonists & inhibitors , Animals , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Melanoma/pathology , Melanoma, Experimental , Mice , Mice, Nude , Xenograft Model Antitumor Assays
3.
Euro Surveill ; 19(33)2014 Aug 21.
Article in English | MEDLINE | ID: mdl-25166348

ABSTRACT

Pathogen adaptation has been proposed to contribute to the resurgence of pertussis. A striking recent example is the emergence of isolates deficient in the vaccine component pertactin (Prn). This study explores the emergence of such Prn-deficient isolates in six European countries. During 2007 to 2009, 0/83 isolates from the Netherlands, 0/18 from the United Kingdom, 0/17 Finland, 0/23 Denmark, 4/99 Sweden and 5/20 from Norway of the isolates collected were Prn-deficient. In the Netherlands and Sweden, respectively 4/146 and 1/8 were observed in a later period (2010­12). The Prn-deficient isolates were genetically diverse and different mutations were found to inactivate the prn gene. These are indications that Prn-deficiency is subject to positive selective pressure. We hypothesise that the switch from whole cell to acellular pertussis vaccines has affected the balance between 'costs and benefits' of Prn production by Bordetella pertussis to the extent that isolates that do not produce Prn are able to expand. The absence of Prn-deficient isolates in some countries may point to ways to prevent or delay the spread of Prn-deficient strains. In order to substantiate this hypothesis, trends in the European B. pertussis population should be monitored continuously.


Subject(s)
Bacterial Outer Membrane Proteins/analysis , Bacterial Outer Membrane Proteins/genetics , Bordetella pertussis/isolation & purification , Virulence Factors, Bordetella/analysis , Virulence Factors, Bordetella/genetics , Whooping Cough/prevention & control , Amino Acid Sequence , Base Sequence , Bordetella pertussis/genetics , Child , Child, Preschool , Cluster Analysis , Communicable Diseases, Emerging/genetics , DNA, Bacterial/genetics , Europe , Female , Genotype , Humans , Infant , Male , Molecular Typing , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Sequence Analysis, DNA , Whooping Cough/epidemiology , Whooping Cough/microbiology
4.
Bioorg Med Chem ; 21(5): 1284-304, 2013 Mar 01.
Article in English | MEDLINE | ID: mdl-23376011

ABSTRACT

The RAS-RAF-MEK-ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine-threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-[4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzo[b]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC(50)=190 nM and with cellular GI(50)=2100 nM, and 6-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC(50)=9 nM and GI(50)=220 nM.


Subject(s)
Imidazoles/chemistry , Naphthols/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Thiophenes/chemistry , Benzofurans/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Melanoma/metabolism , Melanoma/pathology , Naphthols/chemical synthesis , Naphthols/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/metabolism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacology
5.
J Pharm Biomed Anal ; 70: 111-6, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22770733

ABSTRACT

During the stability evaluation of ß-artemether containing finished drug products, a consistent and disproportional increase in the UV-peak areas of ß-artemether degradation products, when compared to the peak area decline of ß-artemether itself, was observed. This suggested that the response factors of the formed ß-artemether degradants were significantly higher than ß-artemether. Dry heat stressing of ß-artemether powder, as a single compound, using different temperatures (125-150 °C), times (10-90 min) and environmental conditions (neutral, KMnO(4) and zinc), resulted in the formation of 17 degradants. The vast majority of degradants seen during the long-term and accelerated ICH stability study of the drug product, were also observed here. The obtained stress results allowed the calculation of the overall average relative response factor (RRF) of ß-artemether degradants, i.e. 21.2, whereas the individual RRF values of the 9 most prominent selected degradants ranged from 4.9 to 42.4. Finally, Ames tests were performed on ß-artemether as well as a representative stressed sample mixture, experimentally assessing their mutagenic properties. Both were found to be negative, suggesting no mutagenicity problems of the degradants at high concentrations. Our general approach and specific results solve the developmental quality issue of mass balance during stability studies and the related genotoxicity concerns of the key antimalarial drug ß-artemether and its degradants.


Subject(s)
Antimalarials/analysis , Artemisinins/analysis , Drug Contamination , Hot Temperature , Models, Chemical , Antimalarials/toxicity , Artemether , Artemisinins/toxicity , Chromatography, High Pressure Liquid , Drug Stability , Drug Storage , Hydrogen-Ion Concentration , Mutagenicity Tests , Powders , Salmonella typhimurium/drug effects , Salmonella typhimurium/genetics , Spectrophotometry, Ultraviolet , Time Factors
6.
J Cardiothorac Vasc Anesth ; 26(4): 617-23, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22406042

ABSTRACT

OBJECTIVES: The EuroSCORE as a predictor for midterm survival after isolated aortic valve replacement (AVR) and combined AVR with coronary artery bypass graft (CABG) surgery was tested. Survival in different risk-stratification groups also was compared to the survival of the general Dutch population. DESIGN: A retrospective analysis of prospectively collected data. SETTING: A single-center study performed in an educational hospital. PARTICIPANTS: All patients (N = 1,652) who underwent AVR with (n = 711) or without (n = 941) CABG surgery from January 2004 through December 2009. INTERVENTIONS: AVR with or without CABG surgery. MEASUREMENTS AND MAIN RESULTS: Univariate Cox regression analyses were used to identify the additive and the logistic EuroSCOREs as independent predictors of midterm mortality. Kaplan-Meier survival curves were used to compare the survival of different patients' risk subgroups, based on both the additive and the logistic EuroSCOREs, with the normal Dutch population matched for age and sex. Both additive and logistic EuroSCOREs were significant predictors of midterm mortality after isolated AVR and AVR with CABG surgery. This was also true for the different risk-stratification groups. Except for survival after AVR with CABG surgery in the high-risk group based on the additive EuroSCORE, no difference was found between survival after surgery and survival of the age- and sex-matched normal population. CONCLUSIONS: Both EuroSCORE models can predict midterm survival after isolated AVR and combined AVR with CABG surgery. However, the EuroSCORE is not a predictor for midterm survival when comparing the patient groups with the general Dutch population matched for age and sex. Except for high-risk patients undergoing AVR with CABG surgery, other risk subgroups have similar midterm survival to that of their age- and sex-matched cohorts of the Dutch population.


Subject(s)
Aortic Valve/surgery , Coronary Artery Bypass/mortality , Heart Valve Prosthesis Implantation/mortality , Aged , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Proportional Hazards Models , Retrospective Studies
7.
J Cardiothorac Vasc Anesth ; 25(6): 1071-5, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21723746

ABSTRACT

OBJECTIVES: The purpose of this study was to evaluate the accuracy of the additive and logistic EuroSCOREs in predicting the operative mortality in patients undergoing aortic valve replacement (AVR) with or without coronary artery bypass graft (CABG) surgery. DESIGN: This was a retrospective analysis of prospectively collected data. SETTING: This was a single-center study performed in an educational hospital. PARTICIPANTS: All patients (n = 1,885) who underwent AVR with (n = 813) or without (n = 1,072) CABG surgery between 1998 and 2007. INTERVENTIONS: AVR with or without CABG surgery. MEASUREMENTS AND MAIN RESULTS: Variable life-adjusted display curves were constructed to compare the observed operative mortality with the additive and logistic EuroSCOREs. The receiver operating characteristics (ROC) curve was used to determine the discriminatory power of the additive and logistic EuroSCOREs. Calibration between the predicted and the observed operative mortality was checked by comparing the predicted probability of the mortality with the additive and logistic EuroSCORE. In the isolated AVR group, the additive EuroSCORE was 5.8% predicted mortality and the logistic EuroSCORE was 7.2%, whereas the observed operative mortality was 3.2%. In the AVR with CABG surgery group, the additive EuroSCORE was 7.2% and the logistic EuroSCORE was 8.8%, whereas the observed operative mortality was 5.3%. ROC curve analyses showed a high discriminatory power for both EuroSCOREs in both patient groups. CONCLUSIONS: Although the additive and the logistic EuroSCOREs had good discriminatory power, they were not able to predict the actual operative mortality accurately. Both EuroSCOREs overestimated the operative mortality, especially in low-risk patients.


Subject(s)
Aortic Valve/surgery , Cardiac Surgical Procedures/adverse effects , Heart Valve Prosthesis Implantation/adverse effects , Risk Assessment/methods , Aged , Area Under Curve , Cardiac Surgical Procedures/mortality , Confidence Intervals , Coronary Artery Bypass , Extracorporeal Circulation , Female , Heart Valve Prosthesis , Heart Valve Prosthesis Implantation/mortality , Humans , Logistic Models , Male , Middle Aged , Predictive Value of Tests , Quality-Adjusted Life Years , ROC Curve , Risk Factors , Sample Size , Sternotomy
8.
Bioorg Med Chem ; 18(18): 6934-52, 2010 Sep 15.
Article in English | MEDLINE | ID: mdl-20667740

ABSTRACT

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-{5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin-4-yl-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-{2-[4-(4-methyl-piperazin-1-yl)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells.


Subject(s)
Furans/chemistry , Imidazoles/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/chemistry , Animals , Binding Sites , Computer Simulation , Female , Humans , Mice , Mutation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Structure-Activity Relationship
9.
J Med Chem ; 53(15): 5639-55, 2010 Aug 12.
Article in English | MEDLINE | ID: mdl-20597484

ABSTRACT

Mutated BRAF serine/threonine kinase is implicated in several types of cancer, with particularly high frequency in melanoma and colorectal carcinoma. We recently reported on the development of BRAF inhibitors based on a tripartite A-B-C system featuring an imidazo[4,5]pyridin-2-one group hinge binder. Here we present the design, synthesis, and optimization of a new series of inhibitors with a different A-B-C system that has been modified by the introduction of a range of novel hinge binders (A ring). The optimization of the hinge binding moiety has enabled the development of compounds with low nanomolar potencies in both BRAF inhibition and cellular assays. These compounds display optimal pharmacokinetic properties that warrant further in vivo investigations.


Subject(s)
Antineoplastic Agents/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazines/chemical synthesis , Pyridines/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Benzenesulfonates/chemistry , Biological Availability , Crystallography, X-Ray , Female , Humans , Hydrogen Bonding , Imidazoles/chemistry , Mice , Mice, Inbred BALB C , Models, Molecular , Neoplasm Transplantation , Niacinamide/analogs & derivatives , Phenylurea Compounds , Protein Binding , Proto-Oncogene Proteins B-raf/chemistry , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Sorafenib , Structure-Activity Relationship , Transplantation, Heterologous
10.
Dalton Trans ; 39(27): 6198-216, 2010 Jul 21.
Article in English | MEDLINE | ID: mdl-20520882

ABSTRACT

The synthesis and catalytic properties of ditopic mono-pincer-mono-porphyrin complexes were investigated. The statistical Adler condensation reaction of 3,5-bis(methoxymethyl)-4-bromo-benzaldehyde, p-tolylaldehyde, and pyrrole, furnished an AB(3)-type tetraphenylporphyrin, containing three meso-p-tolyl groups and one meso-3,5-bis(methoxymethyl)-4-bromophenyl group. This material was converted into the ditopic ligand [2H(Br)], which comprises one porphyrin site and an NCN-pincer type ligand moiety. In order to metalate this compound in a stepwise, site-selective manner, two distinct synthetic routes were followed. Route A relies on the introduction of a metal in the porphyrin cavity followed by pincer metalation and a reversal of this order is employed for route B. For the hetero-bimetallic pincer-porphyrin target compounds, route A invariably proved to be the highest yielding alternative, giving pincer-porphyrin hybrids of general formula [M(1)(M(2)X)] (M(1) = 2H, Mg, Co, Ni, Zn; M(2) = Pd, Br; X = Cl, Br). (195)Pt NMR spectroscopy revealed that the porphyrin metal has a modest influence on the electron density on the NCN-pincer Pt site. When the analogous cationic Pd complexes were used as Lewis acid catalysts for the double Michael addition between methyl vinyl ketone and ethyl alpha-cyanoacetate, it was noted that the catalytic activity did not depend on the central metal for M(1) = 2H, Ni, and Zn. However, when Mg occupied the porphyrin cavity, the rate of the reaction increased by a factor of six. Although a rate enhancement was observed when catalysis was conducted with a mixture of the two constituents of [Mg(PdOH(2))]BF(4) (i.e. MgTTP and [PdOH(2)(NCN)]BF(4)) this could not fully account for the rate enhancement. We believe that the rationale for this behaviour is dual, consisting of "cooperative dual catalysis" and supramolecular aggregation of two or more catalyst-substrate complexes.


Subject(s)
Coordination Complexes/chemistry , Palladium/chemistry , Porphyrins/chemistry , Benzaldehydes/chemistry , Catalysis , Coordination Complexes/chemical synthesis , Crystallography, X-Ray , Ligands , Molecular Conformation , Pyrroles/chemistry
11.
J Med Chem ; 53(7): 2741-56, 2010 Apr 08.
Article in English | MEDLINE | ID: mdl-20199087

ABSTRACT

We describe the design, synthesis, and optimization of a series of new inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF), a kinase whose mutant form (V600E) is implicated in several types of cancer, with a particularly high frequency in melanoma. Our previously described inhibitors with a tripartite A-B-C system (where A is a hinge binding pyrido[4,5-b]imidazolone system, B is an aryl spacer group, and C is a heteroaromatic group) were potent against purified (V600E)BRAF in vitro but were less potent in accompanying cellular assays. Substitution of different aromatic heterocycles for the phenyl based C-ring is evaluated herein as a potential means of improving the cellular potencies of these inhibitors. Substituted pyrazoles, particularly 3-tert-butyl-1-aryl-1H-pyrazoles, increase the cellular potencies without detrimental effects on the potency on isolated (V600E)BRAF. Thus, compounds have been synthesized that inhibit, with low nanomolar concentrations, (V600E)BRAF, its downstream signaling in cells [as measured by the reduction of the phosphorylation of extracellular regulated kinase (ERK)], and the proliferation of mutant BRAF-dependent cells. Concomitant benefits are good oral bioavailability and high plasma concentrations in vivo.


Subject(s)
Drug Design , Oncogene Proteins v-raf/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Sarcoma Viruses, Murine/enzymology , Sequence Homology , Animals , Cell Line, Tumor , Female , Humans , Inhibitory Concentration 50 , Mice , Models, Molecular , Molecular Conformation , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins B-raf/chemistry , Proto-Oncogene Proteins B-raf/metabolism , Structure-Activity Relationship
12.
J Org Chem ; 75(5): 1534-49, 2010 Mar 05.
Article in English | MEDLINE | ID: mdl-20112982

ABSTRACT

Several heteromultimetallic pincer-porphyrin hybrids have been prepared in excellent yields by stepwise metalation of a general precursor, [2H(Br(NCN))(4)], which was designed in such a way so as to guarantee selectivity for either the porphyrin or pincer sites during the metalation steps. First, a metal was introduced in the porphyrin cavity using a metal(II) salt, followed by metalation of the pincer units through oxidative addition to an appropriate metal(0) complex. The resulting multimetallic complexes show an appreciable amount of intramolecular communication between the meso-pincer metal groups and the central metalloporphyrin component. This was manifested in changes of the optical and ligand-binding properties of the metalloporphyrin part upon reactions at the peripheral pincer sites.


Subject(s)
Metalloporphyrins/chemical synthesis , Metals/chemistry , Catalysis , Chimera , Crystallography, X-Ray , Electrochemistry , Electronics , Ligands , Metalloporphyrins/chemistry , Molecular Structure , Oxidation-Reduction
13.
J Med Chem ; 53(5): 1964-78, 2010 Mar 11.
Article in English | MEDLINE | ID: mdl-20148563

ABSTRACT

We recently reported on the development of a novel series of BRAF inhibitors based on a tripartite A-B-C system characterized by a para-substituted central aromatic core connected to an imidazo[4,5]pyridin-2-one scaffold and a substituted urea linker. Here, we present a new series of BRAF inhibitors in which the central phenyl ring connects to the hinge binder and substrate pocket of BRAF with a meta-substitution pattern. The optimization of this new scaffold led to the development of low-nanomolar inhibitors that permits the use of a wider range of linkers and terminal C rings while enhancing the selectivity for the BRAF enzyme in comparison to the para series.


Subject(s)
Imidazoles/chemistry , Imidazoles/pharmacology , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyridones/chemistry , Pyridones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Imidazoles/chemical synthesis , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/metabolism , Pyridones/chemical synthesis , Structure-Activity Relationship
14.
J Med Chem ; 52(13): 3881-91, 2009 Jul 09.
Article in English | MEDLINE | ID: mdl-19473026

ABSTRACT

BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number of substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogenic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC(50) of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.


Subject(s)
Antineoplastic Agents/chemistry , Phenols/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyridines/chemistry , Allosteric Site , Antineoplastic Agents/pharmacology , Inhibitory Concentration 50 , Melanoma/drug therapy , Mutation, Missense , Phenols/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Pyridines/pharmacology , Structure-Activity Relationship
15.
J Med Chem ; 52(8): 2255-64, 2009 Apr 23.
Article in English | MEDLINE | ID: mdl-19323560

ABSTRACT

BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50-70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas.


Subject(s)
Antineoplastic Agents/chemical synthesis , Imidazoles/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyridines/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , In Vitro Techniques , Melanoma, Experimental/metabolism , Mice , Mice, Nude , Microsomes, Liver/metabolism , Mutation , Neoplasm Transplantation , Proto-Oncogene Proteins B-raf/genetics , Pyridines/pharmacokinetics , Pyridines/pharmacology , Structure-Activity Relationship , Transplantation, Heterologous
16.
Angew Chem Int Ed Engl ; 47(39): 7396-421, 2008.
Article in English | MEDLINE | ID: mdl-18726980

ABSTRACT

The coordination chemistry of porphyrins has traditionally involved the ability of the porphyrin's tetrapyrrolic core to accommodate metal ions of varying charges and sizes, and on the organometallic chemistry of the resulting metalloporphyrins. However, the organometallic chemistry of porphyrins is not necessarily restricted to the metal bound in the porphyrin core, but can also be extended to the porphyrin periphery, be it through direct metalation of the porphyrin macrocycle at the meso or beta position, or by attachment to or merger of the porphyrin skeleton with ligands, followed by metalation. This Review focuses on the synthetic strategies used for porphyrins with peripheral metal-carbon bonds. The exciting results that have been produced underscore the importance and future potential of this field.


Subject(s)
Organometallic Compounds/chemistry , Porphyrins/chemical synthesis , Biomimetic Materials/chemical synthesis , Biomimetic Materials/chemistry , Models, Molecular , Photochemistry , Porphyrins/chemistry , Vitamin B 12/chemistry
17.
J Am Chem Soc ; 130(8): 2485-92, 2008 Feb 27.
Article in English | MEDLINE | ID: mdl-18247606

ABSTRACT

The photosynthetic apparatus of green sulfur bacteria, the chlorosome, is generally considered as a highly efficient natural light-harvesting system. The efficient exciton transport through chlorosomes toward the reaction centers originates from self-assembly of the bacteriochlorophyll molecules. The aim of the present work is to realize a long exciton diffusion length in an artificial light-harvesting system using the concept of self-assembled natural chlorosomal chromophores. The ability to transport excitons is studied for porphyrin derivatives with different tendencies to form molecular stacks by self-assembly. A porphyrin derivative denoted as ZnOP, containing methoxymethyl substituents ({meso-tetrakis[3,5-bis(methoxymethyl)phenyl]porphyrinato}zinc(II)) is found to form self-assembled stacks, in contrast to a derivative with tert-butyl substituents, ZnBuP ({meso-tetrakis[3,5-bis(tert-butyl)phenyl]porphyrinato}zinc(II)). Exciton transport and dissociation in a bilayer of these porphyrin derivatives and TiO2 are studied using the time-resolved microwave conductivity (TRMC) method. For ZnOP layers it is found that excitons undergo diffusive motion between the self-assembled stacks, with the exciton diffusion length being as long as 15 +/- 1 nm, which is comparable to that in natural chlorosomes. For ZnBuP a considerably shorter exciton diffusion length of 3 +/- 1 nm is found. Combining these exciton diffusion lengths with exciton lifetimes of 160 ps for ZnOP and 74 ps for ZnBuP yields exciton diffusion coefficients equal to 1.4 x 10(-6) m2/s and 1 x 10(-7) m2/s, respectively. The larger exciton diffusion coefficient for ZnOP originates from a strong excitonic coupling for interstack energy transfer. The findings show that energy transfer is strongly affected by the molecular organization. The efficient interstack energy transfer shows promising prospects for application of such self-assembled porphyrins in optoelectronics.


Subject(s)
Porphyrins/chemistry , Crystallography, X-Ray , Models, Molecular , Molecular Structure , Optics and Photonics , Organometallic Compounds/chemistry , Particle Size , Photochemistry , Porphyrins/chemical synthesis , Zinc/chemistry
18.
Chem Asian J ; 2(7): 889-903, 2007 Jul 02.
Article in English | MEDLINE | ID: mdl-17546581

ABSTRACT

A series of meso-tetrakis-(ERE donor) zinc(II) porphyrins nZn (ERE donor = 4-R-3,5-bis[(E)-methyl]phenyl; 1Zn: E = NMe2, R = Br; 2Zn: E = NMe2, R = H; 3Zn: E = OMe, R = Br; 4Zn: E = OMe, R = H) have been synthesized in excellent yields. As a result of the combination of a Lewis acidic site and eight Lewis basic sites within one molecule, monomeric molecules of nZn self-assemble to form one-dimensional porphyrin polymers [nZn](infinity) in the solid state, as confirmed for 1Zn and 3Zn by X-ray crystallography. The coordination environment around the zinc(II) ions in these polymers is octahedral. They are ligated by four equatorial nitrogen atoms of the porphyrin and two apical E atoms (E = N, O) provided by the EBrE donor groups of adjacent nZn molecules. Complexes 2Zn and 4Zn did not form single crystals, but solid-state UV/Vis analysis points to the formation of similar structures. Solution UV/Vis and 1H NMR spectroscopy indicated that interactions between 1Zn and 2Zn monomers in the polymers are stronger than between 3Zn and 4Zn monomers. Interestingly, they also revealed that the presence of a neighboring bromine atom in the EBrE donor groups has a considerable influence on the coordination properties of the benzylic N or O atoms. The zinc(II) ions of the porphyrins most likely adopt only hexacoordination in the solid state, owing to the unique predisposition of Lewis acidic and basic sites in the nZn molecules. Several parameters of the aggregates, for example, the interplanar separation between porphyrins and the zinc-zinc distances, change as a function of the coordinating E groups. The high degree of modularity in their synthesis makes these zinc(II) porphyrins an interesting new entry in noncovalent multiporphyrin assemblies.


Subject(s)
Metalloporphyrins/chemistry , Polymers/chemistry , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Molecular Structure , Spectrophotometry, Ultraviolet
19.
Dalton Trans ; (13): 1273-6, 2007 Apr 07.
Article in English | MEDLINE | ID: mdl-17372641

ABSTRACT

The potential of "click" 1,2,3-triazoles to act as mono-dentate ligands in late transition metal complexes is explored relative to other commonly-used Lewis bases and it is shown that their coordination strength, determined by their 1- and 4-substituents, is easily tunable.

20.
Org Lett ; 6(18): 3023-6, 2004 Sep 02.
Article in English | MEDLINE | ID: mdl-15330578

ABSTRACT

[reaction: see text] Starting from tetrakis(3,5-bis(bromomethyl)phenyl)porphyrin, pincer-porphyrin hybrid molecules (tetrakis(ECE-pincer)porphyrin; E = N, P, S) based on a tetraphenylporphyrin skeleton have been prepared in high yields. These multi-ligand site compounds could be selectively metalated at their peripheries, which was shown by X-ray crystallography.

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