Nafion-coated cadmium pentacyanonitrosylferrate-modified glassy carbon electrode for detection of dopamine in biological samples.

Introduction : Dopamine is one of the key neurotransmitters (NTs) in nature, which plays a crucial role in the mammalian central nervous system (CNS). Its selective determination in the biological fluids is an essential need in the field of biomedicine studies. Methods : In this work, an amperometric sensor was developed using Nafion-coated cadmium pentacyanonitrosylferrate (CdPCNF) modified glassy carbon (GC) electrode (Nafion|CdPCNF|GC electrode) as an electrocatalyst to detect dopamine (DA) in human serum samples. To develop this sensor, the surface of bare GC electrode was coated with the film of CdPCNF through an electropolymerization method and then the modified electrode was coated with Nafion to minimize interferences, especially those arising from the presence of anionic compounds. The electrocatalytic behavior of the modified electrodes was studied using the cyclic voltammetry and amperometry, and then the ability of the sensor for the determination of DA in synthetic and biological samples was investigated. Results : The modified electrode was showed a significant electrocatalytic activity for the oxidation of DA at pH 7.4. The limit of detection (LOD) was 0.7 µM and also no interference effects arose from ascorbic acid (AA), uric acid (UA) or the other biological NTs was observed in the DA detection using the modified Nafion|CdPCNF|GC electrode. Conclusion : In comparison with the bare electrode, the Nafion|CdPCNF|GC electrode could determine DA in the biological samples with adequate sensitivity and selectivity. Therefore, we propose that the modified electrode is utilizable as an amperometric DA sensor for the biological sample analysis.

Iran supports a great share of biodiversity and floristic endemism for Fritillaria spp. (Liliaceae): A review.

Iran supports a great share of exotic and/or endemic plant genera and species. The genus Fritillaria (Liliaceae) is a precious part of this botanical richness with 19 species, of which 10 are endemic to the country. However, signs are mounting that the country is truly at a crossroads when it comes to preservation of this national wealth. In this regard, an effective conservation strategy should thoroughly consider the classification of Fritillaria, as conservation practices are compromised by knowledge gaps in systematics and taxonomy. As published studies on Fritillaria in Iran have been sporadic and limited in scope, the aim of this review is to provide information necessary to help bridge these information gaps. Our objective is to facilitate increased understanding of the geographic, taxonomic, cytogenetic and phylogenetic status of Iranian Fritillaria, which is vital to meeting the goal of sustainable conservation of the genus in Iran and neighboring areas.

Multifunctional mitoxantrone-conjugated magnetic nanosystem for targeted therapy of folate receptor-overexpressing malignant cells.

BACKGROUND: Targeted delivery of anticancer chemotherapeutics such as mitoxantrone (MTX) can significantly intensify their cytotoxic effects selectively in solid tumors such as breast cancer. In the current study, folic acid (FA)-armed and MTX-conjugated magnetic nanoparticles (MNPs) were engineered for targeted eradication of folate receptor (FR)-positive cancerous cells. Polyethylene glycol (PEG), FA and MTX were covalently conjugated onto the MNPs to engineer the PEGylated FA-MTX-MNPs. The internalization studies were performed using fluorescein isothiocyanate (FITC)-labeled FA-decorated MNPs (FA-FITC-MNPs) in both FR-positive MCF-7 cells and FR-negative A549 cells by means of fluorescence microscopy and flow cytometry. The cellular and molecular impacts of FA-MTX-MNPs were examined using trypan blue cell viability and FITC-labeled annexin V apoptosis assays and 4',6-diamidino-2-phenylindole (DAPI) staining, DNA ladder and quantitative polymerase chain reaction (qPCR) assays. RESULTS: The FR-positive MCF-7 cells showed significant internalization of the FA-FITC-MNPs, but not the FR-negative A549 cells. The FR-positive cells treated with the PEGylated FA-MTX-MNPs exhibited the IC50 values of 3 µg/mL and 1.7 µg/mL, 24 h and 48 h post-treatment, respectively. DAPI staining and DNA ladder assays revealed significant condensation of nucleus and fragmentation of genomic DNA in the FR-positive MCF-7 cells treated with the PEGylated FA-MTX-MNPs as compared to the FR-negative A549 cells. The FITC-labeled annexin V assay confirmed emergence of late apoptosis (>80%) in the FR-positive MCF-7 cells treated with the PEGylated FA-MTX-MNPs, but not in the FR-negative A549 cells. The qPCR analysis confirmed profound cytotoxic impacts via alterations of apoptosis-related genes induced by MTX-FA-MNPs in MCF-7 cells, but not in the A549 cells. CONCLUSION: Our findings evince that the engineered PEGylated FA-MTX-MNPs can be specifically taken up by the FR-positive malignant cells and effectively demolish them through up-regulation of Bcl-2-associated X protein (Bax) and Caspase 9 and down-regulation of AKt. Hence, the engineered nanosystem is proposed for simultaneous targeted imaging and therapy of various cancers overexpressing FRs.

Synthesis of PCEC Copolymers with Controlled Molecular Weight Using Full Factorial Methodology.

PURPOSE: Polycaprolactone (PCL) is a biodegradable polyester and has attracted attention as a suitable carrier for development of controlled drug delivery due to its non-toxicity and biocompatibility. It has been reported that the biodegradability of PCL can be enhanced by copolymerization with PEG. Molecular weight (Mw) and CL block lengths optimization in a series of synthesized PCEC copolymers was the main purpose of this study. METHODS: The composition of copolymers was designed using full factorial methodology. Molecular weight of used PEG (4 levels) and weight ratio of epsilon-caprolactone/PEG (3 levels) were selected as independent variables. The PCEC copolymers were synthesized by ring opening polymerization. Formation of copolymers was confirmed by FT-IR spectroscopy as well as H-NMR. The Mn of PCEC copolymers was calculated from HNMR spectra. The thermal behavior of copolymers was characterized on differential scanning calorimeter. RESULTS: Molecular weight of twelve synthesized copolymers was ranged from 1782 to 9264. In order to evaluate the effect of selected variables on the copolymers composition and Mw, a mathematical model for each response parameter with p-value less than 0.001were obtained. Average percent error for prediction of total Mn of copolymers and Mn of CL blocks were 13.81% and 14.88% respectively. CONCLUSION: In conclusion, the proposed model is significantly valid due to obtained low percent error in Mn prediction of test sets.

Manual Liquid-Based Cytology: A Clinical Pilot Study of the VitroPrep™ Cytology Processing Kit.

OBJECTIVE: It was the aim of this study to assess the utility of the manual liquid-based cytology (LBC) product VitroPrep™ Cytology Processing Kit (ChemQ Bioscience LLC, Research Triangle Park, N.C., USA). STUDY DESIGN: This is a descriptive pilot study. Women underwent cervical sampling processed by the ThinPrep™ automated LBC system followed by cervical sampling for the VitroPrep manual system. The following criteria were assessed on a scale of 1-5 (1 = unsatisfactory, 2 = borderline, 3 = acceptable, 4 = good, 5 = excellent): monolayer cell adhesion, overall cellularity, background clarity, preservation of cellular morphology, red cell lysis, and elimination of mucus/debris. Cytological diagnosis was compared to results from ThinPrep samples. In addition, VitroPrep samples were taken prior to conization procedures and compared to pathology results. Descriptive statistics were performed. RESULTS: Forty-two of 47 women who underwent dual cytologic sampling had satisfactory samples. All scores were 3-5, with >90% graded 4-5. The VitroPrep diagnosis correlated with the ThinPrep diagnosis in 90% (38/42) of cases. All specimens obtained from 15 women prior to conization were satisfactory and correlated abnormal cytologic findings with cervical intraepithelial neoplasia 1-3 pathology. CONCLUSIONS: The VitroPrep Cytology Processing Kit was able to provide adequate specimens for evaluation and diagnosis. This low-cost processing kit may provide a useful alternative in settings where automated LBC systems may not be feasible.

Synthesis, characterization and in vitro anti-tumoral evaluation of Erlotinib-PCEC nanoparticles.

BACKGROUND: Development of a nanosized polymeric delivery system for erlotinib was the main objective of this research. MATERIALS AND METHODS: Poly caprolactone-polyethylene glycol-polycaprolactone (PCEC) copolymers with different compositions were synthesized via ring opening polymerization. Formation of triblock copolymers was confirmed by HNMR as well as FT-IR. Erlotinib loaded nanoparticles were prepared by means of synthesized copolymers with solvent displacement method. RESULTS: Physicochemical properties of obtained polymeric nanoparticles were dependent on composition of used copolymers. Size of particles was decreased with decreasing the PCL/PEG molar ratio in used copolymers. Encapsulation efficiency of prepared formulations was declined by decreasing their particle size. Drug release behavior from the prepared nanoparticles exhibited a sustained pattern without a burst release. From the release profiles, it can be found that erlotinib release rate from polymeric nanoparticles is decreased by increase of CL/PEG molar ratio of prepared block copolymers. Based on MTT assay results, cell growth inhibition of erlotinib has a dose and time dependent pattern. After 72 hours of exposure, the 50% inhibitory concentration (IC50) of erlotinib hydrochloride was appeared to be 14.8 µM. CONCLUSIONS: From the obtained results, it can be concluded that the prepared PCEC nanoparticles in this study might have the potential to be considered as delivery system for erlotinib.

Comparison of Cytotoxic Activity of L778123 as a Farnesyltranferase Inhibitor and Doxorubicin against A549 and HT-29 Cell Lines.

PURPOSE: Farnesyltransferase (FTase) is a zinc-dependent enzyme that adds a farnesyl group to the Ras proteins. L778, 123 is a potent peptidomimetic imidazole-containing FTase inhibitor. METHODS: L778123 was synthesized according to known methods and evaluated alone and in combination with doxorubicin against A549 (adenocarcinomic human alveolar basal epithelial cells) and HT29 (human colonic adenocarcinoma) cell lines by MTT assay. RESULTS: L778123 showed weak cytotoxic activity with IC50 of 100 and 125 for A549 and HT-29 cell lines, respectively. The combination of doxorubicin and L778123 can decrease IC50 of doxorubicin in both cell lines significantly. CONCLUSION: It can be concluded that L778, 123 can be a good agent for combination therapy.

Targeted fluoromagnetic nanoparticles for imaging of breast cancer mcf-7 cells.

PURPOSE: To achieve simultaneous imaging and therapy potentials, targeted fluoromagnetic nanoparticles were synthesized and examined in human breast cancer MCF-7 cells. METHODS: Fe3O4 nanoparticles (NPs) were synthesized through thermal decomposition of Fe(acac)3. Then, magnetic nanoparticles (MNPs) modified by dopamine-poly ethylene glycol (PEG)-NH2; finally, half equivalent fluorescein isothiocyanate (FITC) and half equivalent folic acid were conjugated to one equivalent of it. The presence of Fe3O4-DPA-PEG-FA/FITC in the folate receptor (FR) positive MCF-7 cells was determined via fluorescent microscopy to monitor the cellular interaction of MNPs. RESULTS: FT-IR spectra of final compound confirmed existence of fluorescein on folic acid grafted MNPs. The Fe3O4-DPA-PEG-FA/FITC NPs, which displayed a size rang about 30-35 nm using scanning electron microscopy (SEM) and transmission electron microscopy (TEM), were able to actively recognize the FR-positive MCF-7 cells, but not the FR-negative A549 cells. CONCLUSION: The uniform nano-sized Fe3O4-DPA-PEG-FA/FITC NPs displayed great potential as theranostics and can be used for targeted imaging of various tumors that overexpress FR.

Tamoxifen loaded folic acid armed PEGylated magnetic nanoparticles for targeted imaging and therapy of cancer.

Magnetic nanoparticles (MNPs) have been widely used as drug delivery nanosystems and contrast agent for imaging and detection. To engineer multifunctional nanomedicines for simultaneous imaging and therapy of cancer cells, in the current study, we synthesized tamoxifen (TMX) loaded folic acid (FA) armed MNPs to target the folate receptor (FR) positive cancer cells. To this end, Fe3O4 nanoparticles (NPs) were synthesized through thermal decomposition of Fe(acac)3. Polyethylene glycol (PEG) was treated with excess bromoacetyl chloride (BrAc) and then with 3-aminopropyltriethoxysilane (APS) to synthesize bromoacetyl-terminal polyethylene glycol silane (APS-PEG-BrAc). The latter complex was treated with protected ethylene diamine to form a bifunctional PEG compound containing triethoxysilane at one end and amino group at the other end (APS-PEG-NH2). The Fe3O4-APS-PEG-NH2 NPs were prepared through self-assembly of APS-PEG-NH2 on MNPs, while the amino groups at the end of Fe3O4-APS-PEG-NH2 were conjugated with folic acid (FA), then loaded with TMX (Fe3O4-APS-PEG-FA-TMX). The average size of "Fe3O4-APS-PEG-FA-TMX" NPs was approximately 40 nm. The engineered MNPs were further characterized and examined in the human breast cancer MCF-7 cells that express FR. The TMX loaded MNPs (with loading efficiency of 49.1%) showed sustained liberation of TMX molecules (with 90% release in 72 h). Fluorescence microcopy and flow cytometry analyses revealed substantial interaction of Fe3O4-APS-PEG-FA-TMX NPs with the FR-positive MCF-7 cells. Cytotoxicity analysis resulted in significant growth inhibition in MCF-7 cells treated with Fe3O4-APS-PEG-FA-TMX NPs. Based on these findings, the TMX-loaded FA-armed PEGylated MNPs as a novel multifunctional nanomedicine/theranostic for concurrent targeting, imaging and therapy of the FR-positive cancer cells.

Specific targeting of cancer cells by multifunctional mitoxantrone-conjugated magnetic nanoparticles.

We report on the synthesis of bifunctional mitoxantrone (MTX)-grafted magnetic nanoparticles (MNPs) modified by dopamine-polyethylene glycol-folic acid (DPA-PEG-FA) for targeted imaging and therapy of cancer. MNPs (~7-10 nm) were synthesized using the thermal decomposition reaction of Fe(acac)3. Bromoacetyl (BrAc) terminal polyethylene glycol dopamine (DPA-PEG-BrAc) was synthesized and treated with ethylene diamine to form bifunctional PEG moiety containing dopamine at one end and amino group at the other end (i.e. DPA-PEG-NH2). It was then reacted with Fe3O4 nanoparticles (NPs) to form Fe3O4-DPA-PEG-NH2 NPs. The activated folic acid (FA) was chemically coupled to Fe3O4-DPA-PEG-NH2, forming Fe3O4-DPA-PEG-FA. MTX was then conjugated to Fe3O4-DPA-PEG-FA, forming Fe3O4-DPA-PEG-FA-MTX. Physicochemical characteristics of the engineered MNPs were determined. The particle size analysis and electron microscopy showed an average size of ~35 nm for Fe3O4-DPA-PEG-FA-MTX NPs with superparamagnetic behavior. FT-IR spectrophotometry analysis confirmed the conjugation of FA and MTX onto the MNPs. Fluorescence microscopy, cytotoxicity assay and flow cytometry analysis revealed that the engineered Fe3O4-DPA-PEG-FA-MTX NPs were able to specifically bind to and significantly inhibit the folate receptor (FR)-positive MCF-7 cells, but not the FR-negative A549 cells. Based upon these findings, we suggest the Fe3O4-DPA-PEG-FA-MTX NPs as an effective multifunctional-targeted nanomedicine toward simultaneous imaging and therapy of FR-positive cancers.

Modified synthesis of erlotinib hydrochloride.

PURPOSE: An improved and economical method has been described for the synthesis of erlotinib hydrochloride, as a useful drug in treatment of non-small-cell lung cancer. METHOD: Erlotinib hydrochloride was synthesized in seven steps starting from 3, 4-dihydroxy benzoic acid. In this study, we were able to modify one of the key steps which involved the reduction of the 6-nitrobenzoic acid derivative to 6-aminobenzoic acid derivative. An inexpensive reagent such as ammonium formate was used as an in situ hydrogen donor in the presence of palladium/charcoal (Pd/C) instead of hydrogen gas at high pressure. RESULT: This proposed method proceeded with 92% yield at room temperature. Synthesis of erlotinib was completed in 7 steps with overall yield of 44%. CONCLUSION: From the results obtained it can be concluded that the modified method eliminated the potential danger associated with the use of hydrogen gas in the presence of flammable catalysts. It should be mentioned that the catalyst was recovered after the reaction and could be used again.

Synthesis, characterization, and in vitro evaluation of novel polymer-coated magnetic nanoparticles for controlled delivery of doxorubicin.

Poly (N-isopropylacrylamide-methyl methacrylic acid, PNIPAAm-MAA)-grafted magnetic nanoparticles were synthesized using silane-coated magnetic nanoparticles as a template for radical polymerization of N-isopropylacrylamide and methacrylic acid. Properties of these nanoparticles, such as size, drug-loading efficiency, and drug release kinetics, were evaluated in vitro for targeted and controlled drug delivery. The resulting nanoparticles had a diameter of 100 nm and a doxorubicin-loading efficiency of 75%, significantly higher doxorubicin release at 40°C compared with 37°C, and pH 5.8 compared with pH 7.4, demonstrating their temperature and pH sensitivity, respectively. In addition, the particles were characterized by X-ray powder diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, and vibrating sample magnetometry. In vitro cytotoxicity testing showed that the PNIPAAm-MAA-coated magnetic nanoparticles had no cytotoxicity and were biocompatible, indicating their potential for biomedical application.

Study of aldehyde oxidase-catalyzed metabolic pathway of phenanthridine using MCR-ALS method.

Evaluation of metabolic pathways is one of the challenging areas in biological and pharmaceutical sciences. Phenanthridine oxidation to phenanthridinone is used commonly to study aldehyde oxidase activity. This reaction could pass through phenanthridine N-oxide intermediate. In the present study, the application of multivariate curve resolution, optimized by alternating least squares (MCR-ALS) to investigate this metabolic pathway has been described. The results obtained from MCR-ALS analysis along with those obtained from the use of potassium ferrocyanide method indicated that phenanthridine is directly oxidized to phenanthridinone by rat liver aldehyde oxidase without passing through phenanthridine N-oxide intermediate. It was also found that the later compound is not metabolized by this enzyme.

Aptamer-based Nanosensors: Juglone as an Attached-Redox Molecule for Detection of Small Molecules.

INTRODUCTION: Among several biosensing approaches, electrochemical-based procedures have been described as one of the most common and useful methods for sensing because of their simplicity, sensitivity, accuracy, and low cost. The electroactive species, which called redox, play a main role in the electrochemical-based approaches. Among several redox molecules used for electrochemical experiments, ferrocene is one of the commonly used redox molecules. However, instability of ferrocenium ion in the chloride containing solutions appeared to be weakness of this redox molecule limiting its utilization. METHODS: In the current study, Juglone was attached (using EDC/NHS coupling method) to the 3'-amino-modified terminus of the immobilized specific aptamer of codeine, which was successfully used in a cyclic electrochemical voltammetry procedure. RESULTS: The cyclic voltammogram peak of aptamer-attached Juglone was observed in the potential range of +0.4 to +0.9 V and the fabricated aptamer-based sensor was used for detection of different concentrations of codeine in the phosphate buffer 0.1 M solution containing 2 M NaCl. CONCLUSION: Based on these findings, it can be suggested that the new aptamer-attached Juglone could be considered as an effective alternative redox molecule in particular with oligonucleotide-based sensing systems.

Simultaneous Determination of 6-Mercaptopurine and its Oxidative Metabolites in Synthetic Solutions and Human Plasma using Spectrophotometric Multivariate Calibration Methods.

INTRODUCTION: 6-Mercaptopurine (6MP) is an important chemotherapeutic drug in the conventional treatment of childhood acute lymphoblastic leukemia (ALL). It is catabolized to 6-thiouric acid (6TUA) through 8-hydroxo-6-mercaptopurine (8OH6MP) or 6-thioxanthine (6TX) intermediates. METHODS: High-performance liquid chromatography (HPLC) is usually used to determine the contents of therapeutic drugs, metabolites and other important biomedical analytes in biological samples. In the present study, the multivariate calibration methods, partial least squares (PLS-1) and principle component regression (PCR) have been developed and validated for the simultaneous determination of 6MP and its oxidative metabolites (6TUA, 8OH6MP and 6TX) without analyte separation in spiked human plasma. Mixtures of 6MP, 8-8OH6MP, 6TX and 6TUA have been resolved by PLS-1 and PCR to their UV spectra. RESULTS: Recoveries (%) obtained for 6MP, 8-8OH6MP, 6TX and 6TUA were 94.5-97.5, 96.6-103.3, 95.1-96.9 and 93.4-95.8, respectively, using PLS-1 and 96.7-101.3, 96.2-98.8, 95.8-103.3 and 94.3-106.1, respectively, using PCR. The NAS (Net analyte signal) concept was used to calculate multivariate analytical figures of merit such as limit of detection (LOD), selectivity and sensitivity. The limit of detections for 6MP, 8-8OH6MP, 6TX and 6TUA were calculated to be 0.734, 0.439, 0.797 and 0.482 µmol L-1, respectively, using PLS and 0.724, 0.418, 0783 and 0.535 µmol L-1, respectively, using PCR. HPLC was also applied as a validation method for simultaneous determination of these thiopurines in the synthetic solutions and human plasma. CONCLUSION: Combination of spectroscopic techniques and chemometric methods (PLS and PCR) has provided a simple but powerful method for simultaneous analysis of multicomponent mixtures.

Synthesis of Novel 1,4- Dihydropyridine Derivatives Bearing Biphenyl-2'-Tetrazole Substitution as Potential Dual Angiotensin II Receptors and Calcium Channel Blockers.

INTRODUCTION: We report the synthesis of novel 1,4-dihydropyridine derivatives containing biphenyl-2'-tetrazole moieties. We hypothesized that merging the key structural elements present in an AT1 receptor antagonist with key structural elements in 1,4-dihydropyridine calcium channel blockers would yield novel analogs with potential dual activity for both receptors. This strategy led to the design and synthesis of dialkyl 1,4-dihydro-2,6-dimethyl-4-[2-n-alkyl-1-[2΄-(1H-tetrazole-5-yl) biphenyl -4-yl] methyl] imidazole-4(or 5)-yl]- 3, 5-pyridinedicarboxylate analogs. METHODS: These compounds were obtained by two methods starting from biphenyltetrazolyl-4-(or 5)-imidazolecarboxaldehyde intermediates employing in classical Hantzsch condensation reaction. In the first method, triphenylmethyl protecting group of 4- or 5-carboxaldehyde intermediate was first removed in acidic media and then classical Hantzsch reaction was employed in order to obtain the final products. In the second method, without further deprotection process, protected 4- or 5-carboxaldehyde intermediate directly was used in Hantzsch reaction. RESULTS: The second method was more efficient than the first method since the deprotection and ring closure reaction occurs simultaneously in one pot. CONCLUSION: Eight novel dihydropridines analogs were synthesized using classic Hantzsch condensation reaction. Chemical structures of the compounds were characterized by (1)H NMR, infrared and mass spectroscopy.

A facile synthesis of novel pyrrolizidines under classical and ultrasonic conditions.

Novel pyrrolizidines (1) were synthesized from 1,3-dipolar cycloaddition of azomethine ylides and dipolarophiles (4). The reactions were highly diastereoselective and regioselective and were carried out under reflux and ultrasonic condition at room temperature. In general, milder conditions and moderate improvements in rates and reaction times were observed when ultrasonic condition was used. The products were obtained in high yields, and their structures were determined by (1)H and (13)C NMR spectral data and X-ray diffraction.

Potent 2'-aminoanilide inhibitors of cFMS as potential anti-inflammatory agents.

A series of 2'-aminoanilides have been identified which exhibit potent and selective inhibitory activity against the cFMS tyrosine kinase. Initial SAR studies within this series are described which examine aroyl and amino group substitutions, as well as the introduction of hydrophilic substituents on the benzene core. Compound 47 inhibits the isolated enzyme (IC(50)=0.027 microM) and blocks CSF-1-induced proliferation of bone marrow-derived macrophages (IC(50)=0.11 microM) and as such, serves as a lead candidate for further optimization studies.

2-Hydroxy-4,6-diamino-[1,3,5]triazines: a novel class of VEGF-R2 (KDR) tyrosine kinase inhibitors.

2-Hydroxy-4,6-diamino-[1,3,5]triazines are described which are a novel class of potent inhibitors of the VEGF-R2 (flk-1/KDR) tyrosine kinase. 4-(Benzothiazol-6-ylamino)-6-(benzyl-isopropyl-amino)-[1,3,5]triazin-2-ol (14d) exhibited low nanomolar potency in the in vitro enzyme inhibition assay (IC(50) = 18 nM) and submicromolar inhibitory activity in a KDR-induced MAP kinase autophosphorylation assay in HUVEC cells (IC(50) = 280 nM), and also demonstrated good in vitro selectivity against a panel of growth factor receptor tyrosine kinases. Further, 14d showed antiangiogenic activity in an aortic ring explant assay by blocking endothelial outgrowths in rat aortas with an IC(50) of 1 microM.