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The formation and structure of 2,2‘-bipyridine (22BPY) and 4,4‘-bipyridine (44BPY) monolayers on Au(111) substrate have been studied as a function of the substrate potential. At high potentials, both molecules adsorb onto the substrate and stand vertically with their nitrogen atoms facing the Au(111). The vertically standing molecules stack, like rolls of coins, into polymer-like chains which pack closely in parallel to form ordered monolayers. Decreasing the potential to a critical value, the 22BPY chains become randomly oriented via a reversible order−disorder phase transition. The phase transition, as revealed by scanning tunneling microscopy, is driven by a potential dependent attractive force between the chains. The attractive force is believed to be a substrate-mediated effective force which arises as an adsorbed 22BPY perturbs its surrounding local surface potential and thus the nearby molecules. This hypothesis is supported by a quantitative investigation of the local surface potential using a self-consistent density functional method. In contrast to 22BPY, the 44BPY chains dissolve instead of becoming randomly oriented at low potentials. This behavior may be due to that 44BPY is not as strongly adsorbed on the surface as 22BPY because it has only one nitrogen facing the surface.

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A series of 1-H-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure-activity-relationship study illustrates that the incorporation of a pyrimidine-fused heterocycle at position 4 of the pyrazole is critical for FLT3 and CDK inhibition. Compound 50 (FN-1501), which possesses potent inhibitory activities against FLT3, CDK2, CDK4, and CDK6 with IC values in the nanomolar range, shows antiproliferative activities against MV4-11 cells (IC: 0.008 μM), which correlates with the suppression of retinoblastoma phosphorylation, FLT3, ERK, AKT, and STAT5 and the onset of apoptosis. Acute-toxicity studies in mice show that compound 50 (LD: 186 mg/kg) is safer than AT7519 (32 mg/kg). In MV4-11 xenografts in a nude-mouse model, compound 50 can induce tumor regression at the dose of 15 mg/kg, which is more efficient than cytarabine (50 mg/kg). Taken together, these results demonstrate the potential of this unique compound for further development into a drug applied in acute-myeloid-leukemia (AML) therapeutics.

Assessment of myocardial viability is deemed necessary to aid in clinical decision making whether to recommend revascularization therapy for patients with myocardial infarction (MI). Dianthraquinones such as hypericin (Hyp) selectively accumulate in necrotic myocardium, but were unsuitable for early imaging after administration to assess myocardial viability. Since dianthraquinones can be composed by coupling two molecules of monomeric anthraquinone and the active center can be found by splitting chemical structure, we propose that monomeric anthraquinones may be effective functional groups for necrosis targetability. In this study, eight radioiodinated monomeric anthraquinones were evaluated as novel necrosis avid agents (NAAs) for imaging of necrotic myocardium. All 131I-anthraquinones showed high affinity to necrotic tissues and 131I-rhein emerged as the most promising compound. Infarcts were visualized on SPECT/CT images at 6 h after injection of 131I-rhein, which was earlier than that with 131I-Hyp. Moreover, 131I-rhein showed satisfactory heart-to-blood, heart-to-liver and heart-to-lung ratios for obtaining images of good diagnostic quality. 131I-rhein was a more promising “hot spot imaging” tracer for earlier visualization of necrotic myocardium than 131I-Hyp, which supported further development of radiopharmaceuticals based on rhein for SPECT/CT (123I and 99mTc) or PET/CT imaging (18F and 124I) of myocardial necrosis.

ABSTRACT:Myocardial infarction (MI) leads to substantial morbidity and mortality around the world.Accurate assessment of myocardial viability is essential to assist therapies and improve patient outcomes. 131 I-hypericin dicarboxylic acid ( 131 I-HDA) was synthesized and evaluated as a potential diagnostic agent for earlier assessment of myocardium viability compared to its preceding counterpart 131 I-hypericin ( 131 I-Hyp) with strong hydrophobic property, long plasma half-life and high uptake in mononuclear phagocyte system (MPS). Herein, HDA was synthesized and characterized, and self-aggregation constant K α was analyzed by spectrophotometry. Plasma half-life was determined in healthy rats by γ-counting. 131 I-HDA and 131 I-Hyp were prepared with iodogen as oxidant. In vitro necrosis avidity of 131 I-HDA and 131 I-Hyp was evaluated in necrotic cells induced by hyperthermia. Biodistribution was determined in rat models of induced necrosis using γ-counting, autoradiography, and histopathology. Earlier imaging of necrotic myocardium to assess myocardial viability was performed in rat models of reperfused myocardium infarction using single photon emission computed tomography/computed tomography (SPECT/CT). As a result, the self-aggregation

A rapid and accurate identification of necrotic myocardium is of great importance for diagnosis, risk stratification, clinical decision-making, and prognosis evaluation of myocardial infarction. Here, we explored technetium-99m labeled rhein derivatives for rapid imaging of the necrotic myocardium. Three hydrazinonicotinic acid-linker-rhein (HYNIC-linker-rhein) derivatives were synthesized, and then, these synthetic compounds were labeled with technetium-99m using ethylenediaminediacetic acid (EDDA) and tricine as coligands [Tc(EDDA)-HYNIC-linker-rhein]. The necrosis avidity of the three Tc-labeled rhein derivatives was tested in a mouse model of ethanol-induced muscular necrosis by gamma counting, histochemical staining, and autoradiography. A lead tracer for visualization of necrotic myocardium was assessed by single photon emission computed tomography/computed tomography (SPECT/CT) imaging in a rat model with reperfused myocardial infarction. The necrosis avidity mechanism of the tracer was explored by DNA binding studies in vitro and blocking experiments in vivo. Results showed that the uptake in necrotic muscles of the threeTc-compounds was higher than that in viable muscles (P < 0.001). Autoradiography and histochemical staining results were consistent with selective uptake of the radiotracer in the necrotic regions. Among the these tracers, Tc(EDDA)-HYNIC-ethylenediamine-rhein [Tc(EDDA)-HYNIC-2C-rhein] displayed the best distribution profiles for imaging. The necrotic myocardium lesions were clearly visualized by SPECT/CT using Tc(EDDA)-HYNIC-2C-rhein at 1 h after injection. The necrotic-to-viable myocardium and necrotic myocardium-to-blood uptake ratios ofTc(EDDA)-HYNIC-2C-rhein were 4.79 and 3.02 at 1 h after injection. DNA binding studies suggested HYNIC-linker-rhein bound to DNA through intercalation. The uptake of Tc(EDDA)-HYNIC-2C-rhein in necrotic muscle was significantly blocked by excessive unlabeled rhein, with 77.61% decline at 1 h after coinjection. These findings suggestedTc(EDDA)-HYNIC-2C-rhein emerged as a "hot spot" imaging probe that has a potential for rapid imaging of necrotic myocardium. The necrosis avidity mechanism of Tc(EDDA)-HYNIC-linker-rhein may be due to its interaction with exposed DNA in necrotic tissues.

Early and accurate assessment of therapeutic response to anticancer therapy plays an important role in determining treatment planning and patient management in clinic. Magnetic rseonance imaging (MRI) of necrosis that occurs after cancer therapies provides chances for that. Here, we reported three novel MRI contrast agents, GdL 1 , GdL 2 , and GdL 3 , by conjugating rhein with gadolinium 2-[4,7,10-tris(carboxymethyl)-1,4,7,10tetraazacyclododec-1-yl]acetic acid (Gd-DOTA) through different linkers. The T1 relaxivities of three probes (7.28, 7.35, and 8.03 mM −1 s −1 ) were found to be higher than that of Gd-DOTA (4.28 mM −1 s −1 ). Necrosis avidity of GdL 1 was evaluated on the rat models of reperfused liver infarction (RLI) by MRI, which showed an increase of T1-weighted contrast between necrotic and normal liver during 0.5−12 h. Besides, L 1 was also labeled with 64 Cu to assess its necrosis avidity on rat models of RLI and muscle necrosis (MN) by a γ-counter. The uptakes of 64 CuL 1 in necrotic liver and muscle were higher than those in normal liver and muscle (P < 0.05). Then, the ability of GdL 1 to assess therapeutic response was tested on rats bearing Walker 256 breast carcinoma injected with a vascular disrupting agent CA4P by MR imaging. The signal intensity of tumoral necrosis was strongly enhanced, and the contrast ratio between necrotic and viable tumor was 1.63 ± 0.11 at 3 h after administration of GdL 1 . Besides, exposed DNA in necrosis cells may be an important mechanism of three probes targeting to necrosis cells. In summary, GdL 1 may serve as a promising MRI contrast agent for accurate assessment of treatment response.