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Herein, we report the development of an 18 F-labeled, activity-based small-molecule probe targeting the cancer-associated serine hydrolase NCEH1. We undertook a focused medicinal chemistry campaign to simultaneously preserve potent and specific NCEH1 labeling in live cells and animals, while permitting facile 18 F radionuclide incorporation required for PET imaging. The resulting molecule, [18 F]JW199, labels active NCEH1 in live cells at nanomolar concentrations and greater than 1000-fold selectivity relative to other serine hydrolases. [18 F]JW199 displays rapid, NCEH1-dependent accumulation in mouse tissues. Finally, we demonstrate that [18 F]JW199 labels aggressive cancer tumor cells in vivo, which uncovered localized NCEH1 activity at the leading edge of triple-negative breast cancer tumors, suggesting roles for NCEH1 in tumor aggressiveness and metastasis.

This study serves as a proof of concept for multimodal oxygen imaging in developing an algorithm to make fluorine 18 misonidazole PET more comparable with quantitative electron paramagnetic resonan...

The measurement of extracellular pH (pHe) has significant clinical value for pathological diagnoses and for monitoring the effects of pH-altering therapies. One of the major problems of measuring pHe with a relaxation-based MRI contrast agent is that the longitudinal relaxivity depends on both pH and the concentration of the agent, requiring the use of a second pH-unresponsive agent to measure the concentration. Here we tested the feasibility of measuring pH with a relaxation-based dendritic MRI contrast agent in a concentration-independent manner at clinically relevant field strengths. The transverse and longitudinal relaxation times in solutions of the contrast agent (GdDOTA-4AmP)44-G5, a G5–PAMAM dendrimer-based MRI contrast agent in water, were measured at 3 T and 7 T magnetic field strengths as a function of pH. At 3 T, longitudinal relaxivity (r1) increased from 7.91 to 9.65 mM−1 s−1 (on a per Gd3+ basis) on changing pH from 8.84 to 6.35. At 7 T, r1 relaxivity showed pH response, albeit at lower mean values; transverse relaxivity (r2) remained independent of pH and magnetic field strengths. The longitudinal relaxivity of (GdDOTA-4AmP)44-G5 exhibited a strong and reversible pH dependence. The ratio of relaxation rates R2/R1 also showed a linear relationship in a pH-responsive manner, and this pH response was independent of the absolute concentration of (GdDOTA-4AmP)44-G5 agent. Importantly, the nanoprobe (GdDOTA-4AmP)44-G5 shows pH response in the range commonly found in the microenvironment of solid tumors. Copyright © 2015 John Wiley & Sons, Ltd.

3-[18F]fluoro-4-aminopyridine, [18F]3F4AP, is a radiofluorinated analog of the FDA-approved drug for multiple sclerosis 4-aminopyridine (4AP). This compound is currently under investigation as a PET tracer for demyelination. We recently described a novel chemical reaction to produce metafluorinated pyridines consisting of direct fluorination of a pyridine N-oxide and the utilization of this reaction for the radiochemical synthesis of [18F]3F4AP. In this article, we demonstrate how to produce this tracer using an automated synthesizer and an in-house made flow hydrogenation reactor. We also show the standard quality control procedures performed before releasing the radiotracer for preclinical animal imaging studies. This semi-automated procedure may serve as the basis for future production of [18F]3F4AP for clinical studies.

In a low-resource setting, an ideal disease diagnostic modality is an eye visualization assay that can be performed in minutes by untrained personnel. This paper reports the development of a self-catalytic colorimetric assay to detect the existence of cervical cancer cells by naked eye. The assay consists of a target specific initiator/catalyst, an acid self-catalytic system, and a pH indicator solution. By taking the advantage that trace amount of nucleus staining molecule, hemalum, can function as the initiator, a stained cervical cancer cell with an enlarged nucleus can initiate the self-catalytic reaction in a defined reaction condition to produce a significant amount of acid, which leads to a color change of a pH indicator solution, thereby indicating the presence of the cancer cell. Amplification of at least a trillion fold was achieved within 1.5 min. Due to the minimum engagement of instruments, simplicity and low cost, the assay is a potential tool in clinical to function as a “yes/no” check to facilitate quick decisions for cervical cancer screening. By alternating the method whereby the initiator is associated with the target, the assay can be expanded to screen and detect protein or nucleic acid based biomarkers related to other epidemic diseases in the resource-limited settings.

Aim: The authors have investigated the usefulness of in vivo chemical exchange saturation transfer MRI for detecting gliomas using a dual-modality imaging contrast agent. Materials & methods: A paramagnetic chemical exchange saturation transfer MRI contrast agent, Eu-1,4,7,10-tetraazacclododecane-1,4,7,10-tetraacetic acid-Gly4 and a fluorescent agent, DyLight® 680, were conjugated to a generation 5 polyamidoamine dendrimer to create the dual-modality, nano-sized imaging contrast agent. Results: The agent was detected with in vivo chemical exchange saturation transfer MRI in an U87 glioma model. These results were validated using in vivo and ex vivo fluorescence imaging. Conclusion: This study demonstrated the merits of using a nano-sized imaging contrast agent for detecting gliomas and using a dual-modality agent for detecting gliomas at different spatial scales. Original submitted 9 January 2012; Revised submitted 18 April 2012; Published online 14 August 2012

Inhibitors of histone deacetylases (HDACs) are a promising class of anticancer agents that effect gene regulation. To know the interaction of aliphatic cap groups with HDACs, cyclic tetrapeptide and bicyclic peptide disulfide hybrids were synthesized without aromatic ring in their macrocyclic framework. Benzene ring of l -Phe in chlamydocin was replaced with several aliphatic amino acids and also a fused bicyclic tetrapeptide was synthesized by ring closing metathesis using Grubb’s first generation catalyst. The inhibitory activities of the cyclic peptides against histone deacetylase enzymes were evaluated, which demonstrated most of them are interesting candidates as anticancer agents.

A water-soluble l-lysine dendrimer (6) with links to porphyrins and a fullerene was synthesized, in which the dendrimer surface was modified with carboxylate groups. The aqueous solution of 6 showed the Soret band characteristic of the aggregated porphyrins in the UV−vis spectra; however, this aggregate was dissociated by the addition of 2-hydroxypropyl-β-cyclodextrin (10 wt % in H2O). TEM and AFM showed the formation of submicron-scale particles of 6. TEM showed the spherical particles of 6 with almost uniform size (100−110 nm) in the presence of the cyclodextrin. AFM showed the oval particles of 6 in the absence of the cyclodextrin. DLS measurement indicated that cyclodextrin dissociated the aggregated structure of 6 in H2O. Thus, a large number of porphyrins and fullerenes were successfully accumulated with a narrow size distribution via the particle formation of the amphiphilic dendrimer.

[60]-Fullerene functionalized amino acids with 4–6 methylene spacers from α-carbon to the nitrogen atom of fulleropyrolidine and corresponding multifullerene peptides have been synthesized.

Using copper (II) ion as a model pollutant, we report a new bioremediation concept, which involves the use of green algae Chlamydomonas reinhardtii to efficiently collect copper ions from the solution, followed by encapsulating copper loaded algae with silica, thus reducing the bioavailability of copper ions in the solution. Specifically, the potential of Chlamydomonas reinhardtii as an active copper (II) absorbent was demonstrated by quantifying and characterizing the copper uptake rate, capacity, efficacy, as well as copper retention from C. reinhardtii. Subsequently, a method of encrusting copper loaded C. reinhardtii with silica was developed, taking the advantage that the presences of high abundant polysaccharides and glycoproteins on the cell walls, as well as the presence of (3-amino-propyl) trimethoxysilane (APS) can function as nucleation center for silicification process of tetramethyl orthosilicate (TMOS). Both fluorescence imaging and scanning electron microscope (SEM) imaging confirmed the silica encrustation. It is expected that silica encrustation of algae has the potential for in situ remediation of various contaminants in a wide range of environments while providing long-term stabilization and diminishing the bioavailability of the contaminants.

The naturally occurring cyclic tetrapeptide, chlamydocin, originally isolated from fungus Diheterospora chlamydosphoria, consists of α-aminoisobutyric acid, l-phenylalanine, d-proline and an unusual amino acid (S)-2-amino-8-((S)-oxiran-2-yl)-8-oxooctanoic acid (Aoe) and inhibits the histone deacetylases (HDACs), a class of regulatory enzymes. The epoxyketone moiety of Aoe is the key functional group for inhibition. The cyclic tetrapeptide scaffold is supposed to play important role for effective binding to the surface of enzymes. In place of the epoxyketone group, hydroxamic acid and sulfhydryl group have been applied to design inhibitor ligands to zinc atom in catalytic site of HDACs. In the research for more potent HDAC inhibitors, we replaced the epoxyketone moiety of Aoe with different functional groups and synthesized a series of chlamydocin analogs as HDAC inhibitors. Among the functional groups, methoxymethylketone moiety showed as potent inhibition as the hydroxamic acid. On the contrary, we confirmed that borate, trifruoromethylketone, and 2-aminoanilide are almost inactive in HDAC inhibition.

Introduction Enantiomerically pure aliphatic amino acids having easily modifiable functional groups at the end of the side chain on α-carbon atom are highly interesting synthetic targets as the terminal functional groups can be changed to the required groups which provide a series of non-poteinogenic amino acids [1]. As the double bond is a masked functional group and is stable to most acidic and basic reaction conditions, the classical reactivity of alkenes towards addition, oxidation, etc., can be used for the side chain modification. So it is worthy to synthesize α-amino acids containing side chains with a terminal double bond, 2-amino-(n-1)-alkenoic acids (Aens). As a precursor, it can be easily converted to various amino acids having different side chain functionality. In fact several methods are available for the synthesis of specific ω-unsaturated α-amino acids [2,3]. Here we report a convenient method, for the synthesis of Boc-2-amino-(n-1)-alkenoic acids (Boc-Aen-OH, n = 5-9) from commercially available reagents, diethyl Boc-aminomalonate and ω-bromoalkenes. We also explored the possibility of their use in the synthesis of some new zinc ligands for chlamydocin type cyclic tetrapeptide scaffold in order to develop histone deacetylase inhibitors as anti-cancer agents with optimized pharmacokinetic properties.

A series of chlamydocin analogs with various carbonyl functionalities were designed and synthesized as histone deacetylase (HDAC) inhibitors. Chlamydocin is a cyclic tetrapeptide containing an epoxyketone surrogate in the side chain which makes it irreversible inhibitor of HDACs, whereas apicidins are a class of cyclic tetrapeptides that contain an ethylketone moiety as zinc ligand. We replaced the epoxyketone moiety of chlamydocin with several ketones and aldehyde to synthesize potent reversible and selective HDAC inhibitors. The inhibitory activity of the cyclic tetrapeptides against histone deacetylase enzymes were evaluated and the result showed most of them are potent inhibitors. Some of them have remarkable selectivity among the HDACs.