Hematologic spread of carcinoma results in incurable metastasis; yet, the basic characteristics and travel mechanisms of cancer cells in the bloodstream are unknown. We have established a fluid phase biopsy approach that identifies circulating tumor cells (CTCs) without using surface protein-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. This “HD-CTC” assay finds >5 HD-CTCs/mL of blood in 80% of patients with metastatic prostate cancer (n=20), in 70% of patients with metastatic breast cancer (n=30), in 50% of patients with metastatic pancreatic cancer (n=18), and in 0% of normal controls (n=15). Additionally, it finds HD-CTC clusters ranging from 2 HDCTCs to greater than 30 HD-CTCs in the majority of these cancer patients. This initial validation of an enrichment-free assay demonstrates our ability to identify significant numbers of HD-CTCs in a majority of patients with prostate, breast and pancreatic cancers.

In an effort to seek novel agents targeting prostatespecific membrane antigen (PSMA), 16 ligands (L1−L16) with structural modifications in S1′ binding pocket were synthesized and evaluated for PSMA inhibition. (S)-3-(Carboxyformamido)-2-(3-(carboxymethyl)ureido)propanoic acids proved to be potent PSMA ligands with K i values ranging from 0.08 nM to 8.98 nM, which are in the range of or are higher in potency compared to previously published urea-based ligands. Computational docking was performed to study the binding mode of the two most potent ligands discovered. FITC-conjugated L14 could selectively stain PSMA + LNCaP cells over PSMA − PC3 cells. IRDye800CW conjugated L16 can effectively image tumors in a murine xenograft model of prostate cancer.

Chemical exchange saturation transfer (CEST) is a novel MRI contrast mechanism that is well suited for imaging, however, existing small molecule CEST agents suffer from low sensitivity. We have developed salicylic acid conjugated dendrimers as a versatile, high performance nanoplatform. In particular, we have prepared nanocarriers based on generation 5-poly(amidoamine) (PAMAM) dendrimers with salicylic acid covalently attached to their surface. The resulting conjugates produce strong CEST contrast 9.4 ppm from water with the proton exchange tunable from ~1000 s−1 to ~4500 s−1 making these dendrimers well suited for sensitive detection. Furthermore, we demonstrate that these conjugates can be used for monitoring convection enhanced delivery into U87 glioblastoma bearing mice, with the contrast produced by these nanoparticles persisting for over 1.5 h and distributed over ~50% of the tumors. Our results demonstrate that SA modified dendrimers present a promising new nanoplatform for medical applications.

More than water: Chemical exchange saturation transfer (CEST) contrast agents have used water bound to lanthanides as a source of highly shifted exchangeable proton frequencies. Compounds with the 2‐hydroxybenzoic acid scaffold were investigated as a source of highly shifted protons for CEST MRI contrasting.

Abstract1,2,4-Triazole anion has been identified as an active acyl transfer catalyst suitable for the aminolysis and transesterification of esters.Neutral nucleophiles (Figure 1), such as 4-dialkylaminopyridines (1), 1 N-alkylimidazoles (2), 2 phosphines (3), 3 imidazolylidene carbenes (4), 4 1,2-diamines (5), 5 and the recently introduced bicyclic amidines (6) and isothioureas (7), 6 have proved to be effective acyl transfer catalysts. As such, they have found a variety of applications in organic synthesis. 7 Their chiral derivatives have demonstrated considerable utility in catalyzing enantioselective transformations. 8 By contrast, the potential of anionic nucleophiles in acyl transfer catalysis remains much less explored.In the course of our studies on enantioselective acyl transfer catalysis we became interested in achieving catalytic acylation of amines using easily accessible achiral acyl donors. 9 Carboxylic esters would be especially attractive in this regard, since their uncatalyzed reaction with amines is typically very slow at ambient temperature. However, the aforementioned neutral Lewis base catalysts, 7 which successfully promote acylations with carboxylic anhydrides (1-3, 6 and 7) or acyl chlorides (5), can attack only highly activated esters. Imidazolylidene carbenes 4, which have gained popularity as transesterification catalysts, 4 have also proved to be ineffective in promoting ester aminolysis. 10 Recently, Mioskowski et al. reported that a variety of unactivated esters undergo efficient aminolysis under solvent-free conditions in the presence of TBD 8 (Figure 2), which was proposed to act as a bifunctional Lewis base catalyst. 11 Its catalytic activity, however, is only moderate, requiring a high catalyst loading (30 mol%). E-mail: birman@wustl.edu. We considered the possibility of catalyzing ester aminolysis with anionic nucleophiles, which might be expected a priori to be more nucleophilic than their neutral counterparts, and therefore better able to attack the ester group. Although the anions of protic nucleophiles 9-12 have been reported in the literature to promote this reaction, their catalytic activities were usually rather modest. 12 NIH Public AccessIn an effort to identify more active anionic acyl transfer catalysts potentially suitable for asymmetric catalyst design, we tested the aforementioned 9-12 and several other commercially available protic nucleophiles (8, 13-21) for their ability to promote the reaction of phenyl acetate with isopropylamine in the presence of stoichiometric amounts of DBU (Table 1). For comparison, we also included DMAP 1, a powerful aprotic Lewis base acylation catalyst. Most compounds tested showed only negligible effect. Among the previously reported catalysts, only catechol and cyanide anions effected significant rate acceleration (entries 6 and 7). The most remarkable results were obtained in the azole series (entries 11-16). 1,2,4-Triazole 18 displayed by far the greatest activity among all the nucleophiles tested. Diminished activity was also foun...

Safe imaging agents able to render the expression and distribution of cancer receptors, enzymes or other biomarkers would facilitate clinical screening of the disease. Here, we show that diamagnetic dextran particles coordinated to a urea-based targeting ligand for prostate-specific membrane antigen (PSMA) enable targeted magnetic resonance imaging (MRI) of the PSMA receptor. In a xenograft model of prostate cancer, micromolar concentrations of the dextran –ligand probe provided sufficient signal to specifically detect PSMA-expressing tumours via chemical exchange saturation transfer MRI. The dextran-based probe could be detected via the contrast originating from dextran hydroxyl protons, thereby avoiding the need of chemical substitution for radioactive or metallic labelling. Because dextrans are currently used clinically, dextran-based contrast agents may help extend receptor-targeted imaging to clinical MRI.

N,O-aminals, molecules bearing a geminally N,O-substituted (stereogenic) carbon center, have been recently recognized as an important class of building blocks in organic synthesis. As direct precursors of imines and iminium ions, N,O-aminals were converted through asymmetric organocatalysis or metal catalysis to diverse enantiomerically enriched compounds including N-heterocycles. Furthermore, cyclic N,O-hemiaminals acted as acyclic amino aldehyde surrogates, which were transformed to enantioenriched products otherwise challenging to access. Finally, cyclic N,O-aminals were formed in situ as key intermediates in asymmetric catalysis. In this review, we introduce a wide array of catalytic asymmetric protocols involving the use of four distinct types of N,O-aminals as starting materials or key intermediates.

A series of intra-molecular hydrogen bonded imidazoles and related heterocyclic compounds were screened for their N–H chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) contrast properties. Of the compounds, imidazole-4,5-dicarboxamides (I45DCs) were found to provide the strongest contrast, with the contrast produced at a large chemical shift from water (7.8 ppm) and strongly dependent on pH. We have tested several probes based on this scaffold, and demonstrated that these probes could be applied for in vivo detection of kidney pH after intravenous administration.