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A panel of five zinc-chelated aza-macrocycle ligands and their ability to catalyze the hydration of carbon dioxide to bicarbonate, H(2)O + CO(2) → H(+) + HCO(3)(–), was investigated using quantum-mechanical methods and stopped-flow experiments. The key intermediates in the reaction coordinate were optimized using the M06-2X density functional with aug-cc-pVTZ basis set. Activation energies for the first step in the catalytic cycle, nucleophilic CO(2) addition, were calculated from gas-phase optimized transition-state geometries. The computationally derived trend in activation energies was found to not correspond with the experimentally observed rates. However, activation energies for the second, bicarbonate release step, which were estimated using calculated bond dissociation energies, provided good agreement with the observed trend in rate constants. Thus, the joint theoretical and experimental results provide evidence that bicarbonate release, not CO(2) addition, may be the rate-limiting step in CO(2) hydration by zinc complexes of aza-macrocyclic ligands. pH-independent rate constants were found to increase with decreasing Lewis acidity of the ligand-Zn complex, and the trend in rate constants was correlated with molecular properties of the ligands. It is suggested that tuning catalytic efficiency through the first coordination shell of Zn(2+) ligands is predominantly a balance between increasing charge-donating character of the ligand and maintaining the catalytically relevant pK(a) below the operating pH.

PEGylated dendrimers are attractive for biological applications due to their tunable pharmacokinetics and ability to carry multiple copies of bioactive molecules. The rapid and efficient synthesis of a robust and biodegradable PEGylated dendrimer based on a polyester-polyamide hybrid core is described. The architecture is designed to avoid destructive side-reactions during dendrimer preparation while maintaining biodegradability. Therefore, a dendrimer functionalized with doxorubicin (Dox) was prepared from commercial starting materials in nine, high-yielding linear steps. Both the dendrimer and Doxil™ were evaluated in parallel using equimolar dosage in the treatment of C26 murine colon carcinoma, leading to statistically equivalent results with most mice tumor-free at the end of the sixty day experiment. The attractive features of this dendritic drug carrier are its simple synthesis, biodegradability, and versatility for application to a variety of drug payloads with high drug loadings.

One essential requirement for more sensitive gadolinium-based MRI contrast agents is to slow the molecular tumbling of the gadolinium(III) ion, which increases the gadolinium's relaxivity, or the ability to speed up the NMR relaxation of nearby water molecules. One route to this is through conjugation to high-molecular weight polymers such as dendrimers. In this work, amine functionalized TREN-bis(1,2-HOPO)-TAM-ethylamine and TREN-bis(1-Me-3,2-HOPO)-TAMethylamine ligands have been synthesized and attached to biocompatible 40 kDa esteramide (EA) and poly-L-lysine based (PLL) dendrimers capable of binding up to eight gadolinium complexes. These conjugates have T 1 relaxivities of up to 38.14 ± 0.02 mM -1 s -1 per gadolinium at 37 °C, corresponding to relaxivities of up to 228 mM -1 s -1 per dendrimer molecule. This relaxivity expressed on a "per Gd" basis is several times that of the small molecule complexes, and an order of magnitude higher than that of current commercial agents. Due to their high performance and low toxicity these macromolecules may constitute an attractive complement to currently available gadolinium(III) based contrast agents.In the last three decades, magnetic resonance imaging (MRI) has become one of the most prevalent medical imaging modalities used in clinical radiology, with over 27.5 million MRI's performed in 2007. Paramagnetic gadolinium(III) contrast agents are used to enhance signal in about a third of these scans. This is done through the gadolinium's ability to slow the relaxation of water molecules after disturbance by a magnetic field, a parameter known as relaxivity (r 1 ). Concern about gadolinium dosage and release has increased because of nephrogenic systemic fibrosis (NSF), an incurable thickening of tissue and skin seen in patients with late stage renal failure. This condition appears to arise from the tendency for free gadolinium ions to bind to hydroxyapatite in bone tissue and transport across cellular Supporting Information Available: All conjugation procedures, characterization, cytotoxicity and experimental details; This material is available free of charge via the Internet at http://pubs.acs.org. All current commercial contrast agents use octadentate poly(amino) carboxylate ligands as scaffolds to coordinate gadolinium and contain only one inner coordination water molecule (q = 1). Previous research in the Raymond laboratory has developed hexadentate oxygen donor chelators for gadolinium with similar stability to commercial poly(amino)carboxylate contrast agents by utilizing the oxophilicity of gadolinium. Containing either two 1-Me-3,2-hydroxypyridinonate (HOPO) or two 1,2-HOPO rings and an amine functionalized 2,3-dihydroxyterepthalamide (TAM) ring (Figures 1 and 2),2 -7 these tris(2-aminoethyl)amine (TREN)-capped ligands have at least two coordinated water molecules, with fast exchange rates, allowing a much higher theoretical relaxivity than the small molecule amine based chelators. These complexes exhibit high T 1 relaxivities (10-13 mM -1 s -1 ) and the...

Zinc(II) cyclen, a small molecule mimic of the enzyme carbonic anhydrase, was evaluated under rigorous conditions resembling those in an industrial carbon capture process: high pH (>12), nearly saturated salt concentrations (45% K2CO3) and elevated temperatures (100-130 °C). We found that the catalytic activity of zinc cyclen increased with increasing temperature and pH and was retained after exposure to a 45% w/w K2CO3 solution at 130 °C for 6 days. However, high bicarbonate concentrations markedly reduced the activity of the catalyst. Our results establish a benchmark level of stability and provide qualitative insights for the design of improved small-molecule carbon capture catalysts.

Magnetic resonance imaging (MRI) contrast agents represent a worldwide billion-dollar market annually. While T1 relaxivity enhancement contrast agents receive greater attention and a significantly larger market share, the commercial potential for T2 relaxivity enhancing contrast agents remains a viable diagnostic option due to their increased relaxivity at high field strengths. Improving the contrast and biocompatibility of T2 MRI probes may enable new diagnostic prospects for MRI. Paramagnetic lanthanides have the potential to decrease T1 and T2 proton relaxation times, but are not commercially used in MRI diagnostics as T2 agents. In this article, oxygen donor chelates (hydroxypyridinone, HOPO, and terephthalamide, TAM) of various lanthanides are demonstrated as biocompatible macromolecular dendrimer conjugates for the development of T2 MRI probes. These conjugates have relaxivities up to 374 mm−1s−1 per dendrimer, high bioavailability, and low in vitro toxicity.

Commercial gadolinium magnetic resonance imaging (MRI) contrast agents are limited by low relaxivity (r1) and coordination to only a single water molecule (q = 1). Consequently, gram quantities of these agents must be injected to obtain sufficient diagnostic contrast. In this study, MRI contrast agents for T1 and T2 relaxivity were synthesized using hydroxypyridinone (HOPO) and terephthalamide (TAM) chelators with mesityl and 1,4,7-triazacyclononane (TACN) capping moieties. When covalently conjugated to a highly biocompatible esteramide dendrimer, T2 relaxation rates up to 52 mM-1s-1 and T1 relaxation rates up to 31 mM-1s-1 per gadolinium are observed under clinically relevant conditions. These values are believed to be brought about by using a dendritic macromolecule to decrease the molecular tumbling time of the small molecule complexes. These agents also show high aqueous solubility and low toxicity in vitro. In this study we report six new compounds: three discrete complexes and three dendrimer conjugates.

Advances in clinical diagnostic instrumentation have enabled some imaging modalities to be run concurrently. For diagnostic purposes, multimodal imaging can allow for rapid location and accurate identification of a patient’s illness. The paramagnetic and near Infra-red (NIR) properties of Dy(III) and Yb(III) are interesting candidates for the development of bimodal NIR and magnetic resonance imaging (MRI) contrast agents. To enhance their intrinsic bimodal properties, these lanthanides were chelated using the hexadentate-all-oxygen-donor-ligand TREN-bis-(1-Me)-3,2-HOPO-TAM-NX (NX, where X = 1, 2 or 3) and subsequently conjugated to the esteramide dendrimer (EA), to improve bioavailability, solubility, and relaxivity. Of these new complexes synthesized and evaluated, DyN1-EA had the largest ionic T1 relaxivity, 7.60 mM−1 s−1, while YbN3-EA had the largest ionic T2 relaxivity with a NIR quantum yield of 0.17 % when evaluated in mouse serum. This is the first Yb(III) bimodal NIR/T2 MRI contrast agent of its kind evaluated.