Prototype Nerve-Specific Near-Infrared Fluorophores

Nerve preservation is an important issue during most surgery because accidental transection or injury results in significant morbidity, including numbness, pain, weakness, or paralysis. Currently, nerves are still identified only by gross appearance and anatomical location during surgery, without intraoperative image guidance. Near-infrared (NIR) fluorescent light, in the wavelength range of 650-900 nm, has the potential to provide high-resolution, high-sensitivity, and real-time avoidance of nerve damage, but only if nerve-specific NIR fluorophores can be developed. In this study, we evaluated a series of Oxazine derivatives to highlight various peripheral nerve structures in small and large animals. Among the targeted fluorophores, Oxazine 4 has peak emission near into the NIR, which provided nerve-targeted signal in the brachial plexus and sciatic nerve for up to 12 h after a single intravenous injection. In addition, recurrent laryngeal nerves were successfully identified and highlighted in real time in swine, which could be preserved during the course of thyroid resection. Although optical properties of these agents are not yet optimal, chemical structure analysis provides a basis for improving these prototype nerve-specific NIR fluorophores even further

Asymmetric Total Synthesis of Congeners of Hydramycin, an Anthraquinone-Type Antitumor Agent

Hydramycin is an antitumor antibiotic isolated from Streptomyces violaceus. It is a pyranoanthraquinone-type antitumor agent that has shown broad-spectrum activity against a variety of human-derived cancer cell lines. Among tumors evaluated at the National Cancer Institute (lung, colon, melanoma, breast and prostate), GI50s were \u3c10−10 M in the NCI\u27s 60-cell-line panel. We embarked on the synthesis and evaluation of a simplified congener 2-(1-hydroxy-1-(oxiran-2-yl)ethyl)-4H-naphtho[2,3-h]chromene-4,7,12-trione(17), which would facilitate synthesis while retaining the potent activity. Hydramycin has two chiral centers, and our goal is to design and synthesize all the possible enantiomers (four in total) for the congener of hydramycin 17 in order to ascertain which of the enantiomers is responsible for the observed antitumor activity. The use of enantiospecific techniques such as the Sharpless epoxidation was initially tried to introduce the chiral centers at a later stage during the multi-step synthesis and obtain the required pure enantiomers. Due to some limitations observed with this technique and many other asymmetric epoxidation techniques which utilize very substrate-specific ligands, we then modified the synthetic scheme to use another procedure, the Sharpless asymmetric dihydroxylation in order to obtain two of the pure enantiomers of this congener of hydramycin. The other two enantiomers are selectively obtained using the Sharpless asymmetric dihydroxylation procedure via cyclic sulfate intermediates, followed by a modified irreversible Payne rearrangement procedure. These routes then allowed us to obtain separately all four stereoisomers, each having more than 90% ee as determined on chiral columns with HPLC. The four stereoisomers have been fully characterized and will then be tested separately to ascertain which of the isomers is responsible for the observed antitumor activity

Synthesis of Enantiomerically Pure Lignin Dimer Models for Catalytic Selectivity Studies

A series of highly enantioselective transformations, such as the Sharpless asymmetric epoxidation and Jacobsen hydrolytic kinetic resolution, were utilized to achieve the complete stereoselective synthesis of β-O-4 lignin dimer models containing the S, G, and H subunits with excellent <i>ee</i> (>99%) and moderate to high yields. This unprecedented synthetic method can be exploited for enzymatic, microbial, and chemical investigations into lignin’s degradation and depolymerization as related to its stereochemical constitution. Preliminary degradation studies using enantiopure Co­(salen) catalysts are also reported

Tailored Near-Infrared Contrast Agents for Image Guided Surgery

The success of near-infrared (NIR) fluorescence to be employed for intraoperative imaging relies on the ability to develop a highly stable, NIR fluorescent, nontoxic, biocompatible, and highly excreted compound that retains a reactive functionality for conjugation to a cancer-recognizing peptide. Herein, systematic modifications to previously detailed fluorophore ZW800-1 are explored. Specific modifications, including the isosteric replacement of the O atom of ZW800-1, include nucleophilic amine and sulfur species attached to the heptamethine core. These novel compounds have shown similar satisfactory results in biodistribution and clearance while also expressing increased stability in serum. Most importantly, all of the synthesized and evaluated compounds display a reactive functionality (either a free amino group or carboxylic acid moiety) for further bioconjugation. The results obtained from the newly prepared derivatives demonstrate that the central substitution with the studied linking agents retains the ultralow background in vivo performance of the fluorophores regardless of the total net charge