We report the application of visible-light photoredox catalysis for the formation of C-C bonds between tertiary N-arylamines and nitroalkanes via an oxidative aza-Henry reaction. In the presence of 1 mol % Ir(ppy)(2)(dtbbpy)PF(6), efficient coupling of nitroalkanes with in situ-generated iminium ions provides the desired products in up to 96% yield. Mechanistic studies suggest that reductive quenching of the Ir(3+) excited state by the tertiary amine leads to the ammonium radical cation, with subsequent catalyst turnover (Ir(2+) --> Ir(3+)) likely effected by atmospheric oxygen.

Our previous studies into visible light-mediated aza-Henry reactions demonstrated that molecular oxygen played a vital role in catalyst turnover as well as the production of base to facilitate the nucleophilic addition of nitroalkanes. Herein, improved conditions for the generation of iminium ions from tetrahydroisoquinolines that allow for versatile nucleophilic trapping are reported. The new conditions provide access to a diverse range of functionality under mild, anaerobic reaction conditions as well as mechanistic insights into the photoredox cycle.

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C]MeDAS) was synthesized and evaluated as a novel radiotracer for in vivo microPET imaging of myelination. [ 11 C]MeDAS exhibits optimal lipophilicity for brain uptake with a logPoct value of 2.25. Both in vitro and ex vivo staining exhibited MeDAS accumulation in myelinated regions such as corpus callosum and striatum. The corpus callosum region visualized by MeDAS is much larger in the hypermyelinated Plp-Akt-DD mouse brain than in the wild-type mouse brain, a pattern that was also consistently observed in Black-Gold or MBP antibody staining. Ex vivo autoradiography demonstrated that [ 11 C]MeDAS readily entered the mouse brain and selectively labeled myelinated regions with high specificity. Biodistribution studies showed abundant initial brain uptake of [ 11 C]MeDAS with 2.56% injected dose/whole brain at 5 min post injection and prolonged retention in the brain with 1.37% injected dose/whole brain at 60 min post injection. An in vivo pharmacokinetic profile of [ 11 C]MeDAS was quantitatively analyzed through a microPET study in an Plp-Akt-DD hypermyelinated mouse model. MicroPET studies showed that [ 11 C]MeDAS exhibited a pharmacokinetic profile that readily correlates the radioactivity concentration to the level of myelination in the brain. These studies suggest that MeDAS is a sensitive myelin probe that provides a direct means to detect myelin changes in the brain. Thus, it can be used as a myelin-imaging marker to monitor myelin pathology in vivo.

5-fluorodeoxyuridine (5-FdU, floxuridine) is active against multiple cancers through the inhibition of thymidylate synthase, which consequently introduces uracil and 5-FU incorporation into the genome. Uracil DNA glycosylase (UDG) is one of the main enzymes responsible for the removal of uracil and 5-FU. However, how exactly UDG mediates cellular sensitivity to 5-FdU, and if so whether it is through its ability to remove uracil and 5-FU have not been well characterized. In this study, we report that UDG depletion led to incorporation of uracil and 5-FU in DNA following 5-FdU treatment and significantly enhanced 5-FdU's cytotoxicity in cancer cell lines. Co-treatment, but not post-treatment with thymidine prevented cell death of UDG depleted cells by 5-FdU, indicating that the enhanced cytotoxicity is due to the retention of uracil and 5-FU in genomic DNA in the absence of UDG. Furthermore, UDG depleted cells were arrested at late G1 and early S phase by 5-FdU, followed by accumulation of sub-G1 population indicating cell death. Mechanistically, 5-FdU dramatically reduced DNA replication speed in UDG depleted cells. UDG depletion also greatly enhanced DNA damage as shown by γH2AX foci formation. Notably, the increased γH2AX foci formation was not suppressed by caspase inhibitor treatment, suggesting that DNA damage precedes cell death induced by 5-FdU. Together, these data provide novel mechanistic insights into the roles of UDG in DNA replication, damage repair, and cell death in response to 5-FdU and suggest that UDG is a target for improving the anticancer effect of this agent.