Semiautomatic landmark-based two-dimensional-three-dimensional image fusion in living mice: correlation of near-infrared fluorescence imaging of Cy5.5-labeled antibodies with flat-panel volume computed tomography.

Connecting fluorescence signals with anatomic structures enhances our ability to monitor biologic processes in mice. Here, we present a semiautomated approach to correlate two-dimensional (2D) noninvasive near-infrared fluorescence (NIRF) imaging with three-dimensional (3D), high-resolution, flat-panel volume computed tomography (fpVCT). We developed an algorithm to colocalize fluorescence signals of NIRF-labeled antibodies directed against matriptase and urokinase plasminogen activator receptor (uPAR) to orthotopic carcinomas in mice visualized by fpVCT. For this purpose, mice were anesthetized and fixed on a multimodality animal bed containing fiducial markers filled with iodine-containing contrast agent and fluorescent dye. After intravenous administration of contrast agent and Cy5.5-labeled antibodies, NIRF and fpVCT images were obtained, without repositioning the mice. Binding of Cy5.5-labeled matriptase-specific antibody to pancreatic tumors and Cy5.5-labeled uPAR-specific antibody to mammary carcinomas was assessed by time-domain NIRF imaging measuring the location of fluorescence intensity and its lifetime. In summary, we developed a novel 2D-3D registration technique for image fusion with NIRF imaging and fpVCT to provide complementary information in tumor models on the in vivo association of functional information with anatomic structures. The combination of fpVCT with NIRF imaging will now allow targeted and effective monitoring of preclinical tumor therapies.

Enantioselective total syntheses of the Ipecacuanha alkaloid emetine, the Alangium alkaloid tubulosine and a novel benzoquinolizidine alkaloid by using a domino process.

The first enantioselective syntheses of the Ipecacuanha alkaloid emetine (1) and the Alangium alkaloid tubulosine (2) is described employing a domino Knoevenagel/hetero-Diels-Alder reaction and an enantioselective catalytic transfer hydrogenation of imines as key steps. Thus, hydrogenation of the imine 15 with the catalyst (R,R)-16 gives the tetrahydroisoquinoline 14 with 95 % ee which was transformed into the aldehyde (1S)-7. The three-component domino reaction of (1S)-7 with 6 and 8 led to 19, which in a second domino process was treated with K(2)CO(3) in methanol followed by a hydrogenation to give the benzoquinolizidine 4 together with the diastereomers 22 and 23 in a overall yield of 66 %. Further transformation of 4 with the amines 3 and 5 yielded enantiopure emetine (1) and tubulosine (2), respectively. In addition, starting from 19 the novel benzoquinolizidine alkaloid 34 was synthesised; this compound resembles the vallesiachotamine alkaloid dihydroantirhin 31, which has not been isolated so far but probably must also exist in nature.

Natural product hybrids as new leads for drug discovery.

Natural products play an important role in the development of drugs, especially for the treatment of infections and cancer, as well as immunosuppressive compounds. However, the number of natural products is limited, whereas millions of hybrids as combinations of parts of different natural products can be prepared. This new approach seems to be very promising in the development of leads for both medicinal and agrochemical applications, as the biological activity of several new hybrids exceeds that of the parent compounds. The advantage of this concept over a combinatorial chemistry approach is the high diversity and the inherent biological activity of the hybrids.