Synthesis of diterpene alkaloids

Aconitine, atisine and garrya type diterpene alkaloids show remarkable biological activity and have a number of structural features in common. Due to their complex structure, there is a discrepancy between progress made lately in the identification, isolation and characterization of new members of this family, on one hand, and successful efforts towards their total synthesis, on the other;Our synthetic studies led us to develop a highly reproducible synthesis of adamantane-containing compounds via the corresponding bridgehead anions;Studies on the application of functionalized bridgehead radicals in natural product synthesis resulted in the development of a versatile, mild and highly tolerant procedure for the generation and trapping of bridgehead radicals. The facile and high yield carbon-carbon bond forming reaction mediated by Co(III) complexes under reductive conditions resulted in a very direct entry into the class of gibberellins, aconitine, atisine and spiramine natural compounds. Our thirteen step sequence to a very advanced intermediate in the atisine and spiramine series, possessing the entire carbon framework and suitable functional groups for further conversion into a variety of naturally occurring compounds in this series proceeds in high overall yield and is industrially attractive. A very advanced intermediate in the synthesis of aconitine alkaloids has been prepared using the same bridgehead radical generation methodology

Bridgehead intermediates in organic synthesis. A reproducible synthesis of adamantane-containing compounds

Compounds containing the adamantane subunit have long been of interest to chemists due to the rigid structure and well-defined substitution chemistry of adamantane.l The discovery of the potent antiviral activity of amantadine (1-aminoadamantane) and rimantadine (a-methyl-l-adamantylmethylamine) has stimulated interest in the synthesis of adamantane-containing compounds.2 The significant neuroprotective properties of the NMDA antagonist memantine3 (l-amino-3,5-dimethyladamantane) have also prompted interest in adamantane synthesi

Synthesis of diterpene alkaloids

Aconitine, atisine and garrya type diterpene alkaloids show remarkable biological activity and have a number of structural features in common. Due to their complex structure, there is a discrepancy between progress made lately in the identification, isolation and characterization of new members of this family, on one hand, and successful efforts towards their total synthesis, on the other;Our synthetic studies led us to develop a highly reproducible synthesis of adamantane-containing compounds via the corresponding bridgehead anions;Studies on the application of functionalized bridgehead radicals in natural product synthesis resulted in the development of a versatile, mild and highly tolerant procedure for the generation and trapping of bridgehead radicals. The facile and high yield carbon-carbon bond forming reaction mediated by Co(III) complexes under reductive conditions resulted in a very direct entry into the class of gibberellins, aconitine, atisine and spiramine natural compounds. Our thirteen step sequence to a very advanced intermediate in the atisine and spiramine series, possessing the entire carbon framework and suitable functional groups for further conversion into a variety of naturally occurring compounds in this series proceeds in high overall yield and is industrially attractive. A very advanced intermediate in the synthesis of aconitine alkaloids has been prepared using the same bridgehead radical generation methodology.</p

Bridgehead intermediates in organic synthesis. A reproducible synthesis of adamantane-containing compounds

Compounds containing the adamantane subunit have long been of interest to chemists due to the rigid structure and well-defined substitution chemistry of adamantane.l The discovery of the potent antiviral activity of amantadine (1-aminoadamantane) and rimantadine (a-methyl-l-adamantylmethylamine) has stimulated interest in the synthesis of adamantane-containing compounds.2 The significant neuroprotective properties of the NMDA antagonist memantine3 (l-amino-3,5-dimethyladamantane) have also prompted interest in adamantane synthesisReprinted (adapted) with permission from The Journal of Organic Chemistry, 59(4); 922-923. Doi: 10.1021/jo00083a038. Copyright 1994 American Chemical Society.</p

Molecular Imaging Agents Specific for the Annulus Fibrosus of the Intervertebral Disk

Low back pain is a prevalent medical condition that is difficult to diagnose and treat. Current imaging methods are unable to correlate pain reliably with spinal structures, and surgical removal of painful damaged or degenerating disks is technically challenging. A contrast agent specific for the intervertebral disk could assist in the detection, diagnosis, and surgical treatment of low back pain. The styryl pyridinium (FM) fluorophores were characterized and structure-activity relationships between chemical structure and in vivo uptake were established. Two novel FM fluorophores with improved optical properties for imaging the intervertebral disks were synthesized and evaluated in mice, rats, and pigs. After a single systemic injection, eight of eight FM fluorophores provided high-contrast imaging of the trigeminal ganglia, whereas six of eight provided high-contrast imaging of the dorsal root ganglia. Unexpectedly, three of eight FM fluorophores provided high-contrast imaging of annulus fibrosus tissue of the intervertebral disks, confirmed histologically. We present the first known contrast agent specific for the intervertebral disks and identify the chemical structural motif that mediates uptake. FM fluorophores could be used for image-guided surgery to assist in the removal of intervertebral disk and lay the foundation for derivatives for magnetic resonance imaging and positron emission tomography

Nerve-Highlighting Fluorescent Contrast Agents for Image-Guided Surgery

Nerve damage is the major morbidity of many surgeries, resulting in chronic pain, loss of function, or both. The sparing of nerves during surgical procedures is a vexing problem because surrounding tissue often obscures them. To date, systemically administered nerve-highlighting contrast agents that can be used for nerve-sparing image-guided surgery have not been reported. In the current study, physicochemical and optical properties of 4,4‘-[(2-methoxy-1,4-phenylene)di-(1 E )-2,1-ethenediyl]bis-benzenamine (BMB) and a newly synthesized, red-shifted derivative 4-[(1 E )-2-[4-[(1 E )-2-[4-aminophenyl]ethenyl]-3-methoxyphenyl]ethenyl]-benzonitrile (GE3082) were characterized in vitro and in vivo. Both agents crossed the blood-nerve barrier and blood-brain barrier and rendered myelinated nerves fluorescent after a single systemic injection. Although both BMB and GE3082 also exhibited significant uptake in white adipose tissue, GE3082 underwent a hypsochromic shift in adipose tissue that provided a means to eliminate the unwanted signal using hyperspectral deconvolution. Dose and kinetic studies were performed in mice to determine the optimal dose and drug-imaging interval. The results were confirmed in rat and pig, with the latter used to demonstrate, for the first time, simultaneous fluorescence imaging of blood vessels and nerves during surgery using the FLARE™ (Fluorescence-Assisted Resection and Exploration) imaging system. These results lay the foundation for the development of ideal nerve-highlighting fluorophores for image-guided surgery

Structure-Activity Relationship of Nerve-Highlighting Fluorophores

<div><p>Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR) absorption and emission, would be of immediate benefit to patients and surgeons. Currently, there are only three classes of small molecule organic fluorophores that penetrate the blood nerve barrier and bind to nerve tissue when administered systemically. Of these three classes, the distyrylbenzenes (DSBs) are particularly attractive for further study. Although not presently in the NIR range, DSB fluorophores highlight all nerve tissue in mice, rats, and pigs after intravenous administration. The purpose of the current study was to define the pharmacophore responsible for nerve-specific uptake and retention, which would enable future molecules to be optimized for NIR optical properties. Structural analogs of the DSB class of small molecules were synthesized using combinatorial solid phase synthesis and commercially available building blocks, which yielded more than 200 unique DSB fluorophores. The nerve-specific properties of all DSB analogs were quantified using an <i>ex vivo</i> nerve-specific fluorescence assay on pig and human sciatic nerve. Results were used to perform quantitative structure-activity relationship (QSAR) modeling and to define the nerve-specific pharmacophore. All DSB analogs with positive <i>ex vivo</i> fluorescence were tested for <i>in vivo</i> nerve specificity in mice to assess the effect of biodistribution and clearance on nerve fluorescence signal. Two new DSB fluorophores with the highest nerve to muscle ratio were tested in pigs to confirm scalability.</p> </div