Efforts towards the synthesis of AB, EF and IJ subunits of Adriatoxin

Clem-Publication,       Research-Summary,    Ph.D Research Poster

Adriatoxin was isolated from the digestive glands of mussels Mytilus galloprovincialis by Cimminiello and co-workers in 1997. A closely related toxin, yessotoxin (YTX) has exhibited potent neurotoxic action on cultured cerebellar neurons and has induced a two fold increase in cytosolic calcium. YTX displays potent cytotoxic activities against human tumor cell lines, inducing caspase activation and apoptotic changes.

Structurally adriatoxin consists of 10 fused ether rings, 24 stereocenters, 5 methyl groups of which 4 of them are at the angular positions, and a challenging 7-6-8-tricyclic fused ether ring system (i.e., the E,F,G, rings) with the pyranyl ring having methyl groups that are in a 1,3-diaxial orientation.

As a result of the interesting biological activity that adriatoxin possesses, its scarcity from the natural source, and its structural complexity, our research group became interested in its synthesis. Although no total synthesis of YTX or its analogues has been reported to date, several approaches to its synthesis have been reported. Described herein are our approaches that harness glycal-epoxide rearrangements for the synthesis of the AB, EF and the IJ ring systems of adriatoxin and the attempted couplings of these subunits.1

1. Angew. Chem. Int. Ed. 2008, 47, 8055-8058.

 

Design and synthesis of new (iso-PDAs) for material and optical applications

Clem-Rik-paper

Monodisperse, cross-conjugated (iso-PDA) oligomers ranging from monomer to pentadecamer, have been synthesized by using a palladium-catalyzed cross-coupling protocol. Structural characteristics elucidated by X-ray crystallographic analysis demonstrate a non-planar backbone conformation for the oligomers due to the steric interactions between alkylidene phenyl groups. The electronic absorption spectra of the oligomers show a  slight red-shift of the maximum absorption wavelength as the chain length increases from dimer to pentadecamer, a trend that has saturated by the stage of nonamer.  Fluorescence spectroscopy confirms that the pendent phenyl groups present on the oligomer framework enhance emission, and the relative emission intensity consistently increases as a function of chain length n. The molecular third-order nonlinearities γ, for this oligomer series have been measured via differential optical Kerr effect (DOKE) detection and show a superlinear increase as a function of the oligomer chain length n. Molecular modeling and spectroscopic studies suggests that the iso-PDA oligomers (n>7) adopt a coiled, helical conformation in solution.1

1. Chem. Eur. J. 2005, 11, 321-329

Industrial Accomplishments

  • Fully synthesized and characterization of quinazolinone hit compounds as inhibitors of PARP-1, poly(ADP-ribose)polymerase exhibiting ~60-80 nM activity.
  • Fully synthesized and characterization of korormicin derivatives which has an inhibitory activity towards the growth of marine Gram-negative bacteria.
  • Fully synthesized and characterization of hundreds of novel hit compounds of phenyl-indeno-pyrimidin derivatives as optimized adenosine A2A/A1 receptor antagonists targeting the treatment of Parkinson’s disease (a collaborative CRO with Janssen Pharmaceuticals, Inc.).
  • Team leader in design, synthesis, purification, and identification of new small molecule libraries, scaffolds, building blocks, templates, chemical arrays and new chemical targets for infectious, neurodegenerative and metabolic diseases, pain, inflammation as well as oncology for the various programs underway at Pharma.
  • Involved in the synthesis and building of proprietary ChemKits and ChemCores as drug like ligands in the target areas of G-protein coupled receptors (GPCR), Kinase, and Ion channel based research.