Transition-Metal Mediated Organic Synthesis/Synthetic Methods/Medicinal Chemistry/Chemical Cancer Biology
1) Synthesis and Tandem/Sequential Reactions of Main Group element( Boron and Silicon) Substituted 1,3-Dienes.
The Welker group has pursued the research area of metal-mediated Diels-Alder (DA) reactions for several years. NSF supported our first studies (CHE-9321454 & CHE-9726172) on how to use a transition-metal-substituted diene to affect exo- selective Diels-Alder reactions. This work showed that cobalt-substituted dienes could be used to reverse the normal endo-selectivity of Diels-Alder reactions and provide access to new cycloadduct stereoisomers in high yield and diastereoselectivity. Early in the current decade (CHE-0104083), we demonstrated conclusively that we could do both enantioselective and exo-selective Diels-Alder reactions using transition-metal-substituted dienes. In the last five years (CHE-0450722 and 0749759), we began to prepare some new main group element substituted dienes and we have just begun to tackle their catalytic Diels-Alder chemistry. We have now prepared both boron and silicon-substituted dienes and started to study their tandem reactions.
The primary question which drives most of our current work is: Can we find a way to prepare main group element substituted dienes which can be made to participate in catalytic, enantioselective, and exo selective Diels-Alder reactions? If the answer to this question is yes then we will have provided the organic chemistry community with easy access to highly substituted cyclohexenoid compounds with relative and absolute stereochemistries which were not easily available via classical Diels-Alder chemistry of endo selective dienes.
2) Synthesis and Characterization of Novel Prostate Cancer-Targeted PI3 Kinase Inhibitor Prodrugs.
The phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway is constitutively activated in a significant proportion of advanced prostate tumors, and is considered one of the key mechanisms supporting progression toward an androgen-independent status, for which no effective therapy is available. Recent data coming from clinical trials using the PI3K inhibitors, alone or in combination with other cytotoxic drugs, suggest that they might be a promising adjuvant tool to treat cancer with a constitutive activated PI3K/Akt pathway.
In order to target advanced prostate cancer with the constitutively activated PI3K/Akt pathway, we are synthesizing PI3 kinase inhibitors which can be linked to a peptide which is a substrate for Prostate-Specific Antigen (PSA) protease. We started this work by generating a prostate cancer-specific PI3K inhibitor by coupling the modified form of the LY294002 (HO-CH2-LY294002) (8) with the peptide Mu-LEHSSKLQL (11), which is a substrate for the Prostate-Specific Antigen (PSA) protease. The result is a water soluble and latent PI3K inhibitor prodrug-LY294002 in which activation depends on PSA cleavage. Prodrug-LY294002 does not inhibit PI3K in PSA-negative cells, whereas in prostate cancer cells that produce PSA it inhibits the PI3K/Akt pathway and induces apoptosis.
We have several other related synthetic projects underway where we are preparing analogs of know PI3 kinase inhibitors which can be linked to PSA cleavable peptides and hence will function as prodrugs for the treatment of prostate cancer.