Mark E. Welker

Mark WelkerChemistry Department Chair
William L. Poteat Professor of Chemistry

B.S. Chemistry with Highest Honors, University of North Carolina at Chapel Hill (1981);
Ph.D., Florida State University (L.S. Liebeskind) (1985);
Postdoctoral Fellow (Exxon & NIH), University of California-Berkeley (K.P.C. Vollhardt) (1985-86).
Elected a Fellow in the American Association for the Advancement of Science (AAAS) 2008. Dreyfus Foundation Henry Dreyfus Teacher-Scholar Awardee (1994-99).
Program Officer, Division of Chemistry, Organic and Macromolecular Chemistry Program, National Science Foundation, 2001-2002 and 2005 (off site).
Associate Provost for Research 2003-2008, Associate Provost for Research and Faculty Affairs 2008-2010, Vice Provost 2010-2011, Interim Provost 2011-2012.

Office: Salem 207C / 15A
Phone: (336) 758-5758
Email: welker@wfu.edu

Window on Wake Forest Research Article
Biographical Sketch

Welker Research Group 2014

Back Row: Pamela Lundin, Ron Nelson, Partha Choudhury, Jason Guo, Nuwan Meegalla, Emily Wright, Lee Mendenhall, Mark Welker
Front Row: Ria Mandan, Angela Broadnax, Sapna Pathak

Welker Research Group Ice Bucket Challenge

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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.

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 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.

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Recent Publications

(75) Syntheses of 2-Silicon Substituted 1,3-Dienes.  Partha Choudhury, Christopher Junker, Ramakrishna Pidaparthi, and Mark E. Welker, Journal of Organometallic Chemistry,2014754, 88-93; http://dx.doi.org/10.1016/j.jorganchem.2013.12.046.

(74) Recent Syntheses of PI3K/Akt/mTOR Signaling Pathway InhibitorsMark E. Welker* and George Kulik*, Invited Review article submitted to Bioorganic and Medicinal Chemistry, 2013, 21, 4063-4091; http://dx.doi.org/10.1016/j.bmc.2013.04.083. 

(73) Metal Catalyzed Tandem Diels-Alder/Hydrolysis Reactions of 2-Boron-Substituted 1,3-Dienes.  Liqiong Wang and Mark E. Welker, Journal of Organometallic Chemistry, 2013, 723, 15-18; http://dx.doi.org/10.1016/j.jorganchem.2012.10.023.

(72) Preparation and Diels-Alder/Cross Coupling Reactions of New 2-Boron-Substituted 1,3 –Dienes.  Liqiong Wang and Mark E. Welker, Journal of Organic Chemistry, 2012, 77, 8280-8286; http://dx.doi.org/10.1021/jo3016727.                                                                                          

(71) Synthesis and Characterization of a Novel Cancer-Targeted PI3 Kinase Inhibitor Prodrug.  Daniele Biaz, Tanya A. Pinder, Sazzad Hassan, Yelena Karpova, Freddie Salsbury, Mark E. Welker, and George Kulik.  Journal of Medicinal Chemistry, 2012, 55, 8038-8046; http://dx.doi.org/10.1021/jm300881a.  Selected as the cover paper for the November 26, 2012 issue of J. Med. Chem.; http://pubs.acs.org/action/showLargeCover?jcode=jmcmar&vol=55&issue=22

(70) Ruthenium Carbenes as Multi-Task Catalysts in Stereoselective Ene-Yne Metathesis/Diels-Alder and Ene-Yne Metathesis/Diels-Alder/Cross Coupling Multicomponent Reactions.  Christopher S. Junker and Mark E. Welker, Tetrahedron, 2012, 68, 5341-5345, http://dx.doi.org/10.1016/j.tet.2012.05.011.