Ernest (Ernie) Nolen
Contactenolen@colgate.edu (315) 228-7234
The world of biological molecules is an architectural wonder. As a chemist, I am interested in constructing molecules that mimic aspects of biology for pharmaceutical development. Bringing undergraduate students along in this creative endeavor is one of the most rewarding aspects of teaching at Colgate.
- BS, University of North Carolina, 1979
- PhD, Oregon State University, 1984
- CHEM 101 and 102: General Chemistry I and II
- CHEM 263 and 264: Organic Chemistry I and II
- CHEM 387: Structure Analysis, NMR
- CHEM 452: Metabolic Chemistry
- CHEM 461: Organic Reaction Mechanisms
- CHEM 464: Organic Synthesis
- CHEM 468: Medicinal Chemistry
- CORE 158: Molecules That Rock Your World
- Organic chemistry
- Postdoctoral research associate at University of Pennsylvania (1986) with Amos B. Smith
- Sabbatical research associate at Université Louis Pasteur (1991) with Jean-Marie Lehn and at the Complex Carbohydrate Research Center with Geert-Jan Boons of the University of Georgia
- Special volunteer at the the National Cancer Institute (1998 and 2006) with Joseph Barchi
- Special Volunteer at the National Institute of Diabetes and Digestive and Kidney Diseases (2014) with Kenneth Jacobson
Research grants (PI-only) from NIH-AREA 2017; NSF-MRI 2017; NSF-ARI R2 2010; NIH-AREA 2007; NSF-CCLI 2000; NSF-RUI 1994; ACS-PRF-Type B 2005 and 1993 and Type G 1989; NSF Chemical Instrumentation 1988; the Research Corporation 1987; as well as past summer support from Bristol-Myers/Squibb and Pfizer.
- Nolen, E. G.; *Hornik, E. S.; *Jeans, K. B.; *Zhong, W.; *LaPaglia, D. M. “Synthesis of C-linked α-Gal and α-GalNAc-1’-hydroxyalkanes by C2 functionality transfer” Tetrahedron Lett. 2021, doi.org/10.1016/j.tetlet.2021.
- Lopez-Cano, M.; Filgaria, I.; Nolen, E. G.; Cabre, G.; Hernando, J.; Tosh, D. K.; Jacobson, K. A.; Soler, C.; Ciruela, F. "Optical Control of Adenosine A3 Receptor Function in Psoriasis" Pharmacological Research 2021, 170, 105731. doi.org/10.1016/j.phrs.2021.105731.
- Nolen, E. G.; *Cao, Y. M.; *Lewis, B. D.; *Powers, M. H.; *Thompson, A. W.; *Bennett, J. M. "Stereoselective Synthesis of (4S,5S)-5-Vinyloxazolidin-2-
one-4-carboxylate as a β-Vinylserine Synthetic Equivalent by Vinyl Grignard Addition to an N-Tosyl Version of Garner's Aldehyde." Synlett 2021, 32, 601-604.
- Taura, J.; Nolen, E. G.; Cabre, G.; Hernando, J.; Squarcialupi, L.; Lopez-Cano, M.; Jacobson, K. A.; Fernandez-Duenas, V.; Ciruela, F. "Remote control of movement disorders using a photoactive adenosine A2Areceptor antagonist." J. Controlled Release 2018, 238, 135-142.
- Nolen, E. G.; Ezeh, V. C.; *Feeney, M. J. “Highly Stereoselective Synthesis of C-Vinyl Pyranosides via a Pd0-mediated Cycloetherification of 1-Acetoxy-2,3-dideoxy-oct-2-enitols” Carbohydrate Res. 2014, 396, 43–47
- Nolen, E. G.; *Li, L.; Waynant, K. V. “Synthesis of b-C-GlcNAc Ser from b-C-Glc Ser” J. Org. Chem. 2013, 78, 6798–6801
- Nolen, E.G.; *Donahue, L.A.; *Greaves, R.; *Daly, T.A.; *Calabrese, D.R. "Synthesis of a- and b-C-Glucopyranosyl Serines from a Common Intermediate," Org. Lett. 2008, 10, 4911-14.
- Nolen, E.G.; *Fedorka, C.J.; *Blicher, B. "Synthesis of orthogonally protected S,S-2,6-diaminopimelic acid via olefin cross-metathesis," Synthetic Comm. 2006, 36, 1707-1713.
- Nolen, E. G.; Kurish, A. J.;* Potter, J. M.;* Donahue, L. A.;* Orlando, M. D.* "Stereoselective Synthesis of a-C-Glucosyl Serine and Alanine via a Cross-Metathesis/Cyclization Strategy," Org. Lett. 2005, 7, 3383-3386.
- Nolen, E. G.; Kurish, A. J.;* Wong, K. A.;* Orlando, M. D.* "Short, stereoselective synthesis of C-glycosyl asparagines via an olefin cross-metathesis," Tetrahedron Letters. 2003, 44, 2449.
- Nolen, E. G.; Watts, M. M.;* Fowler, D. J.* "Synthesis of C-Linked Glucopyranosyl Serines via a Chiral Glycine Enolate Equivalent," Organic Letters. 2002, 4, 3963-65.
- Nolen, E. G.; Watts, M. M.;* Fowler, D. J.* "Stereoselective Synthesis of C-Linked Glucopyranosyl Serines," Journal of Undergraduate Chemistry Research. 2002, 2, 63-68.
- Smith III, A.B.; Nolen, E.G.; Shirai, R.; Blase, F.R.; Ohta, M.; Chida, N.; Hartz, R.A.; Fitch, D.M.; Clark, W.M.; Sprengeler, P.A.; "Tremorgenic Indole Alkaloids. 9. Asymmetric Construction of an Advanced F-G-H-Ring Lactone Precursor for the Synthesis of Penitrem D" J. Org. Chem. 1995, 60, 7837.
- Nolen, E.G.; Marsh, A.; *Gardinier, K.M.; Lehn, J.-M.; "Janus Molecules: Synthesis of Double-Headed Heterocycles Containing Two Identical Hydrogen Bonding Arrays" Tetrahedron Lett. 1994, 397.
- Onaka, M.; Shinoda, T.; Izumi, Y.; Nolen, E.G.; "Acidic Clay-Directed Polymerization-Cyclization of Aldehydes and Pyrrole to Porphyrins" Stud. Surf. Sci. Catal. 1994, 90, 85.
- M. Onaka, T. Shinoda, Y. Izumi, and E.G. Nolen, Porphyrin Synthesis in Clay Nanospaces, Chemistry Lett.1993, 117.
Asterisks indicate undergraduate student co-authors who conducted their research in collaboration with a faculty member at Colgate.
Our primary goal is the development of useful synthetic glycopeptide mimics that effectively represent cell surface O-glycopeptides initiated as alpha-linked: O-GalNAc and O-Man Ser/Thr. These mimics or surrogates will provide metabolic stability to enhance bioavailability and are expected to have altered binding affinities to immune surveillance molecules to help break inherent immunotolerance by eliciting T-cell help. The (R-CHOH)-GalNAc-a-Ser/ThrF3 will be prepared as mimics of Tn antigen, O-GalNAc-a-Ser/Thr, and will be incorporated into two biomedically relevant peptides. This improved mimetic design, based on NMR and x-ray crystallographic studies, should have potential therapeutic applications in bioassays, immunotherapy, and antineoplastic activity. The (CH2)-Man/ManF-a-Ser will serve as a robust mimic of hypoglycosylated a-dystroglycan (a-DG) and other O-mannosyl proteins in order to raise glycan-specific antibodies. The generation of new O-Man specific mAbs would be useful for isolation and identification of glycoproteins known to be implicated in not only a range of congenital muscular dystrophies, but also in tumor metastasis and in autoimmune diseases such as multiple sclerosis.
The initial design and syntheses of the desired mimetics are proposed (Aims 1 and 2). After establishing the synthetic routes, we will adjust the protecting groups to provide samples for the NMR analysis and for solid-phase peptide synthesis to explore the conformational (Aim 3), and immunological and tumor inhibition studies (Aim 4).
Aim 1. Design and Syntheses of (R-CHOH)-GalNAc-a-Ser/Thr(F3) with Comparative Analogs:
The all-carbon skeleton, from the Ser/Thr-carbonyl to C6 of the glycoside, of mimics 1 and 2 will be constructed using metathesis chemistry and Pd-catalyzed cyclization. A C-vinyl glycoside with an unprotected hydroxyl at C2 serves as a branching point for synthetic routes. The C2-Gal functionality (hydroxyl for 2 and oxime for 1) will provide a handle for delivery of the pendant hydroxyl group (shown in red) onto the linking chain establishing the R-configuration at C1’—a feature designed to promote good conformational mimicry of O-Tn antigen.
Aim 2. Synthesis (CH2)-Man/Man2F-a-Ser:
As in Aim 1, metathesis and Pd-catalyzed cyclization will afford a gluco-configured derivative. The C2-hydroxyl will be inverted to yield the mannose target 3 and the 2-deoxy-2-fluoromannose 3F.
Aim 3. Conformational Study of the Effects of the Glycopeptide Analogs by NMR Analysis.
O-Glycopeptide structural studies, specifically related to Tn antigen, have highlighted preferred conformations and forces responsible for orienting the glycan moiety with respect to the peptide backbone, and vice versa. The intramolecular interaction of the glycan back toward the peptide is critical for the expected intermolecular interactions of the glycan face presented away from the peptide. Our synthetic (R-CHOH)-mimics 1, and comparative analogs 2, will be analyzed by NMR and molecular dynamics simulations for comparison of the conformational changes affected by altering the natural O-glycosyl linkages. Incorporation of these into simple peptide models and biomedically-relevant peptides will be carried out to provide samples for the NMR studies.
Aim 4. Incorporation of Mimics into MUC1 and a-DG for Immunological Studies and APF for Tumor Inhibition Studies:
The glycopeptides of interest that will be modified are: 1. MUC 1, a mucin transmembrane glycoprotein that includes an extracellular 20-mer tandem repeat displaying tumor-associated carbohydrate antigens, such as Tn antigen, which are typically masked in normal cells but exposed during carcinogenesis; 2. a peptide growth factor, known as antiproliferative factor or APF, which is a glycosylated nonapeptide isolated from bladder cells of patients with interstitial cystitis and found to inhibit bladder tumor cell growth; and 3. three 9-10-mers from a-DG known as common sites for mannosylation. The mimics from Aims 1 and 2 will be incorporated in these glycopeptides using solid-phase peptide synthesis and supplied to collaborators for immunological and inhibition studies.