Faculty Directory

Robin Polt

Professor
Degrees and Appointments: 
B.S. 1981, Indiana U.-Purdue U. Indianapolis
Ph.D. 1986, Columbia University, NYC
Postdoctoral Fellow 1986-1988, ETH, Zurich, Switzerland
Awards and Honors: 
NSF Rotator, 2002-2003
Public Health Service Postdoctoral Fellow, 1986-1988
National Science Foundation Predoctoral Fellow, 1981-1984
Research Summary: 

Cell-surface carbohydrates (glycoproteins & glycolipids) have achieved a prominent place during the past decade, giving rise to the new discipline of "glycobiology." Cell-surface carbohydrates play decisive roles during mammalian fertilization, embryogenesis, normal cellular differentiation and regulation, as well as critical roles in malignancy, tumor growth, and tumor cell metastasis. The vertebrate nervous system seems to be a special beneficiary of the cell-cell communication afforded by glycoconjugates, and we are especially interested in the synthesis of ganglioside analogues which may be useful in probing neuronal development, the formation of synapses, and tumor cell metastasis.

The influence of the carbohydrate moiety on glycoprotein structure and function is an area of interest to the "Polt Group." Using synthetic methods developed in our laboratory, the preferred conformations of various glycopeptide model systems are being determined using state-of-the-art 2-D NMR techniques. This data will permit glycobiologists to understand intracellular trafficking and intercellular transport of glycoproteins at the molecular level. Work done by the "Polt Group" in collaboration with the "Hruby Group" has produced glycopeptide analogues of neurotransmitters which are capable of crossing the blood-brain barrier. These are the first glycopeptide-based neurotransmitters to function as drugs in vivo.

New synthetic methodology developed in the "Polt Group" is focused on the use of metal-ligand interactions to direct C-C and C-O bond formations starting from amino acids, such as L-alanine and D-serine. These new methods are being applied to the synthesis of highly-functionalized natural products such as castanospermine which functions as a glycosidase inhibitor, or to unnatural substrate analogues designed to inhibit glycoprotein processing enzymes (glycosyltransferases).

Publications: 

Chapters

Lou B-H, Szabó LZ, Shenderovich M, Polt RL, Hruby VJ. The Conformational Properties of Glycopeptide Enkephalin Analogues in Solution, Determined by NMR and Molecular Modeling. In Peptides, Chemistry, Structure and Biology. Kaumaya PTP, Hodges RS, Eds. Escom, Leiden, Netherlands 1995

Polt RL. 9-Fluorenylmethoxycarbonylchloride (Fmoc). In Encyclopedia of Reagents for Organic Synthesis. Paquette L, Ed. John Wiley & Sons, Chichester, UK 1995

Polt RL. Amaryllidaceae Alkaloids with Antitumor Activity. In Organic Synthesis: Theory and Applications. Hudlicky T, Ed. JAI Press, Inc., London, UK 1996; Vol 3, pp 109-148

Williams SA, Abbruscato TJ, Szabó LZ, Polt RL, Hruby VJ, Davis TP. The Effect of Glycosylation on the Uptake of an Enkephalin Analogue into the Central Nervous System. In Biology and Physiology of the Blood-Brain Barrier. Couraud & Scherman, Eds. Plenum Press, New York, NY 1996; pp 69-77

Polt RL, Szabó LZ, Hruby VJ, Davis TP, Porreca F, Yamamura HI. Synthesis and Pharmacology of O-Linked Glycopeptide Analogues: A New Class of Opioid Analgesics. In Innovation and Perspectives in Solid Phase Synthesis & Combinatorial Libraries. Epton R, Ed. Mayflower Scientific Ltd, Birmingham, UK 1997; pp 277-280

Polt RL. Synthetic Methods for Glycopeptides. In Carbohydrate Chemistry. Boons G-J, Ed. Chapman and Hall, London, UK 1998; pp 221-242

Polt RL. Benzophenone Imines of Amino Acids as Electrophiles. In Amino Acid Derivatives: A Practical Approach. Barrett GC, Ed. Oxford University Press, Oxford, UK 1999; pp 101-114

Polt RL, Mitchell SA. Glycopeptide Analgesics Derived from Enkephalins. In Glycoscience: Chemistry and Chemical Biology. Fraser-Reid B, Tatsuta K, Theim J, Eds. Springer-Verlag GmbH, Heidelberg, Germany 2001; pp 2355-2392

Journal Publications

O’Donnell MJ, Polt RL. A mild and efficient route to Schiff base derivatives of amino acids. J Org Chem 1982, 47, 2663-2665

Polt RL, Stork G, Carpenter GB, Williard PG. X-ray crystal structure of N-(2-lithiocyclohexenyl)-N,N', N'-trimethyl-1,3-propanediamine: A pentavalent lithium? J Am Chem Soc 1984, 106, 4276-4277

O’Donnell MJ, Bennett WD, Polt RL. Preparation of an electrophillic glycine cation equivalent and its reaction with heteroatom nucleophiles. Tetrahedron Lett 1985, 26, 695-698

Stork G, Shiner CS, Cheng CW, Polt RL. The deprotonation of chelating enamines. Direct formation of .beta.-lithio enamines. J Am Chem Soc 1986, 108, 304-305

Polt RL. PhD Thesis, Columbia University, New York, NY, 1986

Polt RL, Seebach D. Alkylation of imidazolidinone dipeptide derivatives: Preparation of enantiomerically pure di- and tripeptides by "chirality transfer" via a pivaldehyde acetal center. Helv Chim Acta 1987, 70, 1930-1936

Stork G, Polt RL, Li YS, Houk KN. Theoretical studies on the deprotonation of chelating enamines. J Am Chem Soc 1988, 110, 8360-8367

O’Donnell MJ, Bennett WD, Bruder WA, Jacobsen WN, Knuth K, LeClef B, Polt RL, Bordwell FG, Mrozack SR, Cripe TA. Acidities of glycine Schiff bases and alkylation of their conjugate bases. J Am Chem Soc 1988, 110, 8520-8525

Seebach D, Polt RL. Stereoselective alkylation of glycine units in dipeptide derivatives. "Chirality transfer" via a pivaldehyde N,N-acetal center. J Am Chem Soc 1988, 110, 2622-2632

Egli M, Polt RL, Seebach D. Diastereoselective cyclization of a glycyl-alanine azomethine to an imidazolidinone: Determination of the product configuration by x-ray analysis. Chimia 1989, 43, 4-5

Polt RL, Peterson M. Amino alcohols from amino acids: Chelation control via Schiff bases. Tetrahedron Lett 1990, 31, 4985-4986

Szabó LZ, Li YS, Polt RL. O-glycopeptides—A simple beta-stereoselective glycosidation of serine and threonine via a favorable hydrogen-bonding pattern. Tetrahedron Lett 1991, 32, 585-88

Wijayaratne T, Polt RL. Erythrose sesqui-acetals as electrophiles. 2-deoxy-C-nucleosides from D-glucose. Tetrahedron Lett 1991, 32, 4831-4834

Peterson MA, Polt RL. E-1-lithio-alkenes in hydrocarbon solvent. Synth Commun 1992, 22, 477-480

Wijayaratne T, Collins N, Li YS, Bruck MA, Polt RL. Alkoxy Schiff base-oxazolidine tautomerism. Solid state structure of N-diphenylmethylene-L-threonine methyl ester. Acta Crystallogr B Struct Sci 1993, 49, 316-320

Polt RL, Peterson MA, DeYoung L. Aluminoxy-acetals from amino esters: Chirality transfer via sequential addition of hydride and C-nucleophiles. 2-Amino alcohols and sphingosines. J Org Chem 1992, 57, 5469-5480

Polt RL, Szabó LZ, Treiberg J, Li YS, Hruby VJ. General methods for alpha-O-ser/thr or beta-O-ser/thr glycosides and glycopeptides. Solid-phase synthesis of O-glycosyl cyclic enkephalin analogs. J Am Chem Soc 1992, 114, 10249-10258

Polt RL, Fernando Q, Li YS, Rivera M. Unsymmetrical disulfides: bis-cysteine disulfides of meso-2,3-dimercaptosuccinic acid. Tetrahedron Lett 1992, 33, 2961-2964

Peterson MA, Polt RL. N-diphenylmethylene-protected glycosyl acceptors. Selective glycosylation to form lactosyl-threo-ceramides. J Org Chem 1993, 58, 4309-4314

Polt RL, Porreca F, Szabó LZ, Bilsky EJ, Davis P, Abbruscato TJ, Davis TP, Horvath R, Yamamura HI, Hruby VJ. Glycopeptide enkephalin analogues produce analgesia in mice: Evidence for penetration of the blood-brain barrier. Proc Nat Acad Sci USA 1994, 91, 7114-7118

Weber SJ, Abbruscato TJ, Brownson EA, Lipkowski AW, Polt RL, Misicka A, Haaseth RC, Bartosz H, Hruby VJ, Davis TP. Assessment of an in-vitro blood-brain barrier model using several [Met5]enkephalin opioid analogs. J Pharmacol Exp Ther 1993, 261, 1649-1655

Szabó LZ, Polt RL. Stereoselective synthesis of beta-D-glycopyranosyl-L-seriate OR beta-D-glycopyranosyl-L-threoninate derivatives with an unusual migration. Carbohydr Res 1994, 258, 293-297

Hruby VJ, Misicka A, Lipkowski AW, Haaseth RC, Bartosz H, Qian X, Collins N, Meyer JP, Szabò LZ, Polt RL, Porreca F, Davis TP, Yamamura HI. New opioid compounds in analgesia. Regul Peptides Suppl 1994, S71-S72

Sames D, Polt, RL. An enantioselective synthesis of N-methylfucosamine via tandem C-C/C-O bond formation. J Org Chem 1994, 59, 4569-4601

Szabò LZ, Ramza J, Langdon C, Polt RL. Stereoselective synthesis of α or β-O-serinyl/threoninyl-2-deoxy-2-acetamido-glycosides. Carbohydrate Res 1995, 274, 11-28

Maiorino RM, Aposhian MA, Xu Z-F, Li YS, Polt RL, Aposhian HV. Determination and metabolism of dithiol chelating agents: XV. The DMSA-cysteine (1:2) mixed disulfide, a major urinary metabolite of DMSA in the human, increases the urinary excretion of lead in the rat. J Pharmacol Exp Therap 1993, 267, 1221-1226

Sames D, Liu Y, DeYoung L, Polt RL. Preparation of monosilylacetals from esters via iBu2AlH reduction and trapping with N-trimethylsilylimidazole. Addition of allyltrimethylsilane to yield homoallylic alcohols or ethers. J Org Chem 1995, 60, 2153-2159

Sames D, Polt RL. Piperidine triols via enantioselective alkylation and osmylation of alanine Schiff base esters. Synlett 1995, 552-554 (Special issue dedicated to Gilbert Stork)

Polt RL, Szabò LZ, Ramza J. New method of chemical synthesis of O-linked glycopeptides. Postepy Hig Med Dosw 1996, 50, 493-503 (Chem. Abs. No. 126:277763; Published in Polish)

Chruma J, Sames D, Polt RL. N-methylation of amino acids and amino esters via O’Donnell’s Schiff bases. Tetrahedron Lett 1997, 38, 5085-5086

Dangel B, Clarke M, Haley J, Sames D, Polt RL. Amino acid-derived ligands for transition metals: Catalysis via a minimalist interpretation of a metalloprotein. J Am Chem Soc 1997, 119, 10865-10866

Razavi H, Polt RL. Syntheses of iminolyxitols via tandem reduction-alkenylation of O'Donnell's Schiff bases. Tetrahedron Lett 1998, 39, 3371-3374

Mitchell SA, Oates BD, Razavi H, Polt RL. Glycosyltransferase inhibitors: Synthesis of D-threo-PDMP, L-threo-PDMP and other brain glucosylceramide synthase inhibitors from D- or L-serine. J Org Chem 1998, 63, 8837-8842

Polt RL, Sames D, Chruma J. Glycosidase inhibitors: Synthesis of enantiomerically pure fuco-1-deoxy-nojirimycin and other aza-sugars from amino acids via tandem reduction-alkenylation and osmylation. J Org Chem 1999, 64, 6147-6153

Kriss C, Lou B-H, Szabó LZ, Mitchell SA, Hruby VJ, Polt RL. Enkephalin-based drug design: Conformational analysis of O-linked glycopeptides by NMR and molecular modeling. Tetrahedron: Asymmetry 2000, 11, 9-25

Razavi H, Polt RL. Asymmetric syntheses of (-)-8-epi-swainsonine and (+)-1,2-Di-epi-swainsonine. Carbonyl addition thwarted by an unprecedented aza-pinacol rearrangement. J Org Chem 2000, 65, 5693-5706

Elmagbari NO, Sdimid WR, Palian MM, Polt RL, Bilsky EJ. Structure-activity studies with novel opioid glycopeptides: Antinociception and blood-brain barrier penetration. FASEB J 2000, 14, 44

Bilsky EJ, Polt RL, Lipkowski AW, Misicka A, Porreca F, Hruby VJ. Pharmacological strategies for developing opioid peptides as therapeutic agents. FASEB J 2000, 14, 45

Dangel BD, Polt RL. Catalysis by amino acid-derived tetra-coordinate complexes: Enantioselective addition of dialkylzincs to aliphatic and aromatic aldehydes. Org Lett 2000, 2, 3003-3006

Egleton RD, Mitchell SA, Polt RL, Hruby VJ, Davis TP. Glycosylation improves the brain delivery of Met-Enkephalin analogs. Brain Res 2000, 881, 37-46

Bilsky EJ, Egleton RD, Mitchell SA, Huber JD, Jones H, Yamamura HI, Janders J, Davis TP, Davis P, Porreca F, Hruby VJ, Palian MM, Polt RL. Enkephalin glycopeptide analogs produce analgesia with reduced dependence liability. J Med Chem 2000, 43, 2586-2590

Mitchell SA, Pratt MR, Hruby VJ, Polt RL. Solid-phase synthesis of O-linked glycopeptide analogues of enkephalin. J Org Chem 2001, 66, 2327-2342

Palian MM, Jacobsen NE, Polt RL. O-linked glycopeptides retain helicity in water. J Peptide Res 2001, 58, 180-189

Palian MM, Polt RL. Lipo alpha-amino-beta-Hydroxy acids and O-linked glycosides: Building blocks for ceramyl and glycosphingoyl peptides. J Org Chem 2001, 66, 7178-7183

Palian MM, Polt RL. Glycopeptide Analgesics. Drugs of the Future 2001, 26, 561-576

Egleton RD, Mitchell SA, Huber JD, Palian MM, Polt RL, Davis TP. Improved blood-brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation. J Pharm Exp Ther 2001, 299, 967-972

Polt RL, Kelly BD, Dangel BD, Tadikonda UB, Ross RE, Raisimring AM, Astashkin AV. Optically active 4- and 5-coordinate transition metal complexes of bifurcated dipeptide Schiff bases. Inorg Chem 2003, 42, 566-574

Palian MM, Boguslavsky VI, O’Brien DF, Polt RL. Glycopeptide-membrane interactions: Glycosyl enkephalin analogs adopt turn conformations by NMR and CD in amphipathic media. J Am Chem Soc 2003, 125, 5823-5831

Abeytunga DTU, Glick JJ, Gibson NJ, Oland LA, Somogyi A, Wysocki VH, Polt RL. Presence of unsaturated sphingomyelins and changes in their composition during the life cycle of the moth Manduca sexta. J Lipid Res 2004, 45, 1221-1231

Slavish J, Oland LA, Friel D, Polt RL. New PDMP analogues inhibit process outgrowth in an insect cell line. Biorg Med Chem Lett 2004, 14, 1487-1490

Elmagbari NO, Egleton RD, Palian MM, Lowery JJ, Schmid WR, Davis P, Navratilova E, Dhanasekaran M, Keyari CM, Yamamura HI, Porreca F, Hruby VJ, Polt RL, Bilsky EJ. Antinociceptive structure-activity studies with enkephalin-based opioid glycopeptides. J Pharm Exp Therap 2004, 311, 290-297

Egleton RD, Bilsky EJ, Tollin G, Dhanasekaran M, Lowery JJ, Alves I, Davis P, Porreca F, Yamamura HI, Yeomans L, Keyari CM, Polt RL. Biousian glycopeptides penetrate the blood-brain barrier. Tetrahedron: Asymmetry 2005, 16, 65-75

Dhanasekaran M, Polt RL. New prospects for glycopeptide-based analgesia: Glycoside-induced penetration of the blood-brain barrier. Current Drug Delivery 2005, 2, 59-73

Dhanasekaran M, Palian MM, Alves I, Yeomans L, Keyari CM, Davis P, Bilsky EJ, Egleton RD, Yamamura HI, Jacobsen NE, Tollin G, Hruby VJ, Porreca F, Polt RL. Glycopeptides related to β-endorphin adopt helical amphipathic conformations in the presence of lipid bilayers. J Am Chem Soc 2005, 127, 5435-5448

Dhanasekaran M, Keyari CM, Polt RL. Glycosylated neuropeptides: A new vista for neuropsychopharmacology? Med Res Rev 2005, 25, 557-585

Egleton RD, Hawkins BT, Bilsky EJ, Yeomans L, Dhanasekaran M, Polt RL. The role of blood brain barrier transport in the enhanced analgesia of glycopeptide opioids. FASEB J 2006, 20, A240-A241 abstract only

Lowery JJ, Raymond T, Yeomans L, Polt RL, Bilsky EJ. In vivo pharmacology of MMP2200 a delta/mu opioid glycopeptides. FASEB J 2006, 20, A241 abstract only

Lowery JJ, Yeomans L, Keyari CM, Davis P, Porreca F, Knapp BI, Bidlack JM, Bilsky EJ, Polt RL. Glycosylation improves the central effects of DAMGO. Chem Biol Drug Des 2007, 69, 41-47

Book Reviews

Polt RL. Glycopeptide Antibiotics. Nagarajan R, Ed. J Am Chem Soc 1995, 117, 7300

Polt RL. Lipid Synthesis and Manufacture. Gunstone FD, Ed. J Am Chem Soc 2000, 122, 3985