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A formal pose (2007), and a more recent photo (2015)

A brief history

Paul A. BARTLETT grew up in New England, did his schooling in the Boston area, and graduated with an A.B. (Phi Beta Kappa) and an A.M. in Chemistry from Harvard University in 1969. As an undergraduate, he did research with David Dolphin on the synthesis of the alkaloid ipalbidine. His graduate years were spent as an NSF Predoctoral Fellow at Stanford University, working under the direction of William S. Johnson on an ester cleavage reagent and a synthesis of estrone by cationic olefinic cyclization. After receiving his Ph.D. in 1972, Dr. Bartlett spent a year as an NIH Postdoctoral Fellow in the laboratory of S. Jonathan Singer of the Biology Department at UC-San Diego, developing a cleavable protein crosslinking reagent and a water-soluble, derivatizable heavy-metal cluster for specific electron microscopic staining purposes. In 1973, he joined the faculty of the Chemistry Department at the University of California, Berkeley, where he was Professor until he became emeritus in 2003. He has held fellowships from the NSF, NIH, and the Alfred P. Sloan Foundation, and he has been the recipient of the Alexander von Humboldt Senior Scientist Award, the Stuart Pharmaceuticals Award, the Buck-Whitney Medal, and the Cope Scholar Award. He is a fellow of the American Academy of Arts and Science, the American Association for the Advancement of Science, and the Royal Society of Chemistry.

Dr. Bartlett's early research interests involved the development of synthetic methods and their application to problems in natural products chemistry. The focus of this work was on methods of stereocontrol via cyclization reactions, with syntheses of the antibiotics nonactin, tirandamycin A, and polyether targets as representative examples.

The major emphasis during his research career was the application of organic synthesis to biological problems. At the outset, this work focussed on the synthesis and study of enzyme inhibitors and metabolic intermediates. His group devised potent inhibitors of enzymes from a number of classes, in particular the tetrahedral phosphorus derivatives as transition state analog peptidase inhibitors. Dr. Bartlett also addressed issues surrounding the principles of transition state analogy and the influences that structural alterations have on the kinetic and thermodynamic aspects of enzyme-inhibitor interaction.

A major area of interest was the shikimate-chorismate biosynthetic pathway; his group synthesized and evaluated intermediates and inhibitors for more than nine enzymes in the sequence. As their last contribution to this field, his group answered the final mechanistic question in the pathway with the determination of the stereochemical course of EPSP synthase by total synthesis of the unstable tetrahedral intermediate.

An outgrowth of his interests in enzyme inhibitor design was the use and development of structure-based approaches and molecular modeling for the design of three-dimensional peptide mimics and enzyme inhibitors. To aid in this work, he and his group developed the program CAVEAT and a number of 3-D structural databases, including TRIAD and ILIAD.

Dr. Bartlett's latest work revealed his background in organic synthesis through the development of synthetic sequences to illustrate the principles of "combinatorial synthetic design" in constructing "prospecting" libraries of readily accessible, easily diversified, novel structures.

His most recent projects continued his interest in peptidomimetics with the design of molecules to induce or mimic specific peptide and protein conformational elements, such as alpha-helices and beta-sheets. Hybrid oligomers known as "@-tides", which incorporate cyclic amino acid analogs to favor the extended conformation, were investigated as beta-strand mimics and components in peptide host-guest systems.

Throughout his career Dr. Bartlett consulted extensively with scientists in the drug discovery, agrochemical, and software development industries, as listed here. He was a cofounder of Pharmacopeia in 1993 and served as chair of its scientific advisory board until its acquisition by Ligand in 2008. Most recently, he served on the Novartis Science Board from 2000-2011. He has also been called upon to provide expert opinion in patent infringement and validity disputes in the field of drug discovery.

Since becoming professor emeritus in 2003, Dr. Bartlett's creative interests have lead him in an artistic direction, pursuing a novel method of presenting photographic images in a 3-dimensional format. Examples of his "Xtra-Dimensions" approach can be found on his other website xtra-dimensions.com. His outdoor interests still include swimming and bicycling for exercise, with skiing and scuba diving the goals of more extended vacations. The two questions that he has been asked many times over the years frequently begin with "Are you related to the famous Paul Bartlett?" and "Are you still jumping out of airplanes?"; the answer to both questions is no.

Some significant publications from the Bartlett group (click here for a complete listing in reverse-chronological order):

187. Hammond, M.C.; Harris, B.Z.; Lim, W.A.; Bartlett, P.A. "β-Strand Peptidomimetics as Potent PDZ Domain Ligands" Chem. Biol. 2006, 13, 1247-1251.

184. Phillips, S.T.; Piersanti, G.; Bartlett, P.A. "Quantifying amino acid conformational preferences and side chain-side chain interactions in β-hairpins" Proc. Natl. Acad. Sci. USA 2005, 102, 13737-13742.

173. An, M.; Maitra, U.; Neidlein, U.; Bartlett, P.A."5-Enolpyruvylshikimate-3 Phosphate Synthase: Chemical Synthesis of the Tetrahedral Intermediate and Assignment of the Stereochemical Course of the Enzymatic Reaction" J. Am. Chem. Soc. 2003, 125, 12759-12767.

170. Spaller, M.R.; Thielemann, W.; Brennan, P.E.; Bartlett, P.A. "Combinatorial Synthetic Design. Solution and Polymer-Supported Synthesis of Heterocycles via Intramolecular Aza-Diels-Alder and Iminoalcohol Cyclizations" J. Comb. Chem. 2002, 4, 516-522.

167. Bartlett, P.A.; Yusuff, N.; Rico, A.C.; Lindvall, M.K. "Anti-Hydrophobic Solvent Effects: An Experimental Probe for the Hydrophobic Contribution to Enzyme Inhibitor Binding", J. Am. Chem. Soc. 2002, 124, 3853-3857.

166. Phillips, S.T.; Rezac, M.; Abel, U.; Kossenjans, M.; Bartlett, P.A. "'@-Tides': The 1,2-Dihydro-3(6H)-pyridinone Unit as a ß-Strand Mimic", J. Am. Chem. Soc. 2002, 124, 58-66.

156. Smith, W.W.; Bartlett, P.A. "Macrocyclic Inhibitors of Penicillopepsin. 3. Design, Synthesis, and Evaluation of an Inhibitor Bridged Between P2 and P1'", J. Am. Chem. Soc., 1998, 120, 4622-4628.

152. Burger, M. T.; Bartlett, P.A. "Enzymatic, Polymer-Supported Synthesis of an Analog of the Trypsin Inhibitor A90720A: A Screening Strategy for Macrocyclic Peptidase Inhibitors"J. Am. Chem. Soc., 1997, 119, 12697-12698.

150. Austin, R.E.; Maplestone, R.A.; Sefler, A.M.; Liu, K.; Hruzewicz, W.N.; Liu, C.W.; Cho, H.S.; Wemmer, D.E.; Bartlett, P.A. "A Template for Stabilization of a Peptide a-Helix: Synthesis and Evaluation of Conformational Effects by Circular Dichroism and NMR", J. Am. Chem. Soc., 1997, 119, 6461-6472.

149. Marx, M.A.; Grillot, A.-L.; Louer, C.T.; Beaver, K.A.; Bartlett, P.A. "Synthetic Design for Combinatorial Chemistry. Solution and Polymer-Supported Synthesis of Polycyclic Lactams by Intramolecular Cyclization of Azomethine Ylides", J. Am. Chem. Soc., 1997, 119, 6153-6167.

148. Spaller, M.R.; Burger, M.T., Fardis, M.; Bartlett, P.A. "Synthetic Strategies in Combinatorial Chemistry", Curr. Opin. Chem. Biol. 1997, 1, 47-53.

143. Bartlett, P. A. "Design of Enzyme Inhibitors: Answering Biological Questions Through Organic Synthesis" in Organic Synthesis, From Gnosis to Prognosis (NATO Advanced Study Institute), Chatgilialoglu, C. and Snieckus, V., Eds., Kluwer Academic Publishers (Dordrecht) 1996, 137-173.

140. Tian, Z.-Q.; Bartlett, P. A. "Metal Coordination as a Method for Templating Peptide Conformation", J. Am. Chem. Soc., 1996, 118, 943-949.

135. Kozlowski, M. C.; Tom, N. J.; Seto, C. T.; Sefler, A. M.; Bartlett, P. A., "Chorismate-Utilizing Enzymes Isochorismate Synthase, Anthranilate Synthase and p-Aminobenzoate Synthase: Mechanistic Insight Through Inhibitor Design", J. Am. Chem. Soc. 1995, 117, 2128-2140.

133. Lauhon, C. T.; Bartlett, P. A. "Substrate Analogs as Mechanistic Probes for the Bifunctional Chorismate Synthase from Neurospora crassa", Biochemistry 1994, 33, 14100-14108.

132. Etzkorn, F. A.; Guo, T.; Lipton M. A.; Goldberg, S. D.; Bartlett, P. A. "Cyclic Hexapeptides and Chimeric Peptides as Mimics of Tendamistat", J. Am. Chem. Soc. 1994, 116, 10412-10425.

127. Morgan, B.P.; Bartlett, P.A.; Holland, D.R.; Matthews, B.W. "Structure-Based Design of an Inhibitor of the Zinc Peptidase Thermolysin", J. Am. Chem. Soc., 1994, 116, 3251-3260.

126. Lauri, G.; Bartlett, P.A., "CAVEAT: A Program to Facilitate the Design of Organic Molecules", J. Comp. Aided Mol. Design. 1994, 8, 51-66.

120. Alberg, D. G.; Lauhon, C. T.; Nyfeler, R.; Faessler, A.; Bartlett, P. A., "Inhibition of EPSP Synthase by Analogs of the Tetrahedral Intermediate and of EPSP", J. Am. Chem. Soc., 1992, 114, 3535-3546.

119. Phillips, M.A.; Kaplan, A.P.; Rutter, W.J.; Bartlett, P.A., "Transition State Characterization: A New Approach Combining Inhibitor Analogs and Variation in Enzyme Structure", Biochemistry, 1992, 31, 959-962.

116. Kaplan, A.P.; Bartlett, P.A., "An Inhibitor of Carboxypeptidase A with a Ki Value in the Femtomolar Range", Biochemistry 1991, 30, 8165-8170.

114. Kozlowski, M.C.; Bartlett, P.A. "Synthesis of a Potential Transition State Analog Inhibitor of Isochorismate Synthase", J. Am. Chem. Soc. 1991, 113, 5897-5898.

110. Morgan, B.P.; Scholtz, J.M., Ballinger, M., Zipkin, I.; Bartlett, P.A., "Differential Binding Energy: A Detailed Evaluation of the Influence of Hydrogen-Bonding and Hydrophobic Groups on the Inhibition of Thermolysin by Phosphorus-Containing Inhibitors", J. Am. Chem. Soc., 1991, 113, 297-307.

99. Hanson, J.E.; Kaplan, A.P.; Bartlett, P.A., "Phosphonate Analogs of Carboxypeptidase A are Potent Transition State Analog Inhibitors", Biochemistry, 1989, 28, 6294-6305.

96. Alberg, D.G.; Bartlett, P.A., "Potent Inhibition of 5-Enolpyruvylshikimate 3-phosphate Synthase by a Reaction Intermediate Analog", J. Am. Chem. Soc., 1989, 111, 2337-2338.

91. Bartlett, P.A.; Nakagawa, Y.; Johnson, C.R.; Reich, S.; Luis, A., "Chorismate Mutase Inhibitors: Synthesis and Evaluation of Some Potential Transition State Analogs", J. Org. Chem., 1988, 53, 3195-3210.

90. Jackson, D.Y.; Jacobs, J.W.; Sugasawara, R.; Reich, S.H.; Bartlett, P.A.; Schultz, P.G., "An Antibody-Catalyzed Claisen Rearrangement", J. Am. Chem. Soc., 1988, 110, 4841-4842.

87. Bartlett, P.A.; Satake, K., "Does Dehydroquinate Synthase Synthesize Dehydroquinate?", J. Am. Chem. Soc., 1988, 110, 1628- 1630.

75. Bartlett, P.A.; Maitra, U.; Chouinard, P.M., "Synthesis of 'iso- EPSP' and Evaluation of Its Interaction with Chorismate Synthase", J. Am. Chem. Soc., 1986, 108, 8068-8071.

71. Neukom, C.; Richardson, D.P.; Myerson, J.H.; Bartlett, P.A., "A Stereocontrolled Total Synthesis of (+)-Tirandamycin A", J. Am. Chem. Soc., 1986, 108, 5559-5568.

60. Ashley, G.W.; Bartlett, P.A., "Inhibition of Escherichia coli Cytidine Deaminase by a Phosphapyrimidine Nucleoside", J. Biol. Chem., 1984, 259, 13621-13627.

57. Bartlett, P.A.; Meadows, J.D.; Ottow, E., "Enantiodivergent Syntheses of (+)- and (-)-Nonactic Acid and the Total Synthesis of Nonactin", J. Am. Chem. Soc., 1984, 106, 5304-5311.

47. Bartlett, P.A.; Marlowe, C.K., "Phosphonamidates as Transition State Analog Inhibitors of Thermolysin", Biochemistry., 1983, 22, 4618-4624.

24. Jacobsen, N.E.; Bartlett, P.A., "A Phosphorus-Containing Dipeptide Analog as an Inhibitor of Carboxypeptidase A", J. Am. Chem. Soc., 1981, 103, 654-657.

21. Bartlett, P.A., "Stereocontrol in the Synthesis of Acyclic Systems: Application to Natural Product Synthesis", Tetrahedron Report #71, Tetrahedron, 1980, 36, 2-72.

15. Summerton, J.E.; Bartlett, P.A., "Affinity Crosslinking Agents for Nucleic Acids: Use of 6-Bromo-5,5-dimethoxyhexanohydrazide for Crosslinking Cytidine to Guanosine and Crosslinking RNA to Complementary Sequences of DNA", J. Mol Biol., 1978, 122, 145-162.

12. Bartlett, P.A.; Green, F.R. III, "Total Synthesis of Brefeldin A", J. Am. Chem. Soc., 1978, 100, 4858-4865.