Samuel J. Danishefsky
Summary
Our laboratory is dedicated to the discovery and development of new agents of medicinal value through major advances in chemical synthesis. Our research program may be divided into two broad categories: (1) the synthesis of structurally and biologically compelling small molecule natural products and their analogues, and (2) the synthesis of medicinally relevant carbohydrate-based constructs, including glycopeptides, glycoproteins, and carbohydrate vaccines.
Our small molecule research program is particularly focused on the synthesis of natural products which may prove clinically useful in the treatment of cancer or neurodegenerative disorders (such as Alzheimer’s, Huntington’s, and Parkinson’s Diseases). We select for synthesis those compounds which have been reported to possess interesting biological activity. Upon synthesizing the natural product, we employ the process of Diverted Total Synthesis (DTS), which allows us to “edit” the natural product, removing sites of potential nonspecific toxicity and manipulating functionality to produce congeners with enhanced potency and improved pharmacokinetic properties.Through carefully chosen collaborative efforts, we are able to rigorously evaluate the biological activity of these fully synthetic compounds in in vitro and in vivo settings.
Natural product-based efforts currently of interest to our laboratory include the potential anticancer agents, the epothilones, radicicol, migrastatin, and cribrostatin IV. Among the many neurotrophically active natural products that have recently been synthesized in our laboratory are 11-O-debenzoyltashironin, paecilomycine A, spirotenuipesines A-B, scabronine G, and garsubellin A.
The second arm of our research program seeks to apply the power of chemical synthesis to the realm of biologically relevant oligosaccharides and glycoconjugates. Over the past 20 years, we have made valuable advances in the development of enabling methodologies for the synthesis of carbohydrates and complex glycopeptides. Our carbohydrate-based research program spans a range of projects, and currently includes efforts to (1) develop carbohydrate-based anticancer vaccines, (2) develop an improved method by which to diagnosis prostate cancer by distinguishing between the carbohydrates displayed by normal and transformed prostate specific antigen (PSA), (3) develop an HIV vaccine based on a fully synthetic gp120 glycopeptide construct, and (4) synthesize, in homogeneous form, the multiply glycosylated protein, erythropoietin (EPO). Needless to say, each of these projects provides ample opportunity for the continued development of methodologies which prove to have broad value to the field of glycopeptide and glycoprotein synthesis.
R. M. Wilson and S. J. Danishefsky “Pattern Recognition in Retrosynthetic Analysis: Snapshots in Total Synthesis” J. Org. Chem. (Perspective) 72, 4293-4305 (2007).
Min, S.-J.; Danishefsky, S. J. “The Total Synthesis of Paecilomycine A” Angew. Chem. Int. Ed. 46, 2199-2202 (2007).
Dai, M. J.; Danishefsky, S. J. “The Total Synthesis of Spirotenuipesines A and B” J. Am. Chem. Soc. 129, 3498-3499 (2007).
R. M. Wilson and S. J. Danishefsky “ Small Molecule Natural Products in the Discovery of Therapeutic Agents: The Synthesis Connection” J. Org. Chem. (Perspective) 71, 8329-8351 (2006).
Cook, S. P.; Polara, A.; Danishefsky, S. J. “The Total Synthesis of (+/-)-11-O-debenzoyltashironin” J. Am. Chem. Soc. 128, 16440-16441 (2006).
R. M. Wilson and S. J. Danishefsky “Applications of Total Synthesis to Problems in Neurodegeneration: Fascinating Chemistry Along the Way” Acc. Chem. Res. 39, 539-549 (2006).
B. Wu, J. Chen, J. D. Warren, G. Chen, Z. Hua, S. J. Danishefsky “Building Complex Glycopeptides: Development of a Cysteine-Free Native Chemical Ligation Protocol” Angew. Chem. Int. Ed. 45, 4116-4125 (2006).
G. Ragupathi, F. Koide, P. O. Livingston, Y. S. Cho, A. Endo, Q. Wan, M. K. Spassova, S. J. Keding, J. Allen, O. Ouerfelli, R. M. Wilson, S. J. Danishefsky “Preparation and Evaluation of Unimolecular Pentavalent and Hexavalent Antigenic Constructs Targeting Prosate and Breast Cancer: A Synthetic Route to Anticancer Vaccine Candidates” J. Am. Chem. Soc. 128, 2715 -2725 (2006).
C. Chan , R. Heid, S. Zheng, J. Guo, B. Zhou, T. Furuuchi, S. J. Danishefsky “Total Synthesis of Cribrostatin IV: Fine-Tuning the Character of an Amide Bond by Remote Control” J. Am. Chem. Soc. 127, 4596-4598 (2005).
O. Ouerfelli, J. D. Warren, R. M. Wilson, S. J. Danishefsky. “Synthetic Carbohydrate-Based Antitumor Vaccines: Challenges and Opportunities.” Expert Review of Vaccines. 4(5), 677-685 (2005).
J. D. Warren, J. S. Miller, S. J. Keding, S. J. Danishefsky “Toward Fully Synthetic Glycoproteins by Ultimately Convergent Routes: A Solution to a Long-Standing Problem” J. Am. Chem. Soc. 126 (21), 6576-6578 (2004).