Innovations in synthetic chemistry have enabled the discovery of many breakthrough therapies that have improved human health over the past century. In the face of increasing challenges in the pharmaceutical sector, continued innovation in chemistry is required to drive the discovery of the next wave of medicines. Novel synthetic methods not only unlock access to previously unattainable chemical matter, but also inspire new concepts as to how we design and build chemical matter. We identify some of the most important recent advances in synthetic chemistry as well as opportunities at the interface with partner disciplines that are poised to transform the practice of drug discovery and development.
Born August 22, 1953, Dale L. Boger (seated) received his B.Sc. in chemistry from the University of Kansas (1975) and Ph.D. in chemistry from Harvard University (1980). Immediately following graduate school, he returned to the University of Kansas as a member of the faculty in the Department of Medicinal Chemistry (1979Chemistry ( −1985, moved to the Department of Chemistry at Purdue University (1985University ( −1991, and joined the faculty at The Scripps Research Institute (1991 to present) as the Richard and Alice Cramer Professor of Chemistry. His research interests span the fields of organic and bioorganic chemistry and include the development of synthetic methodology, the total synthesis of natural products, heterocyclic chemistry, bioorganic chemistry, medicinal chemistry, the study of DNA−agent and protein−ligand interactions, and antitumor agents.Christopher W. Boyce (standing left) was born January 30, 1972, and grew up in Richmond, MA. Following a year abroad at the Swiss Federal Institute (ETH-Zurich), he received his B.Sc. in chemistry from Rensselaer Polytechnic Institute (1994, summa cum laude). He is currently pursuing a Ph.D. under the direction of Professor Dale L. Boger where he is addressing the synthesis and evaluation of potent DNA alkylation agents related to the CC-1065 and duocarmycin families. Robert M. Garbaccio (standing right) was born on January 20, 1972, and grew up in Old Tappan, NJ. He received his B.A. in chemistry and graduated summa cum laude from Boston University in 1994 where he conducted research in the laboratory of Professor James S. Panek. Presently, he is pursuing a Ph.D. in chemistry at The Scripps Research Institute under the guidance of Professor Dale L. Boger where he is addressing the synthesis and evaluation of potent DNA alkylating agents from the duocarmycin and mitomycin families of antitumor antibiotics. Joel A. Goldberg (standing center) was born June 17, 1972, and grew up in Bedford, NH. After receiving his B.Sc. from Tufts University he joined Professor Boger's laboratory at The Scripps Research Institute where he is pursuing his Ph.D. in Chemistry. His research concentrates on the synthesis and evaluation of potent alkylating agents related to CC-1065 and the duocarmycins.
Radicicol (1) exhibits potent anticancer properties in vitro, which are likely to be mediated through its high affinity (20 nM) for the molecular chaperone Hsp90. Recently, we reported the results of a synthetic program targeting radicicol (1) and monocillin I (2), highlighted by the application of ring-closing metathesis to macrolide formation. These efforts resulted in a highly convergent synthesis of radicicol dimethyl ether but failed in the removal of the two aryl methyl ethers. Simple exchange of these methyl ethers with more labile functionalities disabled a key esterification in the initial route. Through extended experimentation, a successful route to both natural products was secured, along with some intriguing results that emphasize the implications of this design on a broad range of fused benzoaliphatic targets, including analogues of these natural products.
The synthesis and examination of two unique classes of duocarmycin SA analogs are described which we refer to as reversed and sandwiched analogs. Their examination established both the origin of the DNA alkylation selectivity and that both enantiomers of this class of natural products are subject to the same polynucleotide recognition features. The most beautiful demonstration of this is the complete switch in the enantiomeric alkylation selectivity of the reversed analogs which is only consistent with the noncovalent binding model and incompatible with alkylation site models of the origin of the DNA alkylation selectivity. In addition, dramatic alterations in the rates of DNA alkylation were observed among the agents and correlate with the presence or absence of an extended, rigid N2 amide substituent. This has led to the proposal of a previously unrecognized source of catalysis for the DNA alkylation reaction which was introduced in the preceding paper of this issue (J. Am. Chem. Soc. 1997, 119, 4977−4986).
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