CC-1065 and the Duocarmycins:  Synthetic Studies

Abstract

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.

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

“…1) are natural products isolated from the culture broth of Streptomyces species, which have been shown to exert ultra-potent activity against cultured cancer cells and in experimental animals [1][2][3]. More recently, (+)-yatakemycin (10) has been isolated from Streptomyces sp.…”

“…The failure of the clinical progression of CC-1065 and the duocarmycins has prompted many research groups to use these natural products as leads for the design of novel, and more efficacious agents with reduced adverse toxicity. Since their first isolation, a number of total syntheses of these natural products have been extensively reported and reviewed [1,2]. Additionally, numerous investigations have been directed towards the synthesis of authentic alkylating pharmacophores and analogues containing deep-seated structural modifications, defining the relationship between structure, functional reactivity and biological properties.…”

“…Additionally, numerous investigations have been directed towards the synthesis of authentic alkylating pharmacophores and analogues containing deep-seated structural modifications, defining the relationship between structure, functional reactivity and biological properties. Exciting insights into both the synthetic and mechanistic aspects of this family of natural products have 4 previously been described [1,2] and the field has recently been further reviewed [11][12][13][14]. This review serves to update the field over the past decade and will describe novel directions in regard to chemical and biological investigations of synthetic analogues and prodrug derivatives, which aim to increase tumour selectivity and prepare agents for clinical progression.…”

“…4), modification of the minor groove targeting moiety R, and variation of the leaving group X of the seco-CI precursor have been reviewed previously [1]. Modifications to the C-6 phenol of seco-CI (Fig.…”

Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics

“…57 Binding in the minor groove requires some rotation about the amide bond, disrupting conjugation of the vinylogous amide and increasing the electrophilicity of the dienone cyclopropane. 58,59 Its position next the N3 of adenine causes a proximity-induced alkylation of this heteroatom. 57 There are a number of examples of natural products that bear an enone adjacent to a cyclopropyl group.…”