Premium
Design and Synthesis of Dynemicin Analogs
Author(s) -
Maier Martin E.,
Boße Folkert,
Niestroj André J.
Publication year - 1999
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/(sici)1099-0690(199901)1999:1<1::aid-ejoc1>3.0.co;2-d
Subject(s) - enediyne , chemistry , stereochemistry , diradical , natural product , ring (chemistry) , quinone , total synthesis , combinatorial chemistry , ligand (biochemistry) , organic chemistry , singlet state , biochemistry , physics , receptor , nuclear physics , excited state
Dynemicin A is a member of the family of enediyne natural products. It is unique in that it combines a ten‐membered enediyne with an anthraquinone substructure. These features stimulated the development of synthetic approaches to the natural product itself and of analogs thereof. This review summarizes the total syntheses of dynemicin A. In addition, an overview of the known analogs is presented. The analogs can be classified according to the designed trigger mechanism. Most of the analogs contain a removable carbamate on the nitrogen atom. Others are quite similar to the natural lead in that they contain a quinone substructure, which upon reduction causes opening of the oxirane ring. In addition, there are analogs that contain an aromatic sector, the enediyne, and the oxirane ring but lack the nitrogen heterocycle. In these compounds the aryl ring assumes a different conformation from that in dynemicin A. Many of the simplified analogs proved to be quite active in vitro as well in vivo against murine tumor models. A highlight is compound 30 which is much more active than dynemicin A itself. However, looking at all analogs there is no clear‐cut correlation between the DNA‐cleaving ability at neutral pH and the in vitro results. From this one might conclude that there are possibly two mechanisms for antitumor activity. One involves diradical formation whereas the other might be due to a ligand‐receptor interaction.