A multiply convergent platform for the synthesis of trioxacarcins

Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):6709-14. doi: 10.1073/pnas.1015257108. Epub 2011 Jan 18.


Many first-line cancer drugs are natural products or are derived from them by chemical modification. The trioxacarcins are an emerging class of molecules of microbial origin with potent antiproliferative effects, which may derive from their ability to covalently modify duplex DNA. All trioxacarcins appear to be derivatives of a nonglycosylated natural product known as DC-45-A2. To explore the potential of the trioxacarcins for the development of small-molecule drugs and probes, we have designed a synthetic strategy toward the trioxacarcin scaffold that enables access to both the natural trioxacarcins and nonnatural structural variants. Here, we report a synthetic route to DC-45-A2 from a differentially protected precursor, which in turn is assembled in just six steps from three components of similar structural complexity. The brevity of the sequence arises from strict adherence to a plan in which strategic bond-pair constructions are staged at or near the end of the synthetic route.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alkylation / drug effects
  • Aminoglycosides / chemical synthesis*
  • Aminoglycosides / chemistry*
  • Aminoglycosides / pharmacology
  • Antineoplastic Agents, Alkylating / chemical synthesis*
  • Antineoplastic Agents, Alkylating / chemistry*
  • Antineoplastic Agents, Alkylating / pharmacology
  • DNA, Neoplasm / chemistry
  • DNA, Neoplasm / metabolism
  • HeLa Cells
  • Humans
  • Molecular Structure


  • Aminoglycosides
  • Antineoplastic Agents, Alkylating
  • DNA, Neoplasm
  • trioxacarcin