Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743

Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743

^*Department of Chemistry and Chemical Biology and ^†Howard Hughes Medical Institute, Harvard University, 12 Oxford Street, Cambridge, MA 02138

Contributed by E. J. Corey

Abstract

A series of totally synthetic molecules that are structurally related to the marine natural product ecteinascidin 743 (Et 743) has been prepared and evaluated as antitumor agents. The most active of these, phthalascidin, is very similar to Et 743 with regard to in vitro potency and mode of action across a variety of cell types. The antiproliferative activity of phthalascidin (IC₅₀ = 0.1–1 nM) is greater than that of the agents Taxol, camptothecin, adriamycin, mitomycin C, cisplatin, bleomycin, and etoposide by 1–3 orders of magnitude, and the mechanism of action is clearly different from these currently used drugs. Phthalascidin and Et 743 induce DNA–protein cross-linking and, although they seem to interact with topoisomerase (topo) I (but not topo II), topo I may not be the primary protein target of these agents. Phthalascidin and Et 743 show undiminished potency in camptothecin- and etoposide-resistant cells. Phthalascidin is more readily synthesized and more stable than Et 743, which is currently undergoing clinical trials. The relationship of chemical structure and antitumor activity for this class of molecules has been clarified by this study.

Footnotes

↵ ‡ To whom reprint requests should be addressed. e-mail: corey{at}chemistry.harvard.edu.
↵ § At a workshop in Boston sponsored by Pharma Mar on October 16, 1998, Yves Pommier of the National Cancer Institute reported evidence for an Et 743–topo I interaction.
ABBREVIATIONS:

Pt 650,

phthalascidin;

Et 743,

ecteinascidin 743;

topo,

topoisomerase;

A375,

malignant melanoma