William N. Setzer
Synthesis and Mechanistic Studies of Antineoplastic Diacetylenes
The purpose of this study is to synthesize and examine the anticancer activities of a
promising but unstudied class of natural products (the diacetylene class) which we have isolated
from woody members of the "ginseng" family (Araliaceae) from Monteverde, Costa Rica. In
this
project, we propose to synthesize the cancer-cell-killing diacetylene compound 1, from the Costa
Rican tree, Dendropanax arboreus. We have shown that this compound kills human liver
cancer cells, skin cancer (carcinoma) cells and leukemia cells grown in culture, but does not kill
cultures of normal liver, kidney, or connective tissue cells. The proposed research addresses two
critical questions: 1) Is the tumor-cell-killing activity of the diacteylenes restricted to a limited
set
of tumor cell types, or are given compounds broadly active? and 2) What is the cellular
mechanism
by which these compounds kill tumor cells? In order to extend our knowledge of the scope and
generality of the biological activity of these compounds, they will be assayed for
tumor-cell-killing
activity against cell lines derived from human breast, liver, prostate, ovarian, and skin cancers.
These particular cell lines represent some of the most prevalent cancers in the United States, and
those targeted for immediate study by government agencies. Since the mechanism of
cytotoxicity
of the diacetylenes is not known, we will investigate their mechanism of action by determining
their
effect on cellular processes known to be targets of other anticancer agents. It is hoped that this
new
class of potential antitumor agents will provide greater specificity, fewer side effects, and/or an
augmentative activity to currently used chemotherapeutic agents.
1
The diacetylenes described in this proposal represent a new, here-to-fore unstudied class of
potential
anticancer agents. These materials have never been examined in terms of the mechanism of
cytotoxic activity. Thus they represent a class of compounds with a potentially new mechanism
of
activity. Our preliminary results show promising cytotoxic activity against cancer cells but
virtually
no toxicity to normal cells. With the need for new chemotherapeutic agents with novel
mechanisms
of activity, the diacetylenes described in this proposal are a promising new class of
antineoplastic
agents.
