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.