Compounds of natural origin are often
isolated, identified,
and screened for biological activity. Plant members of the Artemisia
genus have been long known throughout the world as important medicinal
agents. For example, artemisinin (not shown) is a well-known anti-malarial
drug. The arteminolides have recently been isolated from the leaves of
Artemisia sylvatica Maxim. Arteminolide A inhibits recombinant rat
FTPase with IC50 of 360 nM. It does not inhibit rat squalene
synthase (IC50 >> 200 uM) or recombinant geranyl-geranyl protein
transferase I (IC50 >> 200 uM). This selectivity suggests that
arteminolide A, or a derivative, could lead to development of a successful
anti-cancer agent. To date, there have been no reports of syntheses of
these natural products, and very limited work directed at this class of
natural products has been undertaken. Our research involves a total
synthesis of arteminolides A-D, as well as the syntheses of several related,
highly bioactive natural products, including the arglabin. Arglabin is of
interest to the medical community, as it is currently being tested
clinically against breast, colon, ovarian and lung cancer. In addition, we
will synthesize the potent natural product dehydromatricarin. The
convergent synthesis of the each of these molecules starts from
1,3-butadiene and is built upon a proposed biosynthetic [4+2] cycloaddition
reaction. The two
coupling partners A and B, as well as dehydromatricarin and
arglabin, are representative structures of the guaianolide sesquiterpenes,
natural products which have been largely overlooked in the synthetic
community. Our syntheses will incorporate a new method for construction of
medium ring carbocycles based on methodology to be developed in our group.
These syntheses will allow us to produce material for use in further
biological testing. In addition, our modular approach to these syntheses
will allow for straightforward derivatization and modification to probe for
biological activity of related, but less complex and more readily available,
structures.
Compounds of natural origin are often
isolated, identified,
and screened for biological activity. Plant members of the Artemisia
genus have been long known throughout the world as important medicinal
agents. For example, artemisinin (not shown) is a well-known anti-malarial
drug. The arteminolides have recently been isolated from the leaves of
Artemisia sylvatica Maxim. Arteminolide A inhibits recombinant rat
FTPase with IC50 of 360 nM. It does not inhibit rat squalene
synthase (IC50 >> 200 uM) or recombinant geranyl-geranyl protein
transferase I (IC50 >> 200 uM). This selectivity suggests that
arteminolide A, or a derivative, could lead to development of a successful
anti-cancer agent. To date, there have been no reports of syntheses of
these natural products, and very limited work directed at this class of
natural products has been undertaken. Our research involves a total
synthesis of arteminolides A-D, as well as the syntheses of several related,
highly bioactive natural products, including the arglabin. Arglabin is of
interest to the medical community, as it is currently being tested
clinically against breast, colon, ovarian and lung cancer. In addition, we
will synthesize the potent natural product dehydromatricarin. The
convergent synthesis of the each of these molecules starts from
1,3-butadiene and is built upon a proposed biosynthetic [4+2] cycloaddition
reaction. The two
coupling partners A and B, as well as dehydromatricarin and
arglabin, are representative structures of the guaianolide sesquiterpenes,
natural products which have been largely overlooked in the synthetic
community. Our syntheses will incorporate a new method for construction of
medium ring carbocycles based on methodology to be developed in our group.
These syntheses will allow us to produce material for use in further
biological testing. In addition, our modular approach to these syntheses
will allow for straightforward derivatization and modification to probe for
biological activity of related, but less complex and more readily available,
structures.
