Terpenes in Human Health - Natural Products Chemistry: Sources, Separations, and Structures - page 113

HISTORICAL NOTE
The compound taxol was discovered by Monroe and Wall seeking to find
anticancer agents and in 1971 they published their findings. Remarkably, it
took many years before further study at the National Cancer Institute (NCI)
advanced the compound into the clinic. The NCI showed great reluctance to
pursue taxol for a number of reasons: the isolation and extraction was difficult,
and the yew tree produced only small amounts of compound. Since the bark is
a finite resource, once the tree is stripped of its bark it dies, and because of the
supply problem taxol did not progress for many years.
However, due to the efforts of Dr. Matthew Suffness at NCI, a fresh review
found taxol to be very active against B16 melanoma, a newly adopted tumor
model, and thus the program gained momentum. In 1978, taxol showed the abil-
ity to cause considerable regression in a mammary tumor xenograft and interest
was increased when the mechanism of action in mitotic tubules was discovered.
By the early 1980s, the NCI put out a bid for industry support and Bristol
Myers Squibb decided to develop taxol into a drug. New research showed taxol
could be obtained from the needles of the yew tree, an ecologically much bet-
ter prospect. Subsequently, it was discovered as a fungal metabolite with the
potential for large-scale production from fermentation.
Although a total synthesis of paclitaxel was independently completed by
two groups, it requires almost 40 steps, resulting in a low overall yield and is
not economically feasible.
The synthesis of paclitaxel uses an elegant combination of isolating large amounts
of a precursor compound related to taxol followed by an additional semisynthetic
step to produce the final product. The first source is the English yew Taxus baccata,
which is available in nature in large quantities where the compound 10-DAB can be
obtained from the needles. The difference between 10-DAB and paclitaxel is that
10-DAB has no ester side-chain at C-13. Thus, to complete the taxol structure, the
prepared side-chain is then attached to the C-13 hydroxyl group of 10-DAB to obtain
paclitaxel on a large scale. In this manner, paclitaxel was manufactured by a semi-
synthetic production from a natural precursor.
10.7 BRYOSTATINS
Bryostatin compounds (Figure 10.15) belong to a group of macrolide lactones. They
were found in a marine species of bryozoan, Bugula neritina . The structure of
bryostatin 1 was determined in 1982 and to date 20 different bryostatins have been
isolated. They are potent modulators of protein kinase C and are currently under
investigation as anticancer agents.