Biomedical Engineering Reference
In-Depth Information
O
O
O
HO
SNAC
R
1
S. venezuelae
N
R
1
R
1
HO
O
R
2
R
2
O
OH
O
O
R
2
OH
O
O
O
O
56
(R
1
= Me; R
2
= Et)
57
(R
1
= H; R
2
=
n-
Pr)
58
(R
1
= H; R
2
=
i
-Pr)
59
(R
1
= Et; R
2
= Et)
60
(R
1
= Me; R
2
= CH=CH
2
)
SCHEME 14.10
Production of pikromycin analogues through triketide feeding.
This work was a success not only because it provided the first example of the
processing of unnatural precursors by the pikromycin biosynthetic pathway, but also
in the small number of compounds produced,
appeared to exhibit amodest increase
in antibiotic activity against
E. coli, S. aureus
, and
B. subtilis
. This preliminary result
suggests that a broader effort should have great potential for the identification of a
superior antibiotic.
60
14.4.3. Complex Precursors
In the previous section, the precursors discussed were not (as of the publishing of the
studies) available for purchase. They were, however, reasonably straightforward to
synthesize in gram quantities. The amino acid analogues used in the production of
balhimycin were easily obtained in fewer than five steps, while the diketide pre-
cursors fed to the DEBS system are generally accessible in fewer than seven steps.
These approaches exploited the ability of natural biosynthetic systems to take these
simple precursors and transform them into complex natural product analogues.
The main drawback of the work presented so far lies in the limitations of where the
diversity can be introduced. This limitation is a direct consequence of the simplicity
of the precursors.
In this section, we concern ourselves with examples in which the precursors are
large, complex molecules that require only one or two enzymatic transformations to
yield the compound of interest. From the perspective of the synthetic chemist, this is
possibly the most useful application of precursor-directed biosynthesis, as it is
frequently the case that performing the final transformations in a selective and high
yielding fashion prevents a substantial obstacle to an otherwise complete effort. This
statement holds true especially for glycosylated macrocyles, such as the molecules
discussed in this chapter.
14.4.3.1. Apoptolidin The apoptolidins (apoptolidins A
are shown
in Scheme 14.11) are a class of polyketides that have shown promise in the treatment
of various cancers. For some time, efforts toward a formal total synthesis for several of
61
and D
62
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