Biomedical Engineering Reference
In-Depth Information
HO
HO
O
O
OH
OH
O
O
O
O
OH
OH
OH
OH
NH
NH
H
3
CO
H
3
CO
O
O
O
OCH
2
COOH
O
O
O
N(Et)
2
O
O
Rifamycin B
Rifamide
HO
HO
O
O
OH
OH
O
O
O
O
OH
OH
O
OH
NH
NH
H
3
CO
H
3
CO
N
N
O
NH
O
N
O
O
OH
N
O
O
N
Rifabutin
Rifampicin
FIGURE 6.9
Rifamycin B and semisynthetic analogs.
6.5.2 I
MPROVEMENTS
IN
N
ATURAL
P
RODUCTS
THROUGH
T
OTAL
S
YNTHESIS
Although the total synthesis of natural products has been the forte of many prominent academic
laboratories, only a few totally synthetic analogs of natural products have been introduced into
commerce. The continued development of efi cient and selective synthetic methods could provide
alternative supply routes for simpler natural products in the future. Regardless of the issue of practi-
cal scalability, total synthesis enables the production and testing of analogs that often illuminate
key features of the structure that are critical for biological activity. Paul Wender's research on the
bryostatins, potent cytotoxic principles isolated from marine invertebrates, illustrates some of the
key insights that can be revealed through total synthesis.
6.5.3 B
IOSYNTHETIC
M
ODIFICATIONS
Genetic engineering of biosynthetic pathways to create specii c modii cations in chemical struc-
ture of secondary metabolites is now a practical reality in bacterial systems. In the simplest cases,
a single enzymatic function is eliminated by inactivating the respective gene, resulting in an
altered product. One such example is shown in Figure 6.10 from the work of scientists at Biotica
Technologies, Cambridge, U.K., where the oxidation state of the aromatic ring in the ansamycin
antibiotic macbecin is reduced from quinone to phenol. This was accomplished by inactivation of
the gene
macM
that was found through genetic analysis to code for the specii c enzyme respon-
sible for addition of the
para
oxygen to the phenol ring that is further oxidized to the quinone.
