Biomedical Engineering Reference
In-Depth Information
This section lists several examples where this type of approach has led to the
successful production of a natural product analogue.
14.4.1.1. Borrelidin Borrelidin
1
is a polyketide antibiotic isolated from the
bacterium
S. parvulus
T
u4055 that shows promise in the treatment of cancer through
inhibition of angiogenesis. Although this compound is promising, it is quite
cytotoxic to healthy cells and as such possesses a narrow therapeutic window.
Owing to the complexity of the molecule, traditional medicinal chemistry efforts
were deemed impractical and a precursor-directed approach was used to identify a
safer compound.
Borrelidin, like many polyketides, is synthesized in a three-step process [9,10].
It begins with the biosynthesis of a
trans
-(1
R
,2
R
)-cyclopentane-1,2-dicarboxylic acid
(1,2-CPDA) that is subsequently loaded onto the polyketide synthase. After several
rounds of elongation, the molecule is cyclized. Post-PKS modification involves the
oxidation of the C12 methyl group by the cytochrome P450-type monooxygenase
BorI and its subsequent transformation to a nitrile group. The gene cluster responsible
for borrelidin production has been sequenced, and the resulting information was used
to produce a strain incapable of synthesizing 1,2-CPDA. Unexpectedly, supplement-
ing a culture of this mutant strain with exogenous 1,2-CPDA led to titers that were
15-fold greater than those seen in the wild-type host [11].
A series of more than 40 analogues of 1,2-CPDA were then fed to the mutant
strain in an effort to identify promising compounds. Through this study, the authors
determined that the
trans
-dicarboxylic moiety was essential for incorporation into
the biosynthetic pathway. Scheme 14.1 illustrates a few selected compounds that were
successfully obtained through this approach (
2
-
4
). Biological testing of these
compounds revealed that the cyclobutyl analogue
€
possessed reduced cytotoxicity
along with a modest increase in its ability to inhibit angiogenesis compared to the
natural product, leading to a substantial increase in therapeutic index [11].
2
14.4.1.2. Rapamycin Along with erythromycin, rapamycin
is among the
molecules for which the most progress has been made using precursor-directed
biosynthesis. Produced by a hybrid PKS-NRPS in
S. hygroscopius
, rapamycin
exhibits antifungal and immunosuppressant bioactivities, the latter resulting from
the binding of the rapamycin-FKBP12 complex to mTOR.
5
O
HO
R
O
O
O
Wild
type
OH
OH
OH
OH
SCH
3
1,2-CPDA
OH
O
1
3
O
O
NC
12
O
O
R
OH
CPDA
mutant
R
OH
OH
2
4
SCHEME 14.1
Precursor-directed biosynthesis of selected borrelidin analogues.
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