Biomedical Engineering Reference
In-Depth Information
R
1
R
1
HO
O
HO
R
2
O
Cerulenin
MeO
O
O
Nocardiopsis
O
OH
OH
OH
O
O
O
OH
H
OH
H
MeO
O
OH
MeO
O
O
HO
HO
O
O
OH
OH
MeO
HO
61
(R
1
= Me; R
2
= )
63
(R
1
= Me; R
2
= H)
O
HO
MeO
HO
62
(R
1
= H; R
2
= )
O
64
(R
1
= H; R
2
= H)
HO
SCHEME 14.11
Glycosylation of synthetic apoptolidin aglycones by
Nocardiopsis
in the
presence of cerulenin.
these compounds were hindered by the difficulty of selectively installing the three
required sugars in the final steps. This complication is commonly encountered during
attempts at the total synthesis of glycosylated natural products and it is one the
precursor-directed biosynthesis is particularly well situated to address.
In a majority of the work discussed thus far, considerable knowledge regarding
the biosynthesis of the parent natural product is required. This could include
knowledge of the identity of the primer or extender molecules to be replaced or a
more in-depth knowledge of the biosynthetic gene cluster to utilize in the construction
of blocked mutants. The novelty of the precursor-directed approach applied to
apoptolidin glycosylation is that it required very little such knowledge.
In this work (Scheme 14.11), the authors took the
Nocardiopsis
bacterium
known to be the wild-type producer of apoptolidin and grew it in the presence of a
sublethal amount of the cerulenin, a compound known to inhibit the KS domain of
PKSs. This culture was incapable of producing any apoptolidins but when substituted
with synthetic aglycones, production was recovered as cerulenin has little effect on
glycosyltransferases. This work was not a complete success as only two of the three
sugars observed in wild-type apoptolidin were transferred to the aglycones, resulting
in
, but the presence of these two sugars was sufficient to bring a 50-fold
increase in bioactivity against human lung carcinoma cells compared to the agly-
cone [56]. In this study, it is suggested that the failure of this system to install the third
sugar was a result of its incorporation prior to cyclization. This is a phenomenon rarely
observed in polyketide biosynthesis and as such should not be a complication that will
arise in the extension of this type of approach to the production of analogues of
different compounds.
63
and
64
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