Biomedical Engineering Reference
In-Depth Information
fashioned of units linked by alternating peptide and ester bonds. The method in which
beauvericin is produced is also rather unique in that the simple building blocks D-2-
hydroxyisovaleric acid (Hiv) and phenylalanine are first coupled, yielding an ester
with exposed carboxyl and amino groups on the termini. Three of these dipeptidol
intermediates are iteratively coupled and cyclized by the NRPS to yield the final
compound.
Early studies into the biosynthesis of beauvericin showed the incorporation of
radioactive valine, suggesting its role as a precursor to Hiv. This result was used as a
guide for the earliest work toward the production of beauvericin analogues through
precursor-directed biosynthesis in which the authors reasoned that if valine was
indeed converted into Hiv, then it may be possible to incorporate structurally related
amino acids such as isoleucine into the same series of pathways to produce dipeptidol
intermediates in which the Hiv group had been replaced by 2-hydroxy-3-methyl-
pentanoic acid (Hmp). These could then be coupled with two other dipeptidols,
containing Hiv or Hmp, and cyclized to yield a beauvericin analogue. This approach
led to the successful production of compounds
(Scheme 14.9) [51].
A subsequent study expanded this approach to examine the ability of the
beauvericin biosynthetic system to incorporate not only analogues of Hiv, but also
those of phenylalanine. 2-Fluorophenylalanine and 3-fluorophenylalanine were both
found to be successfully incorporated at one, two, or all the three positions; the
analogues produced from the former were, however, unable to be separated from each
other. This work led to the successful isolation of several analogues, all of which
assayed for their antihaptotactic ability. The compounds produced through the
incorporation were found to have very modest increase in their antihaptotactic
46
-
48
R
1
R
4
O
O
O
OH
N
HO
O
O
O
Beauveria bassiana
R
2
X
3 X
O
R
6
N
N
O
NH
2
O
HO
R
5
O
Y
O
R
3
45
(R
1
= Me; R
2
= Ph; R
3
= Me; R
4
= Ph; R
5
= Me; R
6
= Ph)
46
(R
1
= H; R
2
= Ph; R
3
= Me; R
4
= Ph; R
5
= Me; R
6
= Ph)
47
(R
1
= H; R
2
= Ph; R
3
= H; R
4
= Ph; R
5
= Me; R
6
= Ph)
48
(R
1
= H; R
2
= Ph; R
3
= H; R
4
= Ph; R
5
= H; R
6
= Ph)
49
(R
1
= Et; R
2
= Ph; R
3
= Et; R
4
= Ph; R
5
= Et; R
6
= Ph)
50
(R
1
= H; R
2
= 2-F-Ph; R
3
= H; R
4
= Ph; R
5
= H; R
6
= Ph)
51
(R
1
= H; R
2
= 2-F-Ph; R
3
= H; R
4
= 2-F-Ph; R
5
= H; R
6
= Ph)
52
(R
1
= H; R
2
= 2-F-Ph; R
3
= H; R
4
= 2-F-Ph; R
5
= H; R
6
= 2-F-Ph)
53
(R
1
= Et; R
2
= 2-F-Ph; R
3
= Et; R
4
= Ph; R
5
= Et; R
6
= Ph)
54
(R
1
= Et; R
2
= 2-F-Ph; R
3
= Et; R
4
= 2-F-Ph; R
5
= Et; R
6
= Ph)
55
(R
1
= Et; R
2
= 2-F-Ph; R
3
= Et; R
4
= 2-F-Ph; R
5
= Et; R
6
= 2-F-Ph)
SCHEME 14.9
Precursor-directed biosynthesis of analogues of beauvericin.
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