Chemistry Reference
In-Depth Information
Although reactive immunization does not appear to solve the problem of creating
active sites with multiple catalytic residues, this approach has the decided advantage of
selecting antibodies on the basis of their ability to initiate a chemical reaction (albeit on
a substrate surrogate) as opposed to tight binding to a stable hapten. The efficacy of the
resulting catalysts speaks for itself.
4.7
Practical Applications
As the above examples attest, catalytic antibody technology can be a powerful and ver-
satile approach for creating new catalysts. Not surprisingly, various practical applica-
tions have been envisaged to capitalize on this capability.
In theory, the programmable stereoselectivities of catalytic antibodies makes them
well suited for asymmetric synthesis. Several such transformations have been carried
out on a preparative scale. Kinetic resolution of the epothilone precursor
19
with the
aldolase antibody 38C2 is instructive (Scheme 4.9) [57]. The reaction proceeds in good
yield (37%) and high enantiomeric excess (90%). However, so much catalyst is needed
(0.5 g of IgG antibody was used for the resolution of 0.75 g
19
) that large-scale produc-
tion is likely to be impractical in many cases. As most antibody catalysts are much less
efficient than the aldolases, catalyst costs will generally be appreciable.
Reactions difficult or impossible to carry out with existing methodology have been
identified as another opportunity for this technology [60]. Successful antibody catalysis
of normally disfavored exo rather than endo Diels-Alder cycloadditions [25], syn rather
than anti eliminations [61], and 6-endo-tet rather than 5-exo-tet ring closures [62]
encourage such thinking (Scheme 4.10). It is even possible to use antibody binding
energy to control the energetics and interconversion of short-lived excited-state species
[63]. If the low specific activities of these catalysts can be improved, many exciting
applications will be realizable.
Because antibodies have long serum half-lives, they can also be used in vivo. Selec-
tive activation of prodrugs has received particular attention. For instance, inactive es-
ters of chloramphenical [64] and 5-fluorodeoxyuridine [65] have been converted into
their bioactive forms by hydrolytic antibodies, yielding sufficient antibiotic in test
experiments to inhibit bacterial growth. In another example, etoposide prodrug
27
has been activated for chemotherapeutic applications by sequential aldolase-catalyzed
Scheme 4.9 Kinetic resolution of 19, a precursor to the natural
product epothilone C, was accomplished by degrading the unwanted
stereoisomer by an antibody-catalyzed retro-aldol reaction.
