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4 Design Principles and Development of Prodrugs for Multiply …
4.3.2 Chemical
Bio-orthogonal prodrugs
The term bio-orthogonal chemistry is used to differentiate any chemical reaction
which takes place in living systems without interfering with inherent biochemical
processes. Such reactions have been applied to activate prodrugs through strain
promoted bio-orthogonal chemical processes and subsequent drug release. This has
been developed for the release of a number of drugs including cytotoxic agents
typified by the insightful work of Matikonda, Gamble and co-workers (Matikonda
et al. 2015, 2018). Their prodrug activation strategy involved five steps with a key
initial one being a strain-promoted 1,3-dipolar cycloaddition reaction of an aryl azide
(linked in turn to the inactive cytotoxin unit) to a substituted trans-cyclooctene to
give an unstable 1,2,3-triazoline derivative which could fragment and rearrange with
nitrogen loss to give an imine linked prodrug unit. Acid catalysed hydrolysis of the
imine then triggered a further 1,6-elimination to release the active cytotoxic drug.
This type of activation approach is adaptable in principle to antibacterial release as
shown by Czuban et al. (2018) who have reported on targeted treatment of local bacterial infections using the catch and release strategy. Their strategy requires an initial
local injection of material with a tetrazine attached to an alginate gel at the target
infected site in vivo, followed by a systemic dose of the prodrug, then a concentration
phase when the the two components come in contact and ‘catch’, and finally prodrug
activation. The ‘catch’ in this case involves an inverse electron demand Diels–Alder
reaction between the strained trans-cyclooctene amide-linked antibiotic prodrug unit
and the 1,2,4,5-tetrazine diene component with release of nitrogen. The activation
and release stage is mediated by spontaneous isomerization (tautomerisation) in the
dihydrodiazine ring which then promotes elimination of carbon dioxide and release of
the antibiotic (daptomycin or vancomycin) near the infection site. This then leaves
an aromatic 1,2-diazine unit (after tautomerisation) fused to the cyclooctane and
attached to the gel. The number of stages in this approach is a little problematic and
the challenge will be to simplify and make the process more compact, but at least
the principles have been established.
There are other bio-orthogonal approaches to prodrug cleavage (Weiss et al. 2015)
involving non-biological, physical or chemical initiators to ultimately release the
active component or components from the prodrug which could also be useful if
the prodrug can be concentrated in bacteria or at their surface. A good review on
biorthogonal approaches to ‘on demand’ prodrug activation is that by Ji et al. (2019).
The emphasis here is on the click and release approach, but one needs to watch
overly complicated designs and a reliance on intermolecular reactions which can be
problematic in terms of getting reactants together in sufficient concentration in vivo.
Secondary intramolecular reactions would thus be preferable and ways to incorporate
this possibility in the overall prodrug design should be further investigated.
Combinations of biological and chemical triggers can also be effective and these
usually involve enzymatic cleavage of a prodrug followed by further chemical reaction of the intermediate produced to give other bioactive products. Scope exists
4 Design Principles and Development of Prodrugs for Multiply …
4.3.2 Chemical
Bio-orthogonal prodrugs
The term bio-orthogonal chemistry is used to differentiate any chemical reaction
which takes place in living systems without interfering with inherent biochemical
processes. Such reactions have been applied to activate prodrugs through strain
promoted bio-orthogonal chemical processes and subsequent drug release. This has
been developed for the release of a number of drugs including cytotoxic agents
typified by the insightful work of Matikonda, Gamble and co-workers (Matikonda
et al. 2015, 2018). Their prodrug activation strategy involved five steps with a key
initial one being a strain-promoted 1,3-dipolar cycloaddition reaction of an aryl azide
(linked in turn to the inactive cytotoxin unit) to a substituted trans-cyclooctene to
give an unstable 1,2,3-triazoline derivative which could fragment and rearrange with
nitrogen loss to give an imine linked prodrug unit. Acid catalysed hydrolysis of the
imine then triggered a further 1,6-elimination to release the active cytotoxic drug.
This type of activation approach is adaptable in principle to antibacterial release as
shown by Czuban et al. (2018) who have reported on targeted treatment of local bacterial infections using the catch and release strategy. Their strategy requires an initial
local injection of material with a tetrazine attached to an alginate gel at the target
infected site in vivo, followed by a systemic dose of the prodrug, then a concentration
phase when the the two components come in contact and ‘catch’, and finally prodrug
activation. The ‘catch’ in this case involves an inverse electron demand Diels–Alder
reaction between the strained trans-cyclooctene amide-linked antibiotic prodrug unit
and the 1,2,4,5-tetrazine diene component with release of nitrogen. The activation
and release stage is mediated by spontaneous isomerization (tautomerisation) in the
dihydrodiazine ring which then promotes elimination of carbon dioxide and release of
the antibiotic (daptomycin or vancomycin) near the infection site. This then leaves
an aromatic 1,2-diazine unit (after tautomerisation) fused to the cyclooctane and
attached to the gel. The number of stages in this approach is a little problematic and
the challenge will be to simplify and make the process more compact, but at least
the principles have been established.
There are other bio-orthogonal approaches to prodrug cleavage (Weiss et al. 2015)
involving non-biological, physical or chemical initiators to ultimately release the
active component or components from the prodrug which could also be useful if
the prodrug can be concentrated in bacteria or at their surface. A good review on
biorthogonal approaches to ‘on demand’ prodrug activation is that by Ji et al. (2019).
The emphasis here is on the click and release approach, but one needs to watch
overly complicated designs and a reliance on intermolecular reactions which can be
problematic in terms of getting reactants together in sufficient concentration in vivo.
Secondary intramolecular reactions would thus be preferable and ways to incorporate
this possibility in the overall prodrug design should be further investigated.
Combinations of biological and chemical triggers can also be effective and these
usually involve enzymatic cleavage of a prodrug followed by further chemical reaction of the intermediate produced to give other bioactive products. Scope exists