4.3 Release Mechanisms and Prodrug Design
147
also for possibilities with the reverse triggers, that is with the active drug or drugs
being released in the second stage by enzymatic action after an initial chemical or
photochemical reaction activation step.
An example of biologically-induced release followed by chemical release has
been noted for the broad spectrum anti-fungal agent Isavuconazole (Rautio et al.
2018). In this case the quaternary salt prodrug Isavucazonium sulfate undergoes
initial activation by esterase enzyme-mediated hydrolysis of a remote ester unit.
The alcohol unit revealed then proceeds spontaneously to a rapid intramolecular
cyclisation reaction which triggers in turn a N-dealkylation step to release the active
Isavuconazole. Application of this strategy to prodrug design in antibacterial settings
should also be assessed.
4.3.3 Physical
Physically-initiated release or activation mechanisms are also important in the
prodrug setting. Extensive work has been done on photo-induced bio-orthogonal
chemistry for spatio-temporal control in delivering molecules for interaction with
biological targets (Li et al. 2020) as part of the photopharmacology field (Arrue
and Ratjen 2017; Velema et al. (2014). Applications of phototriggered targeting in
nanomedicine (Arrue and Ratjen 2017) remain to be fully explored in the antibacterial
area as are applications of photo-switchable antibiotics in interfering with quorum
sensing (Feringa 2017). This suggests in turn that photoswitching could be combined
with drug release from a prodrug although this would mean visible- or near IR-light
induced bond cleavage not UV light induced reactions in view of the negative effects
of UV light. However, initial design ideas might usefully come from an assessment of
known UV-photocleavable protecting groups and then modification of the structural
features to include chromophores which would absorb light mainly in the visible or
preferably the NIR region.
For photo-activated prodrugs, new designs could come from compounds known to
undergo photoisomerisation rather than light induced cleavage reactions producing
other products. For example, one might base new designs on analogues of a substituted dihydropyrene system. Such a dihydropyrene system has been described with
a donor N(CH 3 ) 2 and acceptor (NO 2 ) substituent which are coupled in the coloured
form and on one photon near infrared excitation is isomerised to a colourless crossconjugated product in which these groups are uncoupled. This isomer then converts
back thermally (T) to the coloured form (a negative T-type photochromic system)
(Klaue et al. 2018). From these results it could be of interest to look at heterocyclic
analogues, for example the new diaza analogue proposed in Scheme 4.7a. In this
conjugated system the donor tertiary amino and the nitro acceptor group are coupled.
A 6π electrocyclic internal ring opening to give the cross-conjugated system where
the donor and acceptor groups are uncoupled (Scheme 4.7b) on irradiation with
near infrared light would be expected to occur. This could then expose the resultant
α,β-unsaturated nitroalkene moiety to nucleophilic attack by a number of sulfur- or
147
also for possibilities with the reverse triggers, that is with the active drug or drugs
being released in the second stage by enzymatic action after an initial chemical or
photochemical reaction activation step.
An example of biologically-induced release followed by chemical release has
been noted for the broad spectrum anti-fungal agent Isavuconazole (Rautio et al.
2018). In this case the quaternary salt prodrug Isavucazonium sulfate undergoes
initial activation by esterase enzyme-mediated hydrolysis of a remote ester unit.
The alcohol unit revealed then proceeds spontaneously to a rapid intramolecular
cyclisation reaction which triggers in turn a N-dealkylation step to release the active
Isavuconazole. Application of this strategy to prodrug design in antibacterial settings
should also be assessed.
4.3.3 Physical
Physically-initiated release or activation mechanisms are also important in the
prodrug setting. Extensive work has been done on photo-induced bio-orthogonal
chemistry for spatio-temporal control in delivering molecules for interaction with
biological targets (Li et al. 2020) as part of the photopharmacology field (Arrue
and Ratjen 2017; Velema et al. (2014). Applications of phototriggered targeting in
nanomedicine (Arrue and Ratjen 2017) remain to be fully explored in the antibacterial
area as are applications of photo-switchable antibiotics in interfering with quorum
sensing (Feringa 2017). This suggests in turn that photoswitching could be combined
with drug release from a prodrug although this would mean visible- or near IR-light
induced bond cleavage not UV light induced reactions in view of the negative effects
of UV light. However, initial design ideas might usefully come from an assessment of
known UV-photocleavable protecting groups and then modification of the structural
features to include chromophores which would absorb light mainly in the visible or
preferably the NIR region.
For photo-activated prodrugs, new designs could come from compounds known to
undergo photoisomerisation rather than light induced cleavage reactions producing
other products. For example, one might base new designs on analogues of a substituted dihydropyrene system. Such a dihydropyrene system has been described with
a donor N(CH 3 ) 2 and acceptor (NO 2 ) substituent which are coupled in the coloured
form and on one photon near infrared excitation is isomerised to a colourless crossconjugated product in which these groups are uncoupled. This isomer then converts
back thermally (T) to the coloured form (a negative T-type photochromic system)
(Klaue et al. 2018). From these results it could be of interest to look at heterocyclic
analogues, for example the new diaza analogue proposed in Scheme 4.7a. In this
conjugated system the donor tertiary amino and the nitro acceptor group are coupled.
A 6π electrocyclic internal ring opening to give the cross-conjugated system where
the donor and acceptor groups are uncoupled (Scheme 4.7b) on irradiation with
near infrared light would be expected to occur. This could then expose the resultant
α,β-unsaturated nitroalkene moiety to nucleophilic attack by a number of sulfur- or