Tetrahedron Letters
A double branched photosensitive prodrug: synthesis
and characterization of light triggered drug release
Wei Liu a, Li Liang a, Pik Kwan Lo b, Xiao Jun Gou a, Xiao Hua Sun a,
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a Department of Pharmacy, School of Pharmacy & Bioengineering, Chengdu University, Chengdu, Sichuan Province 610106, PR China
b Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel oNB based, double branched photosensitive prodrug 1, and a biphenyl counterpart 2 were
designed and synthesized. Their photo-triggered drug release properties were studied by HPLC and
UV–vis spectra. The isobestic points in UV–vis spectra of prodrug 1 indicated that homogeneous photol-
ysis reaction happened upon xenon-based light irradiation. HPLC analysis confirmed that (antitumor)
Received 3 November 2015
Revised 25 December 2015
Accepted 19 January 2016
Available online 19 January 2016
chlorambucil was released quickly accompanied with photobyproducts. Prodrug 1 has a half-time (t1/2
)
of 12.4 min, indicated a good sensitivity towards the light irradiation, making it a promising candidate
for applications where UV light is limited.
Keywords:
Photoremovable protecting group
Drug release
Ó 2016 Elsevier Ltd. All rights reserved.
o-Nitrobenzyl
Prodrug
Chlorambucil
Introduction
mentioned above, the major bottle neck for its biological/
pharmacological application is that the efficient release of caged
Photoremovable protecting groups (PPGs), either prompted by
one-photon excitation or two-photon excitation, have attracted
much attention in the area of drug delivery systems (DDS) in
recent years.1 The release of active drug molecules from PPGs irra-
diated by photons pave the way for effective DDS, as light can be
used as extraneous non-physical contact stimulus with precise
spatiotemporal control.2
Among the photolabile protecting platforms developed, the
wavelength used to irradiate PPGs usually fall in the UV range,
except for coumarin series (kmax = 400–500 nm),3 due to their
intrinsic mono-aromatic ring system. This is a major drawback
for their in vivo biological applications because (1): light scatting
and tissue chromophores absorbance cause poor penetration depth
and (2): long-term exposure to UV radiation is harmful to
biological tissues.4 Thus, there is an application-driven research
for molecules sensitive to visible light or IR light as drug carriers
in designing efficient photoresponsive DDS.1b,5
molecule requires UV lights, which is detrimental to the organism.
Molecular engineering has already been started by researchers to
address this problem.8 Two effective strategies employed to
facilitate long wavelength absorption are the introduction of elec-
tro-donating and/or electro-withdrawing substitutes to promote
the internal charge transfer (ICT), and the elongation of D–p–A
backbone to increase the molar absorptivity.9 On the other hand,
it has to be emphasized that structural modification towards PPGs
is not guaranteed to promote their photolytic performance, and in
fact, can sometimes have a negative impact on their photochemical
properties.10 Jullien, Goeldner, Bolze and Zhu groups recently
reported the design of donor–acceptor biphenyl oNB and styryl-
2-nitrobenzyl (SNB) derivatives as PPGs, which showed better pho-
tosensitivities by either one-photon or two-photon irradiation
compared with classical 4,5-dimethoxy-2-nitrobenzyl (DMNB)
protecting group.1b,8,11
Therefore, to better understand the structure–property rela-
tionship for developing efficient photoremovable DDS, we
designed and synthesized an oNB based photosensitive prodrug 1
(shown in Fig. 1), a double branched dipolar molecule containing
two oNB moieties binding two chlorambucil molecules, and 2, a
monomeric counterpart.11a
o-Nitrobenzyl (oNB) derivative, which was first introduced as
photosensitive protecting group in 1970,6 has gained much atten-
tion due to its well-studied photolysis mechanism.7 It is also easy
to be synthetically accessed and has efficient photosensitivity. It
had become one of the most widely used PPGs. However, as
The designed prodrug 1 has two D–p–A backbones constructed
by di(ethylene glycol) fragments and opposite nitro groups bound
together with the conjugated three aromatic rings. It is expected to
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0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.