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DOI: 10.1002/cmdc.201500127
Full Papers
Rational Design of Ruthenium Complexes Containing
2,6-Bis(benzimidazolyl)pyridine Derivatives with
Radiosensitization Activity by Enhancing p53 Activation
Zhiqin Deng, Lianling Yu, Wenqiang Cao, Wenjie Zheng, and Tianfeng Chen*[a]
The rational design of metal-based complexes is an effective
strategy for the discovery of potent sensitizers for use in
cancer radiotherapy. In this study, we synthesized three ruthe-
nium complexes containing bis-benzimidazole derivatives:
Ru(bbp)Cl3 (1), [Ru(bbp)2]Cl2 (2a) (in which bbp=2,6-bis(benzi-
midazol-1-yl)pyridine), and [Ru(bnbp)2]Cl2 (2b) (where bnbp=
2,6-bis-(6-nitrobenzimidazol-2-yl)pyridine). We evaluated their
radiosensitization capacities in vitro and mechanisms of action.
Complex 2b was found to be particularly effective in sensitiz-
ing human melanoma A375 cells toward radiation, with a sensi-
tivity enhancement ratio of 2.4. Along with this potency, com-
plex 2b exhibited a high degree of selectivity between human
cancer and normal cells. Mechanistic studies revealed that 2b
promotes radiation-induced accumulation of intracellular reac-
tive oxygen species (ROS) by reacting with cellular glutathione
(GSH) and then causing DNA stand breaks. The subsequent
DNA damage induces phosphorylation of p53 (p-p53) and up-
regulates the expression levels of p21, which inhibits the ex-
pression of cyclin-B, leading to G2M arrest. Moreover, p-p53 ac-
tivates caspases-3 and -8, triggers cleavage of poly(ADP-ribose)
polymerase (PARP), finally resulting in apoptosis. Taken togeth-
er, the results of this study provide a strategy for the design of
ruthenium-based radiosensitizers for use in cancer therapy.
Introduction
Radiation therapy has been used widely as a clinical treatment
for controlling or killing malignant cells for more than 100
years with varying degrees of success.[1] More than 50% of
cancer patients will undergo radiation therapy of some form,
alone or in combination with other treatments.[2] Although ra-
diation therapy has improved significantly over the last few de-
cades, many patients still suffer from localized side effects fol-
lowing treatment, such as fatigue, skin irritation, intestinal
damage, and oral mucositis.[3] Therefore, any improvement in
radiation therapy will benefit numerous people.
cisplatin and its analogues has been limited by serious side ef-
fects, a restricted spectrum of activity, and poor tumor selectiv-
ity.[6] Ruthenium-based complexes are potential alternatives to
cisplatin because of their suitability for the design of antitumor
agents; this includes a favorable ligand exchange rate, a good
range of accessible oxidation states, and, most importantly,
their photoactivated biological applications.[7] James and co-
workers demonstrated that Ru complexes of 4-nitroimidazoles
have good radiosensitizing properties and relatively low toxici-
ty.[8] Recently, Sgambellone et al.[9] discovered that the complex
[Ru(tpy)(5CNU)3]2+ (tpy=2,2:6,2-terpyridine and 5CNU=5-cya-
nouracil) shows much greater cytotoxicity after irradiation with
visible light, showing its potential for use in photodynamic
therapy (PDT). A similar potential can be applied to the Ru–
polypyridyl complexes discovered by Howerton et al.[10] Benzi-
midazoles possess the characteristics of favorable bioactivity
and fluorescence, are important pharmacophores for many
drugs, and exhibit a variety of pharmacological activities, such
as antiparasitic, antioxidant, and anti-inflammatory activities.[11]
Our previous work has shown that Ru complexes containing
bis-benzimidazole derivatives are able to effectively induce
DNA damage in cancer cells, and these complexes show great
selectivity between human cancer and normal cells.[12] More-
over, Gupta et al. and Wright et al. discovered that nitrobenzi-
midazole can effectively sensitize tumor cells to radiation.[13] In-
spired by these results, we hypothesized that Ru complexes
containing bis-benzimidazole derivatives could be activated by
X-ray radiation, as it possesses higher energy than visible light,
thereby sensitizing cancer cells to radiation. For this purpose,
three Ru–bis-benzimidazole complexes were synthesized
In the past decades, radiosensitizers have been widely used
as an effective strategy to improve the local–regional effects of
radiotherapy. The low absorption of radiation across biological
tissues limits the targeting of tumor cells, thus decreasing the
therapeutic efficacy. Metals exhibit higher radiation absorption
across tissue sections, leading to potentiation of the effective-
ness of radiation.[4] Therefore, the rational design of metal-
based complexes is a good strategy toward the discovery of
potent radiosensitizers. Moreover, considerable evidence has
shown that enhancing DNA damage and inhibiting DNA repair
processes can sensitize tumor cells to radiation.[5] For this
reason, many metal-based complexes, especially platinum
complexes, have been developed as radiosensitizers, owning
to their DNA-targeting properties. However, the application of
[a] Z. Deng, L. Yu, Dr. W. Cao, Prof. W. Zheng, Prof. T. Chen
Department of Chemistry, Jinan University
Guangzhou 510632, (P.R. China)
Supporting information for this article is available on the WWW under
ChemMedChem 2015, 10, 991 – 998
991
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