COMMUNICATION
DOI: 10.1002/chem.201201605
Nitric Oxide Donor-Based Platinum Complexes as Potential Anticancer
Agents
Jian Zhao,[a] Shaohua Gou,*[a, b] Yanyan Sun,[a, b] Runting Yin,[a, b] and Zhimei Wang[a, b]
Platinum-based antitumor drugs such as cisplatin, carbo-
platin, and oxaliplatin represent one of the most important
classes of chemotherapeutic agents available for the treat-
ment of solid tumors.[1] Nevertheless, the serious side effects
and insurmountable cross-resistance of platinum-based
drugs cannot be ignored. Therefore, numerous attempts
have been made to overcome these drawbacks.[2] An effec-
tive method used in clinical trials is to combine platinum
complexes with other active drugs to enhance the drug sen-
sitivity and decrease the side effects; some of these ap-
proaches achieved the expected result.[3] Therefore, it is a
reasonable approach for antitumor drug development to
tether classical platinum moieties to some active pharmaco-
phore to obtain a synergistic effect on targeting the tumor
cells.
Nitric oxide (NO), a water-soluble gaseous free radical, is
well known for its biological functions in vasodilation, neu-
rotransmission, the immune system, and cell apoptosis. Dif-
ferent concentrations of NO have different effects on cell
apoptosis. In general, the high concentration of nitric oxide
leads to inhibition of cell growth and induces apoptotic cell
death, whereas low concentrations of nitric oxide promotes
cell growth.[4] However, the antineoplastic mechanism of
nitric oxide is rather complicated.[5] Nitric oxide produced
by active macrophages induces cytostasis and cytotoxicity on
tumor cells and parasites, the mechanism seeming to be the
inhibition of ribonucleotide reductase.[6] In recent reports,
nitric oxide also shows antiproliferative ability, which is
caused by its ability to inhibit the expression of CDK 2, thus
inducing the expression of p21.[7] Owing to its specific anti-
tumor function, researchers are increasingly interested in
compounds that are capable of generating nitric oxide
in situ, that is., nitric oxide donors.[8]
The antitumor activity of nitric oxide was first confirmed
when nitrates synthesized by murine macrophages resulted
in cytotoxicity against tumor cells;[9] since then, research ef-
forts have been devoted to designing hybrids of nitric oxide
donors as anticancer agents.[10] Furthermore, a few indirect
ways have been adopted, such as treating nitric oxide pro-
drugs with platinum-based drugs to study the role of nitric
oxide in enhancing the cytotoxicity and overcoming cross-re-
sistance of platinum complexes. For instance, the cytotoxici-
ty of cisplatin was enhanced by long-acting nitric oxide
donors in head and neck squamous cell carcinoma cell
lines.[11] NCX-4040, an aspirin-based nitric oxide donor, can
resensitize and potentiate the activity of cisplatin on drug-
resistant human ovarian xenograft tumors.[12] In addition,
GTN, which is a typical nitric oxide donor, can improve the
chemosensitivity of carboplatin in patients with lung adeno-
carcinoma.[13] Organic nitrates, the oldest class of nitric
oxide donors, have long been used to relieve angina pecto-
ris. Their safety and the fact that they show minor side ef-
fects in clinical applications make organic nitrates ideal
agents for the release of nitric oxide. Based on the above
study, we intend to design and prepare platinum complexes
with organic nitrates as ligands so as to enhance the cytotox-
icity and overcome cross-resistance of platinum drugs.
Notably, all the platinum-based drugs available in the
clinic at present are the so called classical platinum com-
plexes that adhere to the structure-activity relationships
summarized by Cleare and Hoeschele.[14] Although numer-
ous nonclassical platinum complexes have been investigated,
only a few of them were tested in clinical trials and none of
them have come into the clinic so far.[15] Thus, the study of
cisplatin analogues with improved pharmaceutical properties
is still an effective way to discover new platinum-based
drugs. In this work, a number of platinum complexes con-
taining either nitrooxy acetate (L1) or 3-(nitrooxy)cyclobu-
tane-1,1-dicarboxylate (L2, Scheme 1), in which the nitro-
oxy-based ligand acts as both a nitric oxide donor and a
leaving group, are reported with their antitumor activity
(Figure 1). Since complex 1 is easily viscous when exposed
to the air, it was not tested in this work.. The other com-
[a] J. Zhao, Prof. Dr. S. Gou, Y. Sun, Dr. R. Yin, Z. Wang
Pharmaceutical Research Center
School of Chemistry and Chemical Engineering
Southeast University
Nanjing 211189 (P. R. China)
Fax : (+86)83272381
1
plexes were characterized by IR and H NMR spectroscopy
[b] Prof. Dr. S. Gou, Y. Sun, Dr. R. Yin, Z. Wang
Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research
Southeast University
and ESI-MS (see the Supporting Information). HPLC was
used to determine the levels of purity of the newly synthe-
sized complexes. In the HPLC chromatograms of complexes
2 and 3, which contain nitrooxy acetate ligands, there were
two main peaks that appeared very early on, with the major
Nanjing 211189 (P. R. China)
Supporting information for this article is available on the WWW
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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