Photoactivatable Cell-Selective Dinuclear trans-Diazidoplatinum(IV) Anticancer Prodrugs
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F18%3A00501669" target="_blank" >RIV/68081707:_____/18:00501669 - isvavai.cz</a>
Alternative codes found
RIV/61989592:15310/18:73589810
Result on the web
<a href="https://pubs.acs.org/doi/10.1021/acs.inorgchem.8b02599" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.inorgchem.8b02599</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.inorgchem.8b02599" target="_blank" >10.1021/acs.inorgchem.8b02599</a>
Alternative languages
Result language
angličtina
Original language name
Photoactivatable Cell-Selective Dinuclear trans-Diazidoplatinum(IV) Anticancer Prodrugs
Original language description
A series of dinuclear octahedral Pt-IV complexes trans,trans,trans-[{Pt(N-3)(2)(py)(2)(OH)(OC(O)CH2CH2C(O)NH)}(2)R] containing pyridine (py) and bridging dicarboxylate [R =CH2CH2- (1), trans-1,2-C6H10- (2), p-C6H4- (3),CH2CH2CH2CH2- (4)] ligands have been synthesized and characterized, including the X-ray crystal structures of complexes 1 center dot 2MeOH and 4, the first photoactivatable dinuclear Pt-IV complexes with azido ligands. The complexes are highly stable in the dark, but upon photoactivation with blue light (420 nm), they release the bridging ligand and mononuclear photoproducts. Upon irradiation with blue light (465 nm), they generate azidyl and hydroxyl radicals, detected using a 5,5-dimethyl-1-pyrroline N-oxide electron paramagnetic resonance spin trap, accompanied by the disappearance of the ligand-to-metal charge-transfer (N-3> Pt) band at ca. 300 nm. The dinuclear complexes are photocytotoxic to human cancer cells (465 nm, 4.8 mW/cm(2), 1 h), including A2780 human ovarian and esophageal OE19 cells with IC50 values of 8.8-78.3 mu M, whereas cisplatin is inactive under these conditions. Complexes 1, 3, and 4 are notably more photoactive toward cisplatin-resistant ovarian A2780cis compared to A2780 cells. Remarkably, all of the complexes were relatively nontoxic toward normal cells (MRCS lung fibroblasts), with IC50 values >100 mu M, even after irradiation. The introduction of an aromatic bridging ligand (3) significantly enhanced cellular uptake. The populations in the stages of the cell cycle remained unchanged upon treatment with complexes in the dark, while the population of the G2/M phase increased upon irradiation, suggesting that DNA is a target for these photoactivated dinuclear Pt-IV complexes. Liquid chromatography-mass spectrometry data show that the photodecomposition pathway of the dinuclear complexes results in the release of two molecules of mononuclear platinum(II) species. As a consequence, DNA binding of the dinuclear complexes after photoactivation in cell-free media is, in several respects, qualitatively similar to that of the photoactivated mononuclear complex FM-190. After photoactivation, they were 2-fold more effective in quenching the fluorescence of EtBr bound to DNA, forming DNA interstrand cross-links and unwinding DNA compared to the photoactivated FM-190.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10402 - Inorganic and nuclear chemistry
Result continuities
Project
<a href="/en/project/GA18-09502S" target="_blank" >GA18-09502S: Targeting resistance to chemotherapy of tumor cells to reinstate their susceptibility to novel, existing and unsuccessful anticancer metallodrugs</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Inorganic Chemistry
ISSN
0020-1669
e-ISSN
1520-510X
Volume of the periodical
57
Issue of the periodical within the volume
22
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
14409-14420
UT code for WoS article
000451244700045
EID of the result in the Scopus database
2-s2.0-85055985380