Metal complexes as molecular switches and probes in DNA

Doctoral Dissertation uoadl:1309532 631 Read counter

Unit:
Τομέας ΙΙΙ [Ανόργανη Χημεία – Ανόργανη Χημική Τεχνολογία – Περιβαλλοντική Χημεία]
Library of the School of Science
Deposit date:
2014-04-09
Year:
2014
Author:
Καπλάνης Μιχαήλ
Dissertation committee:
Χριστίνα-Άννα Μητσοπούλου, Καθηγήτρια ΕΚΠΑ (επιβλέπουσα), Γεώργιος Πιστόλης, Ερευνητής Α΄ ΕΚΕΦΕ Δημόκριτος, Ιωάννης Παπαευσταθίου, Επίκ. Καθηγητής ΕΚΠΑ
Original Title:
Χρήση συμπλόκων ενώσεων ως μοριακών διακοπτών και ανιχνευτών στο DNA
Languages:
Greek
Translated title:
Metal complexes as molecular switches and probes in DNA
Summary:
In the current thesis, we describe the design of metal complexes acting as DNA
probes and potential chemotherapeutic agents. A series of novel metal complexes
was synthesized and characterized using IR, NMR, UV-Vis and emission
spectroscopy. The crystal structure of the complex [Re(CO)3(pq)(py)]PF6 has
been determined by X-ray diffraction methods. We also studied their DNA-binding
properties with a range of techniques such as CD, CV, viscosity measurements,
Tm, UV-Vis and emission titration. Their DNA photocleavage ability and the in
vitro antitumor effect against human breast (MCF-7), prostate (PC3) and
glioblastoma (T98G) cancer were also studied. Moreover, their ability to
inhibit PAF and to modulate the PAF-basic metabolic enzymes was studied. The
complexes of the type fac-[Re(CO)3(a-diimine)L]0/+ interact with CT-DNA mainly
via a groove binding mode, in contrast to the substituted dppz complex, which
intercalates in the base pairs. Although the dppz complex interacts stronger
than the other complexes and acts as a molecular light switch, it is difficult
to promote the DNA photo-cleavage. The other a-diimine Re(I) complexes showed
nicking of the plasmid pBR322 upon irradiation. Mechanistic studies revealed
the necessity of the oxygen in the photocleavage ability of the pq complexes.
The phendione complex cleaves the single strand through an independent oxygen
mechanism.
The tetra-rhenium porphyrin complex {H2TPyP[Re(CO)3(pq)]4}4PF6 strongly
interacts with the DNA grooves. Its strong DNA-binding affinity is due to the
electrostatic interactions with the phosphate backbone. The porphyrin complex
is photocatalytically more reactive than the monomeric complex. The
Gallium(III) porphyrin complex binds to DNA with outside self-stacking. Despite
the low DNA-binding affinity of the metalloporphyrin, it showed a double strand
breaks via a mechanism that involves single oxygen generation. In vitro
cytotoxicity studies of the complexes against MCF-7, PC3 and T98G were
determined using MTT assay. The coordination of the phendione with the Re(I)
center significantly reduces the toxicity presented by the ligand. In contrast,
pq complexes exhibit strong toxicity compared with the nontoxic free pq ligand.
The data reveal the crucial role of the axial ligand and the charge of the
complex of type [Re(CO)3(pq)(L)]0/+ (L=Cl, MeCN, py), in the cytotoxicity
properties. The Ga(III) metalloporphyrin showed strong toxicity against MCF-7
and PC3 cell lines, but moderate toxicity against T98G cells. In contrast to
the free ligands, complexes [Re(CO)3(phendione)Cl], [Re(CO)3[dppz(COOEt)2]Cl],
and mainly the precursor molecule [Re(CO)5Cl] exhibit strong inhibition of PAF
aggregation. Moreover, the complexes affect the PAF-biosynthetic enzymes,
lyso-PAF-AT and PAF-CPT, whereas complex [Re(CO)3(phendione)Cl] affect the PAF
catabolism.
Keywords:
Re(I) complexes, Ga(III)-porphyrin, DNA binding, Cytotoxicity studies, PAF
Index:
Yes
Number of index pages:
xv-xxvii
Contains images:
Yes
Number of references:
232
Number of pages:
xxvii, [1], 248
document.pdf (5 MB) Open in new window