The binding properties of some novel ruthenium (III) complexes with human serum transferrin
Aim. The transferrin cycle gained increased interest in recent years and it holds promise as an attractive system for strategies of drug targeting to tumors. Neoplasic cells exhibit a large demand of iron and therefore express highly transferrin receptors. As a consequence, transferrin conjugates c...
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Інститут молекулярної біології і генетики НАН України
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| Цитувати: | The binding properties of some novel ruthenium (III) complexes with human serum transferrin / A.L. Arsene, V. Uivarosi, N. Mitrea, C.M. Dragoi, A. Nicolae // Вiopolymers and Cell. — 2011. — Т. 27, № 2. — С. 141-146. — Бібліогр.: 20 назв. — англ. |
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irk-123456789-1564012019-06-19T01:24:56Z The binding properties of some novel ruthenium (III) complexes with human serum transferrin Uivarosi, V. Mitrea, N. Dragoi, C.M. Nicolae, A. Arsene, A.L. Biomedicine Aim. The transferrin cycle gained increased interest in recent years and it holds promise as an attractive system for strategies of drug targeting to tumors. Neoplasic cells exhibit a large demand of iron and therefore express highly transferrin receptors. As a consequence, transferrin conjugates can preferentially interact with cancer cells. This strategy is exploited nowadays for targeting novel anti-cancer drugs. Recent data showed that ruthenium (III) compounds possess antitumor and antimetastatic effects, due to their affinity for crucial biomolecules (like transferrin). Methods. The paper presents the transferrin-binding properties of some novel ruthenium (III) complexes with general formula RuL2 (DMSO) mCl3 ·nH2O ((Ru-nf) L: norfloxacin (nf), m = 1, n = 1; (Ru-cpx) L: ciprofloxacin (cpx), m = 2, n = 2; (Ru-oflo) L: ofloxacin (oflo), m = 1, n = 1; (Ru-levo) L: levofloxacin (Levo), m = 2, n = 8; (Ru-pip) L: pipemidic acid (pip), m = 1, n = 2, DMSO: dimethylsulfoxide). We investigated, in vitro, the interactions of these ligands with human transferrin through spectroscopic techniques, with the ultimate goal of preparing adducts with good selectivity for cancer cells. Results. All studied complexes interact with human serum transferrin; the molar ratio [complex]/[transferrin] strongly influences the binding affinity. Conclusions. The best interaction between the complexes studied and transferrin is achieved for a molar ratio of 8; the best interaction was registered for Ru-pip, followed by Ru-nf. Keywords: ruthenium (III) complexes, transferrin. Мета. Останніми роками трансфериновий цикл викликає по - силений інтерес як перспективна система цільової доставки протипухлинних препаратів безпосередньо в пухлину. Неопластичні клітини потребують багато заліза, через що експресують велику кількість трансферинових рецепторів. Внаслідок цього кон ’югати трансферину здатні насамперед взаємодіяти з раковими клітинами. Цю стратегію у наш час використовують для пошуку нових протиракових препаратів. Останні дані демонструють, що сполукам рутенію (III) притаманні протипухлинні і антиметастатичні ефекти завдяки їхній афінності до важливих біомолекул (таких як трансферин). Методи. У статті представлено трансферин-зв’язувальні властивості деяких нових комплексів рутенію (III) загальною формулою RuL2 (DMSO) mCl3 ×nH2O ((Ru-nf) L: норфлоксацин (nf), m = 1, n = = 1; (Ru-cpx) L: ципрофлоксацин (cpx), m = 2, n = 2; (Ru-of) L: офлоксацин (oflo), m = 1, n = 1; (Ru-levo) L: левофлоксацин (Levo), m = 2, n = 8; (Ru-pip) L: піпемідинова кислота (pip), m = = 1, n = 2, DMSO: диметилсульфоксид). Ми вивчали взаємодію in vitro цих лігандів з трансферином людини методом спектроскопії для одержання адуктів з високою селективністю до ракових клітин. Результати і висновки. Всі досліджувані комплекси взаємодіють з сироватковим трансферином людини, молярне співвідношення [комплекс]/[трансферин] значно впливає на зв’язувальні властивості. Найкращу взаємодію між аналізованими комплексами і трансферином відмічено при молярному співвідношенні 8:1, а також для Ru-pip і Ru-nf. Ключові слова: комплекси рутенію (III), трансферин. Цель. В последние годы трансферриновый цикл вызывает повышенный интерес как перспективная система целевой доставки противоопухолевых препаратов непосредственно в опухоль. Неопластические клетки испытывают высокую потребность в железе и, следовательно, экспрессируют много трансферриновых рецепторов. Вследствие этого конъюгаты трансферрина способны преимущественно взаимодействовать с раковыми клетками. Эту стратегию в настоящее время используют для поиска новых противораковых препаратов. Последние данные показывают, что соединения рутения (III) обладают противоопухолевым и антиметастатическим эффектами благодаря их аффинности к важным биомолекулам (таким как трансферрин). Методы. В статье представлены трансферрин-связывающие свойства некоторых новых комплексов рутения (III) с общей формулой RuL2 (DMSO) mCl3 ×nH2O ((Ru-nf) L: норфлоксацин (nf), m = 1, n = 1; (Ru-cpx) L: ципрофлоксацин (cpx), m = 2, n = 2; (Ru-of) L: офлоксацин (oflo), m = 1, n = 1; (Ru-levo) L: левофлоксацин (Levo), m = 2, n = 8; (Ru-pip) L: пипемидиновая кислота (pip), m = 1, n = 2, DMSO: диметилсульфоксид). Мы изучили взаимодействие in vitro этих лигандов с человеческим трансферрином методом спектроскопии для получения аддуктов, обладающих хорошей селективностью к раковым клеткам. Результаты и выводы. Все исследуемые комплексы взаимодействуют с человеческим сывороточным трансферрином, молярное соотношение [комплекс]/ [трансферрин] сильно влияет на связывающие свойства. Наилучшее взаимодействие между изучаемыми комплексами и трансферрином отмечено при молярном соотношении 8:1, а также для Ru-pip и Ru-nf. Ключевые слова: комплексы рутения (III), трансферрин. 2011 Article The binding properties of some novel ruthenium (III) complexes with human serum transferrin / A.L. Arsene, V. Uivarosi, N. Mitrea, C.M. Dragoi, A. Nicolae // Вiopolymers and Cell. — 2011. — Т. 27, № 2. — С. 141-146. — Бібліогр.: 20 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00008D http://dspace.nbuv.gov.ua/handle/123456789/156401 611.018.54 + 661.896 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| language |
English |
| topic |
Biomedicine Biomedicine |
| spellingShingle |
Biomedicine Biomedicine Uivarosi, V. Mitrea, N. Dragoi, C.M. Nicolae, A. Arsene, A.L. The binding properties of some novel ruthenium (III) complexes with human serum transferrin Вiopolymers and Cell |
| description |
Aim. The transferrin cycle gained increased interest in recent years and it holds promise as an attractive
system for strategies of drug targeting to tumors. Neoplasic cells exhibit a large demand of iron and therefore express highly transferrin receptors. As a consequence, transferrin conjugates can preferentially interact with cancer cells. This strategy is exploited nowadays for targeting novel anti-cancer drugs. Recent
data showed that ruthenium (III) compounds possess antitumor and antimetastatic effects, due to their affinity for crucial biomolecules (like transferrin). Methods. The paper presents the transferrin-binding properties of some novel ruthenium (III) complexes with general formula RuL2
(DMSO) mCl3
·nH2O ((Ru-nf) L:
norfloxacin (nf), m = 1, n = 1; (Ru-cpx) L: ciprofloxacin (cpx), m = 2, n = 2; (Ru-oflo) L: ofloxacin (oflo),
m = 1, n = 1; (Ru-levo) L: levofloxacin (Levo), m = 2, n = 8; (Ru-pip) L: pipemidic acid (pip), m = 1, n = 2,
DMSO: dimethylsulfoxide). We investigated, in vitro, the interactions of these ligands with human transferrin through spectroscopic techniques, with the ultimate goal of preparing adducts with good selectivity for
cancer cells. Results. All studied complexes interact with human serum transferrin; the molar ratio [complex]/[transferrin] strongly influences the binding affinity. Conclusions. The best interaction between the
complexes studied and transferrin is achieved for a molar ratio of 8; the best interaction was registered for
Ru-pip, followed by Ru-nf.
Keywords: ruthenium (III) complexes, transferrin. |
| format |
Article |
| author |
Uivarosi, V. Mitrea, N. Dragoi, C.M. Nicolae, A. Arsene, A.L. |
| author_facet |
Uivarosi, V. Mitrea, N. Dragoi, C.M. Nicolae, A. Arsene, A.L. |
| author_sort |
Uivarosi, V. |
| title |
The binding properties of some novel ruthenium (III) complexes with human serum transferrin |
| title_short |
The binding properties of some novel ruthenium (III) complexes with human serum transferrin |
| title_full |
The binding properties of some novel ruthenium (III) complexes with human serum transferrin |
| title_fullStr |
The binding properties of some novel ruthenium (III) complexes with human serum transferrin |
| title_full_unstemmed |
The binding properties of some novel ruthenium (III) complexes with human serum transferrin |
| title_sort |
binding properties of some novel ruthenium (iii) complexes with human serum transferrin |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| publishDate |
2011 |
| topic_facet |
Biomedicine |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/156401 |
| citation_txt |
The binding properties of some novel ruthenium (III)
complexes with human serum transferrin / A.L. Arsene, V. Uivarosi, N. Mitrea, C.M. Dragoi, A. Nicolae // Вiopolymers and Cell. — 2011. — Т. 27, № 2. — С. 141-146. — Бібліогр.: 20 назв. — англ. |
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Вiopolymers and Cell |
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| fulltext |
The binding properties of some novel ruthenium (III)
complexes with human serum transferrin
A. L. Arsene1, V. Uivarosi2, N. Mitrea1, C. M. Dragoi1, A. Nicolae1
1Department of Biochemistry of University of Medicine and Pharmacy «Carol Davila», Faculty of Pharmacy
6th Traian Vuia St., 020956, Bucharest, Romania
2Department of Inorganic Chemistry of University of Medicine and Pharmacy «Carol Davila», Faculty of Pharmacy
6th Traian Vuia St., 020956, Bucharest, Romania
andreeanitulescu@hotmail.com
Aim. The transferrin cycle gained increased interest in recent years and it holds promise as an attractive
system for strategies of drug targeting to tumors. Neoplasic cells exhibit a large demand of iron and the-
refore express highly transferrin receptors. As a consequence, transferrin conjugates can preferentially in-
teract with cancer cells. This strategy is exploited nowadays for targeting novel anti-cancer drugs. Recent
data showed that ruthenium (III) compounds possess antitumor and antimetastatic effects, due to their affi-
nity for crucial biomolecules (like transferrin). Methods. The paper presents the transferrin-binding pro-
perties of some novel ruthenium (III) complexes with general formula RuL2(DMSO) mCl3·nH2O ((Ru-nf) L:
norfloxacin (nf), m = 1, n = 1; (Ru-cpx) L: ciprofloxacin (cpx), m = 2, n = 2; (Ru-oflo) L: ofloxacin (oflo),
m = 1, n = 1; (Ru-levo) L: levofloxacin (Levo), m = 2, n = 8; (Ru-pip) L: pipemidic acid (pip), m = 1, n = 2,
DMSO: dimethylsulfoxide). We investigated, in vitro, the interactions of these ligands with human transfer-
rin through spectroscopic techniques, with the ultimate goal of preparing adducts with good selectivity for
cancer cells. Results. All studied complexes interact with human serum transferrin; the molar ratio [com-
plex]/[transferrin] strongly influences the binding affinity. Conclusions. The best interaction between the
complexes studied and transferrin is achieved for a molar ratio of 8; the best interaction was registered for
Ru-pip, followed by Ru-nf.
Keywords: ruthenium (III) complexes, transferrin.
Introduction. A number of biological studies have hi-
ghlighted in the last years a novel mechanism of action
for anticancer drugs, regardless their covalent binding
with the DNA. The literature presents experimental
evidence for an important affinity between the chemo-
therapeutic medicines and other crucial biomolecules
like plasma proteins.
In this regard, transferrin became an interesting and
promising biomolecule over the last years for the deve-
lopment of new biochemical mechanisms of drug tar-
geting to tumor tissues [1–3]. Neoplasic cells demand
high amounts of iron for their growth and therefore
express the transferrin receptor at a high rate. As a con-
sequence, transferrin conjugates can preferentially
interact with cancer cells through transferrin receptors.
This strategy is exploited nowadays for targeting novel
anti-cancer drugs.
In the last years, following the success of cisplatin,
several metal complexes other than platinum have been
considered as possible alternatives. It was particularly
found that ruthenium (III) compounds possess anti-
tumor and antimetastatic activities [4]. Four classes of
ruthenium (III) complexes were imposed as promising
antitumor agents. Ammine-chloro derivatives comple-
141
ISSN 0233–7657. Biopolymers and Cell. 2011. Vol. 27. N 2. P. 141–146
Institute of Molecular Biology and Genetics NAS of Ukraine, 2011
xes like cis-[Ru(III)(NH3)4Cl2]
+ and fac-[Ru(III)
(NH3)3Cl3] were developed by M. Clarke [5]. A large
number of ruthenium (II) and ruthenium (III) mixed
complexes with sulfoxide ligands were synthesized
and characterized by the group of Alessio [6]. Between
them, Na{trans-[Ru(III)Cl4(DMSO)(Him)]} (Him =
= imidazole), nicknamed NAMI, and the more stable
[H2Im][trans-Ru(III)Cl4(DMSO)(Him)], also known
as NAMI-A are very promising [7]. Anionic ruthenium
(III) complexes with heterocyclic nitrogen ligands of
general formula RuCl4L2 have been synthesized by
Keppler et al. [8].
The derivatives with the formula trans-
[RuCl4(L)2]
–, where L is imidazole (KP418) or indazole
(KP1019 and KP1339), and the counterion (LH)+ or
Na+ are very promising. KP1019 completed phase-I cli-
nical trials [9].
Ruthenium polyaminocarboxylate complexes, a class
of ruthenium (III) complexes with polydentate mixed
donor ligands from the H4EDTA family were prepared
and tested by the group of Gonzalez-Vilchez [10].
The literature studies demonstrated the affinity of
these complexes for transferrin and provide evidence
for formation of stable adducts between them [11–16].
Therefore transferrin is investigated presently as a na-
tural carrier of the drugs to the tumor tissue, mainly
because of the high affinity of this iron-protein and the
large number of transferrin receptors on the surface of
tumor cells.
This paper presents the transferrin-binding proper-
ties of some novel ruthenium (III) complexes with
mixed ligands of the type RuL2(DMSO) mCl3·nH2O
((Ru-nf) L: norfloxacin (nf), m = 1, n = 1; (Ru-cpx) L:
ciprofloxacin (cpx), m = 2, n = 2; (Ru-oflo) L: ofloxa-
cin (of), m = 1, n = 1; (Ru-levo) L: levofloxacin (Levo),
m = 2, n = 8; (Ru-pip) L: pipemidic acid (pip), m = 1,
n = 2, DMSO: dimethylsulfoxide) [17–20]. All comp-
lexes display an octahedral stereochemistry with the
quinolone ligand acting as monodentate coordinated
through N4 atom of piperazinyl ring. The structures of
the ligands and the general structure of complexes are
presented in Fig. 1.
Materials and methods. During the experiment
the following reagents were used: Tris («Merck», Ger-
many), serum transferrin («Merck»), working soluti-
ons of the studied ruthenium (III) complexes. The
experimental procedure implied the following steps:
The first step implied the preparation of Tris buffer
pH 7 (5⋅10–3 M Tris, 5⋅10–2 M NaCl).
The preparation of each of the ruthenium comple-
xes stock solutions 10–5 M, using Tris buffer pH 7 as
solvent. When using this stock solution it was diluted
1:10 with Tris buffer (final complex working solution
10–6 M).
It was prepared a 10–5 M stock solution of human
serum transferrin in pH 7 Tris buffer: in a 10 ml
volumetric flask 0.0077g of human seric transferrin
were weighed and disolved in pH 7 Tris buffer. When
using this stock solution it was diluted 1:10 with Tris
buffer (final transferrin working solution 10–6 M).
For each studied complex we used 6 test tubes con-
taining the reagents, as described in Table 1.
The test tubes (performed in triplicate) were incu-
bated for 24 hours at room temperature, in the dark. Af-
terwards, the UV spectra (λ = 275 nm) were immedia-
tely recorded using an UV-Vis Cary 100 Bio spectro-
photometer («Varian Inc.», USA).
Results and discussion. In this study we conduc-
ted an extensive in vitro characterization of adducts
142
ARSENE A. L. ET AL.
NX1
X2
N
N
O
COOHR2
N X1
X2
N
N
R3
R2
O
HOOC
R3
ClCl
Cl DMSO
R1
R1
Ru
Compound X1 X2 R1 R2 R3
Pipemidic acid N N C2H5 H H
Norfloxacin H H C2H5 F H
Ciprofloxacin H H F H
Ofloxacin H H F CH3
Levofloxacin H H F CH3
Fig. 1. Structures of the investigated quinolones and general structure
of their Ru (III) complexes
between some possible ruthenium (III) drugs (newly
synthesized) and human serum transferrin and we
gained insight into the intriguing chemistry of these
complexes. It is to mention that we also possess unpu
lished data regarding the interactions of our newly syn-
thesized ruthenium (III) complexes with human serum
albumin (HSA) and DNA, but their affinity and bin-
ding to both HSA and DNA is importantly different,
compared with the interactions with transferrin (from
with the interaction stoichiometry to the reactivity
patterns).
The present study evoked that there exists chemical
binding between the substances investigated and trans-
ferrin and also that this interaction (including the che-
mical stoichiometry) is complicated and needs proper
investigations in respect to their solution behaviour (re-
flected in the organisms fluids behaviour) and their
protein binding ability. Nevertheless, the accurate
knowledge of this binding (interaction) is crucial at this
stage of the development of a newly possible antitumor
drug since it directly reflects in the IC50 and toxicity.
The knowledge of the transferrin cycle has rapidly
increased in recent years and it holds promise as an at-
tractive system for strategies of drug targeting to tumor
tissues. Indeed, tumor cells exhibit a large demand of
iron for their growth and therefore express the transfer-
rin receptor at a high rate. As a consequence, transfer-
rin conjugates that retain a good affinity for the trans-
ferrin receptor can preferentially interact with cancer
cells. This strategy is exploited nowadays for targeting
novel anti-cancer drugs. For example, Keppler’s com-
plexes were the first ruthenium (III) complexes whose
interactions with human serum transferrin were inves-
tigated in solution by various techniques, including
spectrophotometry, at different stoichiometry binding
stages [8, 9, 14]. Also, such a strategy was used to achi-
eve targeting on adriamycin to neoplastic tissues [2].
In our case, the major behaviour of our ruthenium
(III) complexes reflected in the transferrin spectrosco-
pic absorbance. In this regard transferrin absorbance in
UV was modified (has decreased) in the presence of the
studied ruthenium complexes, as it can be seen in Table
2 and Fig. 2–6.
The studied ruthenium complexes interact in vitro
with transferrin. This fact has been experimentally ob-
served by the diminish of the absorbance value of trans-
ferrin in UV, consequent to the direct contact complex-
transferrin.
By analyzing the obtained results, it can be conclu-
ded that the complex Ru-nf produces the most impor-
tant decrease in the UV transferrin absorbance, when
used in the molar ratio [Ru-nf]/[transferrin] = 1/1. The
decrease in the UV absorbance of this protein due to an
interaction with the research complexes (molar ratio
[complex]/[transferrin] = 1/1) has varied as follows:
Ru-nf > Ru-pip > Ru-levo > Ru-oflo > Ru-cpx.
143
THE BINDING OF RUTHENIUM (III) COMPLEXES WITH TRANSFERRIN
Molar ratio
[Ru-cx]/[transferrin]
Procentual decrease of the transferrin absorbance due to the complex, %
Ru-cpx Ru-nf Ru-oflo Ru-pip Ru-levo
1 0.118624 15.77699 12.93001 15.18387 13.04864
2 10.32028 37.01068 30.60498 45.43298 31.55397
4 12.81139 45.67023 43.89087 57.33096 37.84104
8 17.55635 50.77106 44.72123 67.61566 45.90747
Table 2
Procentual decrease of the transferrin absorbance due to the interaction with the studied ruthenium complexes
Reagents P1 P2 P3 P4 Transferrin blank Complex blank
AutoComplex solution, 10–6 M 1 ml 2 ml 4 ml 8 ml – 4 ml
Transferrin solution, 10–6 M 1 ml 1 ml 1 ml 1 ml 4 ml –
Molar ratio [complex]/[transferrin] 1/1 2/1 4/1 8/1 – –
Table 1
Working tehnique for studing the interactions of the studied complexes with transferrin
When using the molar ratio [complex]/[transfer-
rin] = 2/1 it was observed, as well, a decrease of the UV
absorbance of human serum transferrin, in vitro. The
procentual dynamics of this phenomenon is: Ru-pip >
> Ru-nf > Ru-levo > Ru-oflo > Ru-cpx.
When using the molar ratio [complex]/[transfer-
rin] = 4/1 it was observed a decrease of the UV absor-
bance of human serum transferrin, in vitro. The pro-
centual variation of the absorbances was as follows:
Ru-pip > Ru-nf > Ru-oflo > Ru-levo > Ru-cpx.
When using the molar ratio [complex]/[transfer-
rin] = 8/1 it was observed a decrease of the UV absor-
bance of human serum transferrin, in vitro. The pro-
centual dynamics of the absorbances was as follows:
Ru-pip > Ru-nf > Ru-levo > Ru-oflo > Ru-cpx.
Our further studies will focus on other critical drug
development issues, like testing of these complexes
and on in vivo tumor models.
Conclusions. The experimental results regarding
the interaction of the studied ruthenium complexes
with human serum transferrin have revealed a series of
important aspects:
All the studied complexes interact in vitro with
transferrin, fact proved by the decrease of transferrin
UV absorbance due to the contact with these compo-
unds, in all concentrations;
The ruthenium complex with pipemidic acid inten-
sively reduces the transferrin UV absorbance, followed
by the ruthenium complex with norfloxacin;
The weakest interaction complex-transferrin has
been registered in the case of ruthenium-ciprofloxacin;
The molar ratio [complex]/[transferrin] = 8/1 has
presented the strongest UV detectable interactions, in
the chosen experimental conditions, for all the evalua-
ted complexes.
144
ARSENE A. L. ET AL.
%
16
0
2
4
6
8
10
12
14
1 2 3 4 5
Fig. 2 Dynamics of human serum transferrin UV absorbance after the
interaction with the studied complexes (molar ratio [complex]/[trans-
ferrin] = 1/1); y axis – absolute values of transferrin absorbance in-
hibition for a molar ratio of interaction [complex]/[transferrin] = 1/1:
1 – [transferrin]/[Ru-cpx]; 2 – [transferrin]/[Ru-nf]; 3 – [transferrin]/
[Ru-oflo]; 4 – [transferrin]/[Ru-pip]; 5 – [transferrin]/[Ru-levo]
0
10
20
30
40
50
60
1 2 3 4 5
%
Fig. 4 Dynamics of human serum transferrin UV absorbance after the
interaction with the studied complexes (molar ratio [complex]/[trans-
ferrin] = 4/1); y axis – absolute values of transferrin absorbance in-
hibition for a molar ratio of interaction [complex]/[transferrin] = 4/1:
1 – [transferrin]/[Ru-cpx]; 2 – [transferrin]/[Ru-nf]; 3 – [transferrin]/
[Ru-oflo]; 4 – [transferrin]/[Ru-pip]; 5 – [transferrin]/[Ru-levo]
0
10
20
30
40
50
1 2 3 4 5
%
Fig. 3 Dynamics of human serum transferrin UV absorbance after the
interaction with the studied complexes (molar ratio [complex]/[trans-
ferrin] = 2/1); y axis – absolute values of transferrin absorbance in-
hibition for a molar ratio of interaction [complex]/[transferrin] = 2/1:
1 – [transferrin]/[Ru-cpx]; 2 – [transferrin]/[Ru-nf]; 3 – [transferrin]/
[Ru-oflo]; 4 – [transferrin]/[Ru-pip]; 5 – [transferrin]/[Ru-levo]
Acknowledgements. This work was partially sup-
ported by the PNII grant nr. 61048/2007 of the Roma-
nian Ministry of Education and Research.
А. Л. Арсене, В. Уйва розі, Н. Мітреа, С. М. Дра гой, А. Ніко лае
Зв’я зу вальні влас ти вості де я ких но вих ком плексів ру тенію (ІІІ)
з си ро ват ко вим транс фе ри ном лю ди ни
Ре зю ме
Мета. Останніми ро ка ми транс фе ри но вий цикл вик ли кає по -
си ле ний інте рес як пер спек тив на сис те ма цільо вої дос тав ки
про ти пух лин них пре па ратів без по се ред ньо в пу хли ну. Неоплас-
тичні клітини по тре бу ють ба га то заліза, че рез що експре су -
ють ве ли ку кількість транс фе ри но вих ре цеп торів. Внаслідок
цього кон ’ю га ти транс фе ри ну здатні на сам пе ред взаємодіяти
з ра ко ви ми кліти на ми. Цю стра тегію у наш час ви ко рис то ву -
ють для по шу ку но вих про ти ра ко вих пре па ратів. Останні дані
де мо нстру ють, що спо лу кам ру тенію (III) при та манні про ти-
пух линні і ан ти ме тас та тичні ефек ти за вдя ки їхній афінно-
сті до важ ли вих біомо ле кул (таких як транс фе рин). Ме то ди.
У статті пред став ле но транс фе рин-зв’я зу вальні влас ти вості
де я ких но вих ком плексів ру тенію (III) за галь ною фор му лою
RuL2(DMSO) mCl3⋅nH2O ((Ru-nf) L: нор флок са цин (nf), m = 1, n =
= 1; (Ru-cpx) L: цип роф лок са цин (cpx), m = 2, n = 2; (Ru-of) L:
офлок са цин (oflo), m = 1, n = 1; (Ru-levo) L: ле воф лок са цин
(Levo), m = 2, n = 8; (Ru-pip) L: піпеміди но ва кис ло та (pip), m =
= 1, n = 2, DMSO: ди ме тил суль фок сид). Ми вив чали взаємодію
in vitro цих лігандів з транс фе ри ном лю ди ни ме то дом спект-
рос копії для одержання адуктів з ви со кою се лек тивністю до
рако вих клітин. Ре зуль та ти і вис нов ки. Всі досліджу вані
комплек си взаємодіють з си ро ват ко вим транс фе ри ном лю ди -
ни, мо ляр не співвідно шен ня [ком плекс]/[транс фе рин] знач но
впли ває на зв’я зу вальні влас ти вості. Най кра щу взаємодію між
аналізо ва ни ми ком плек са ми і транс фе ри ном відмічено при мо -
ляр но му співвідно шенні 8:1, а та кож для Ru-pip і Ru-nf.
Клю чові сло ва: ком плек си ру тенію (III), транс фе рин.
А. Л. Арсене, В.Уйва ро зи, Н. Мит реа, С. М. Дра гой, А. Ни ко лае
Свя зы ва ю щие сво йства не ко то рых но вых ком плек сов ру те ния
(III) с че ло ве чес ким сы во ро точ ным транс фер ри ном
Ре зю ме
Цель. В по след ние годы транс фер ри но вый цикл вы зы ва ет по-
вы шен ный ин те рес как пер спек тив ная сис те ма це ле вой до-
став ки про ти во о пу хо ле вых пре па ра тов не пос ре дствен но в
опу холь. Не оп лас ти чес кие клет ки ис пы ты ва ют вы со кую по -
треб ность в же ле зе и, сле до ва тель но, экс прес си ру ют мно го
транс фер ри но вых ре цеп то ров. Всле дствие это го конъ ю га ты
транс фер ри на спо соб ны пре и му щес твен но вза и мо де йство -
вать с ра ко вы ми клет ка ми. Эту стра те гию в на сто я щее вре -
мя ис поль зу ют для по ис ка но вых про ти во ра ко вых пре па ра тов.
Пос лед ние дан ные по ка зы ва ют, что со е ди не ния ру те ния (III)
об ла да ют про ти во о пу хо ле вым и ан ти ме тас та ти чес ким эф -
фек та ми бла го да ря их аф фин нос ти к важ ным би о мо ле ку лам
(та ким как транс фер рин). Ме то ды. В статье пред став ле ны
транс фер рин-свя зы ва ю щие сво йства не ко то рых но вых ком -
плек сов ру те ния (III) с об щей фор му лой RuL2(DMSO) mCl3⋅nH2O
((Ru-nf) L: нор флок са цин (nf), m = 1, n = 1; (Ru-cpx) L: цип роф -
лок са цин (cpx), m = 2, n = 2; (Ru-of) L: офлок са цин (oflo), m = 1,
n = 1; (Ru-levo) L: ле воф лок са цин (Levo), m = 2, n = 8; (Ru-pip) L:
пи пе ми ди но вая кис ло та (pip), m = 1, n = 2, DMSO: ди ме тил -
суль фок сид). Мы из учи ли вза и мо де йствие in vitro этих ли ган -
дов с че ло ве чес ким транс фер ри ном ме то дом спек трос ко пии
для по лу че ния ад дук тов, об ла да ю щих хо ро шей се лек тив но-
стью к ра ко вым клет кам. Ре зуль та ты и вы во ды. Все ис сле ду -
е мые ком плек сы вза и мо де йству ют с че ло ве чес ким сы во ро-
точ ным транс фер ри ном, мо ляр ное со от но ше ние [ком плекс]/
[транс фер рин] силь но вли я ет на свя зы ва ю щие сво йства. На и -
луч шее вза и мо де йствие меж ду из уча е мы ми ком плек са ми и
транс фер ри ном от ме че но при мо ляр ном со от но ше нии 8:1, а
так же для Ru-pip и Ru-nf.
Клю че вые сло ва: ком плек сы ру те ния (III), транс фер рин.
145
THE BINDING OF RUTHENIUM (III) COMPLEXES WITH TRANSFERRIN
0
10
20
30
40
50
60
1 2 3 4 5
%
Fig. 5 Dynamics of human serum transferrin UV absorbance after the
interaction with the studied complexes (molar ratio [comp- lex]/[trans-
ferrin] = 8/1); y axis – absolute values of transferrin absorbance in-
hibition for a molar ratio of interaction [complex]/[transferrin] = 8/1:
1 – [transferrin]/[Ru-cpx]; 2 – [transferrin]/[Ru-nf]; 3 – [transferrin]/
[Ru-oflo]; 4 – [transferrin]/[Ru-pip]; 5 – [transferrin]/[Ru-levo]
Molar ratio [complex]/[transferrin]
0
10
20
30
40
50
60
70
80
1 2 3 4
%
1
2
3
5
4
Fig. 6 Comparative procentual values of human serum transferrin UV
absorbance after binding with the studied ruthenium complexes; y
axis – absolute values of transferrin absorbance inhibition after comp-
lex binding; 1 – [transferrin]/[Ru-cpx]; 2 – [transferrin]/[Ru-nf]; 3 –
[transferrin]/[Ru-oflo]; 4 – [transferrin]/[Ru-pip]; 5 – [transferrin]/
[Ru-levo]
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UDC611.018.54 + 661.896
Received 10.01.11
146
ARSENE A. L. ET AL.
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