Download role of the ancillary ligands on the coordination modes

V Simposio Pharmaco-Bio-Metallics
Oral Communication
Nuovi farmaci inorganici in oncologia
ROLE OF THE ANCILLARY LIGANDS ON THE COORDINATION MODES
OF THE MODEL NUCLEOBASES 1-METHYLCYTOSINE AND
9-METHYLADENINE IN PLATINUM(II) PHOSPHINO COMPLEXES
D. Montagner, B. Longato
Dipartimento di Scienze Chimiche, Universita' di Padova, Via Marzolo 1, 35131-Padova, Italy.
e-mail: [email protected]
Introduction
Since the discovery of the antitumoral activity of cisplatin, most of the studies on the interaction of
DNA components with a metal centres deal with complexes of platinum(II) stabilized by N-donor
ligands (NH3 and amines)[1]. Here we report the reactivity of the nucleobases 1-methylcytosine (1MeCy) and 9-methyladenine (9-MeAd) toward the hydroxo complexes cis-[L2Pt(µ-OH)]2(NO3)2,
(L= PMe3, 1a; PMe2Ph, 1b; PMePh2, 1c and PPh3, 1d), showing that the coordination mode of these
biomolecules is dependent on the nature of the ancillary ligands L.
Results and Discussion
Early experiments showed that complexes 1a and 1b, in DMSO or CH2Cl2, react with 1-MeCy in a
molar ratio 1:2 to give the cyclic polynuclear species cis-[L2Pt{1-MeCy(-H)}]n(NO3)n (n=2 when L
is PMe3 (2a); n=3 when L is PMe3 (3a) and PMe2Ph (3b)) in which the NH2-deprotonated
nucleobase binds the metal centers through the N(3),N(4) atoms (Scheme 1)[2].
2+
H
O
L
O
H
N
N'
N'
N
Pt
Pt
Pt
L
L
L
L
L
3+
2+
L
L
Pt
N'
N
L
L
N
Pt
L
N'
N
2, 5
1
L
(-)
H
N
N
=
(3)N
O
_
L
3, 6
H
N
N
'
N
Pt
L =PMe3, a; PMe2Ph, b; PMePh 2, c; PPh3, d.
(-) _
L
Pt
(7)
N
(1)N
in 2 and 5 ;
(1)
N
in 3 and 6
N
(3)
Me
N(9)
Me
Scheme 1.
When the hydroxo complex is stabilized by PPh3, 1-MeCy reacts with 1d in a molar ratio 1:4 to
give the bis-adduct cis-[L2Pt{1-MeCy(-H)}(1-MeCy)]NO3, 4, containing a deprotonated and a
neutral 1-MeCy ligands on the same metal centre. The
31
P{1H} NMR spectrum of 4 exhibits one
AB multiplet (in DMSO-d6: δ 12.4 (1JPPt 3180 Hz) and 0.27 (1JPPt 3600 Hz, 2JPP 20.0 Hz)), in
1
V Simposio Pharmaco-Bio-Metallics
Oral Communication
Nuovi farmaci inorganici in oncologia
agreement with the formation of a single reaction product. In the 1H NMR spectrum, the presence of
one of the NH resonances at δ 10.6 suggests that platination of the neutral nucleobase occurs at the
N(4) atom, as result of a tautomeric shift of one of the exocyclic NH2 protons to the endocyclic
N(3) site. On the contrary, a complex mixture of products was obtained in the reaction of 1-MeCy
with 1c. Similar effects of the phosphine ligands on the reactivity of 1 with 9-MeAd were found.
Deprotonation of the nucleobase in the reaction with 1a leads to the formation of the dimer cis[L2Pt{9-MeAd(-H)}]2(NO3)2, (L= PMe3, 5, Scheme 1) while the trimers 6b and 6c are formed if L
is PMe2Ph and PMePh2, respectively [3,4]. When the hydroxo complex is stabilized by PPh3 (1d)
the main reaction product is the mononuclear species cis-[L2Pt{9-MeAd(-H)}]NO3,7, in which the
adeninate ion binds the metal centre through the N(6) and N(7) atoms, as shown by
31
P-1H
heterocorrelate NMR experiments (Figure 1).
Figure 1. HMBC 31P-1H spectrum of 7 in CDCl3
Conclusion
Steric and electronic properties of the phosphine ligands play an important role on defining the
nuclearity and the binding modes of the nucleobases in these cytosine and adenine complexes. In
addition, the nature of L affects their stability in solution of acetonitrile [5]. While 3a,b and 6b can
be prepared (and are indefinitely stable) in CH3CN solution, their PMePh2 and PPh3 analogues
undergo
complete solvolysis with insertion of a solvent molecole into one of the platinum-
nucleobase bonds.
References
[1] B. Lippert, Coord. Chem. Rev. 1999, 182, 263-295.
[2] L. Schenetti, G. Bandoli, A. Dolmella, G. Trovò, B. Longato, B. Inorg. Chem. 1994, 33, 31693176.
[3] B. Longato, G. Bandoli, A. Mucci and L.Schenetti, Eur. J. Inorg. Chem. 2001, 3021-3029.
[4] B. Longato, L. Pasquato, A. Mucci, L. Schenetti and E. Zangrando, Inorg. Chem. 2003, 42,
7861-7871.
2
V Simposio Pharmaco-Bio-Metallics
Oral Communication
Nuovi farmaci inorganici in oncologia
[5] B. Longato, D. Montagner, G. Bandoli and E. Zangrando,, Inorg. Chem., submitted.
3