“Lantern-Shaped” Platinum(III) Complexes with Axially Bound 9-Ethylguanine or 1-Methylcytosine (L) of General Formula [Pt2{HN=C(But)O}4L2](NO3)2

The synthesis, NMR characterization, and X-ray crystallography of “lantern-shaped” platinum(III) complexes with four pivaloamidate bridging ligands and two 9-ethylguanines (9-EtG) or 1-methylcytosines (1-MeC) in axial positions are reported: cis-N2O2-[Pt2{HN=C(But)O}4(9-EtG)2](NO3)2 and cis-N2O2-[Pt2{HN=C(But)O}4(1-MeC)2](NO3)2. The last complex is, to the best of our knowledge, the first dinuclear compound of platinum(III) with axially bound 1-MeC.


Experimental
Physical Measurements. Elemental analyses were obtained with an Elemental Analyzer mod. 1106 Carlo Erba instrument. 1 H, 13 C, and 195 Pt NMR spectra were recorded with a DPX 300 Avance Bruker instrument. 1

X-Ray
Crystallography. Selected crystals of compounds 1 and 2 were mounted on a Bruker AXS X8 APEX CCD system equipped with a four-circle Kappa goniometer and a 4K CCD detector (radiation MoKα). For data reduction and unit cell refinement the SAINT-IRIX package was employed [36].
The unit cell dimensions were calculated from all reflections and the structures were solved using direct methods technique in the P 2 1 /c space group.
The model was refined by full-matrix least-square methods. All non-hydrogen atoms were refined anisotropically, except for atoms of tert-butyl group (disordered in the case of 2) and of solvent of crystallization (disordered tetrahydrofurane for 1 and disordered 1,4-dioxane for 2) that required isotropic treatment in order to maintain satisfactory thermal displacement parameters.
In the case of complex 1, the hydrogen atoms were located by Fourier difference and refined isotropically except for the hydrogen atoms of the tert-butyl groups that were placed at calculated positions and refined given isotropic parameters equal to 1.5 times the U(eq) of the atom to which they are bound.
In the case of complex 2, all hydrogen atoms were placed at calculated positions and refined given isotropic parameters equivalent to 1.5 (methyl groups) or 1.2 (other groups) times those of the atom to which they are attached.

Synthesis and Characterization. 9-EtG and 1-MeC both react with lantern shaped [Pt 2 {HN=C(Bu t )O} 4 (NO 3 ) 2 ]
(which has a cis-N 2 O 2 configuration on both platinum subunits), in methanol, giving, respectively, compounds 1 and 2 in almost quantitative yields. The new formed complexes exhibit single 195 Pt NMR signals (−69.8 and 28.2 ppm for 1 and 2, respectively, solvent CD 3 OD + 10% H 2 O), which are indicative of dinuclear Pt(III) species with symmetrical capping of the axial sites (the precursor complex, [Pt 2 {HN=C(Bu t )O} 4 (NO 3 ) 2 ], resonates at −4.41 ppm in CD 3 OD). The 1 H-NMR spectrum in CD 3 OD + 10% H 2 O of complex 1 exhibits a single set of signals for 9-EtG with frequencies at 11.32, 8.17, 6.71, 4.29, and 1.51 ppm assigned, respectively, to NH, H(8), NH 2 , CH 2 , and CH 3 protons (corresponding signals of free 9-EtG fall at 10.85, 7.78, 6.30, 4.07, and 1.40 ppm, respectively). The 0.40 ppm downfield shift of the 9-EtG H8 proton suggests that the coordination occurs through N7. One set of signals is also observed for the pivaloamidate ligands with resonance peaks at 8.66 and 1.23 ppm assigned, respectively, to NH and tertbutyl protons (the corresponding protons in the precursor complex [Pt 2 {HN=C(Bu t )O} 4 (NO 3 ) 2 ] resonate at 7.54 and 1.22 ppm, respectively). The deshielding of about 1 ppm observed for the amidic protons of the pivaloamidate ligands may be attributed to the interaction with the guanine base in apical position (see following discussion).
The 1 H-NMR spectrum of compound 2 in CD 3 OD + 10% H 2 O exhibits one set of signals for 1-MeC with resonance peaks at 8.82 and 6.82 (these first two peaks exhibiting a strong exchange peak in the 2D NOESY experiment), 7.83, 5.95, and 3.45 ppm assigned, respectively, to the two unequivalent aminic protons and to H(6), H(5), and methyl group (corresponding signals of free 1-MeC fall at 7.18 (broad singlet), 7.55, 5.85, and 3.35 ppm). The unequivalence of the aminic protons in coordinated 1-MeC is due to the partial double bond character of the C4-N4 linkage, which is reinforced by the metal coordination to N3 [44,45]. The average deshielding of the aminic protons   [22,23]. Thus the Pt-Pt distance is influenced by the nature of the axial ligands and an N7-coordinated guanine appears to exert a trans influence similar to that of a chloride. The platinum coordination squares are perfectly eclipsed (maximum twist angle 1.5 • ); such a conformation allows the greatest separation between the platinum atoms. The platinum atoms are displaced from the equatorial coordination planes by 0.087Å towards the axial 9-EtG, such a displacement being a measure of the strength with which the four bridging ligands pull together the two metal centers.
The THF solvent molecule is disordered, the oxygen atom of 50% of the molecules pointing in the direction opposite to that of the other 50% molecules. As a consequence THF appears as a flat 1,4-dioxane-type molecule with the two oxygens having occupancy factor 0.5 and the carbons occupancy factor 1. The accuracy of the X-ray data is not allowed to distinguish between carbon atoms belonging to the differently oriented THF molecules.

[Pt
Compound 2 crystallizes incorporating two molecules of 1,4-dioxane per molecule of complex. The asymmetric unit comprises half molecule of complex and one of dioxane and the structure is generated by inversion at the midpoint of the Pt-Pt linkage (Figure 3). Each Pt(III) atom has a distorted octahedral geometry with the N3 of 1-MeC and the second platinum subunit in axial positions.
The Pt-Pt distance (2.4523(4)Å) is very similar to the analogous distance observed in compound 1. As for 1, the platinum coordination squares are perfectly eclipsed (maximum twist angle of 0.8 • ), and the platinum atoms are displaced from the equatorial coordination planes by 0.090Å towards the axial cytosine. Also the equatorial Pt-N [1.967(5) and 1.982(5)Å] and Pt-O distances [2.011(4) and 2.025(4)Å] are in the range of those observed in 1 and reported for four-coordinate platinum(II) and sixcoordinate platinum(IV) complexes [4].
The tert-butyl groups are disordered and each set of three methyl groups can occupy two different positions, each position with occupancy factor 0.5. Also the 1,4-dioxane solvent molecules are disordered. The position is fixed for the two oxygen atoms while the four carbon atoms can occupy two different positions each one with occupancy factor 0.5. In each case the 1,4-dioxane molecule adopts a chair conformation.

Conclusions
The coordination of 9-EtG and 1-MeC to the axial sites of quadruply bridged dinuclear species of platinum(III) has been established. The complexes are stable in solution as well as in the solid state. Complex 1 is one of the few examples of dinuclear platinum(III) species with axially bound guanines, while complex 2 is, to the best of our knowledge, the first compound of this type (axially bound 1-MeC). The axial Pt-N3 bond in 2 is 0.010Å longer than the axial Pt-N7 bond in 1. Since the Pt-Pt core is very similar in the two cases, we argue that the longer distance found in 2 is indicative of a weaker binding of 1-MeC as compared to 9-EtG. Previous attempts to bind 1-MeC in the axial positions of a dinuclear platinum(III) complex, (e.g., cis-[Pt 2 (NH 3 ) 4 (1-Mec-N3,N4) 2 XY]Z n , X and Y stand for axial ligands of different types and Z stands for counteranion(s)) have been unsuccessful [52]. In contrast our dinuclear Pt(III) core, with four pivaloamidate bridging ligands, readily binds nucleobases, comprising 1-MeC, forming stable compounds. It is possible that the presence in the equatorial platinum coordination plane of groups with good H-bond donor/acceptor properties, and therefore able to establish additional bonds with the apical ligands, gives a decisive contribution to the formation of such complexes. H-bond interaction causes, in the case of 1, a downfield shift of the pivaloamidate amidic proton by 1.12 ppm and, in the case 2, a downfield shift of one aminic proton of 1-MeC by 1.64 ppm. In the latter case the H-bond is bifurcated and the 1-MeC aminic proton, (N4c)H41c, interacts, simultaneously, with the oxygen atoms of two cis pivaloamidate ligands. In principle, the 1-MeC could form, in addition to the H-bond described above, also an H-bond between the 1-MeC oxygen, O2c, and the pivaloamidate amidic protons; such an H-bond, however, does not form or is extremely weak (downfield shift of the amidic proton of only 0.51 ppm as compared to 1.12 ppm observed in compound 1). A possible cause of weakness of the latter H-bond is the dihedral angle of 45 • between 1-MeC and pivaloamidate planes; such an angle is optimal for the bifurcated H-bond involving the aminic group but is detrimental for a potential H-bond involving the 1-MeC oxygen.
In fact it appears that, while a proton can interact with two oxygens (bifurcated H-bond), one oxygen can only interact with one proton (regular H-bond as observed in compound 1). "Lantern shaped" platinum(III) complexes have been shown, by Cervantes and coworkers, to be endowed with antitumor activity (e.g., [Pt 2 (2-mercaptopyrimidine) 4 Cl 2 ] and [Pt 2 (2-mercaptopyridine) 4 Cl 2 ]) [30][31][32]. It will be worth investigating the antitumor activity of our amidate complexes for which we have shown a greater propensity to form adducts with nucleobases in apical positions.