Four platinum(II) metallointercalating complexes of 1,10-phenanthroline (phen) with the chiral ancillary ligands trans-R,R- and trans-S,S-1,2-diaminocyclohexane (R,R- and S,S-dach, respectively), and N,N'-dimethyl-R,R- and N,N'-dimethyl-S,S-1,2-diaminocyclohexane (Me(2)-R,R-dach and Me(2)-S,S-dach, respectively) have been synthesised and characterised. The crystal structure of [Pt(Me(2)-S,S-dach)(phen)](ClO(4))(2)1.5 H(2)O (C(20)H(26)Cl(2)N(4)O(9.5)Pt) has been determined; orthorhombic, space group P2(1)2(1)2(1)(No. 19), a=23.194(8), b=25.131(9), c=8.522(3) A. In vitro cytotoxic assays (IC(50)) in the human bladder cancer cell line 5637 and in the murine leukemia L1210 cell line revealed that [Pt(S,S-dach)(phen)](ClO(4))(2) (0.091 and 0.13 microM, respectively) and [Pt(R,R-dach)(phen)](ClO(4))(2) (0.54 and 1.50 microM, respectively) were more cytotoxic than cisplatin (0.31 and 0.50 microM, respectively) and considerably more cytotoxic than their methylated counterparts, [Pt(Me(2)-R,R-dach)(phen)](ClO(4))(2) and [Pt(Me(2)-S,S-dach)(phen)](ClO(4))(2) (both>23 microM). Chiral discrimination for [Pt(S,S-dach)(phen)](ClO(4))(2) over its R,R-enantiomer was observed in all 13 cancer cell lines investigated. Moreover, [Pt(S,S-dach)(phen)](ClO(4))(2) was more active than cisplatin in all cell lines tested and shows only partial cross-resistance to cisplatin in two cisplatin resistant cell lines.

The crystal structures of M10(PO4)6X2, where M = Ca or Pb and X = OH¯, F¯, Cl¯ or Br¯, have been determined by Rietveld refinement of powder synchrotron X-ray and neutron diffraction data. All the compounds are hexagonal with space group P 63/m. For the calcium compounds, the lattice parameters are a = 9.4302(5), 9.3475(3), 9.5902(6), 9.6482(6) and c = 6.8911(2), 6.8646(1), 6.7666(2), 6.7788(2) Å, for X = OH¯, F¯, Cl¯, Br¯, respectively. For the lead compounds, the corresponding lattice parameters are a = 9.8612(4), 9.7547(5), 9.9767(4), 10.0618(3) and c = 7.4242(2), 7.2832(2), 7.3255(1), 7.3592(1) Å. In these compounds there are two cation sites, a channel of M(I) atoms and a triangle of M(II) atoms. The anion interacts most strongly with the M(II) atoms with the interaction dictating the position of the anion relative to the M(II) triangle. In Ca10(PO4)6X2, the F¯ ion sits within the triangle planes, while the larger OH¯ and Cl¯ anions are disordered above and below the M(II) triangles. The even larger Br¯ is midway between two triangles at (0, 0, ). Despite the larger size of the isostructural lead compounds, no anions are found in the triangles. The F¯, Cl¯ and Br¯ ions are at (0, 0, ) and the OH¯ ion is disordered at (0, 0, z). This difference in behaviour is possibly related to the lead 6s electrons. In this paper, the experimental results are presented and possible reasons for the observed differences are discussed.

Four platinum(II) complexes of 1,10‐phenanthroline (phen) and 3,4,7,8‐tetramethyl‐1,10‐phenanthroline (3,4,7,8‐Me4phen), with the chiral ancillary ligands (1R,3S) and (1S,3R)‐1,3‐diamino‐1,2,2‐trimethylcyclopentane (R,S‐tmcp and S,R‐tmcp, respectively) have been synthesised and their biological activity quantified using an in vitro cytotoxicity assay against the L1210 murine leukaemia cell line. [Pt(R,S‐tmcp)(3,4,7,8‐Me4phen)]Cl2 and [Pt(S,R‐tmcp)(3,4,7,8‐Me4phen)]Cl2 showed an increase in biological activity over their non‐methylated complexes, [Pt(R,S‐tmcp)(phen)]Cl2 and [Pt(S,R‐tmcp)(phen)]Cl2. Some chiral discrimination was observed in the in vitro cytotoxicity experiments with the complexes having (S,R) configuration showing higher biological activity in L1210 cells. Titrations of the metal complexes into ct‐DNA and observation of the changes induced in the CD spectra were used to determine the binding constants. The binding of these metal complexes to the hexamer d(GTCGAC)2 was studied using two‐dimensional 1H NMR spectroscopy. The addition of metal complexes to the hexamer produced upfield shifts of the metal complex of selected resonances, characteristic of intercalation for [Pt(tmcp)(phen)]Cl2, whereas the [Pt(tmcp)(3,4,7,8‐Me4phen)]Cl2 complexes only partially intercalate and in a “side‐on” fashion. Through the observation of NOE cross‐peaks, two‐dimensional NMR experiments provided some insight into the site and groove preferences of these complexes when binding to DNA. Here, we report the biological activity of platinum(II) complexes containing an intercalator and a chiral diamine, which influences the degree to which the complexes can interact with DNA. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

The synthesis of a pair of enantiomeric Pt(II) complexes, [Pt(R,R-eap)Cl2] and [Pt(S,S-eap)Cl2] (eap = N,N-diethyl-2,4-pentanediamine), designed to bind enantioselectively to GpG and ApG sequences of DNA is described. The in vitro cytotoxicity of each of the enantiomers toward murine leukemia and human bladder tumor cells has been measured. The R,R enantiomer was found to be more active in the leukemia cells, but the difference was not as great as expected (IC50; R,R 14 microM, S,S 33 microM). In the bladder tumor cell line, no significant difference in activity was found. The two enantiomers had similar mutagenicity in the Salmonella reversion assay, but the R,R enantiomer was more cytotoxic in the bacterial cells. A structural analysis of the R,R enantiomer revealed that the ligand adopted an unexpected configuration, and a strain energy minimization analysis showed that this was a consequence of interactions between the diamine ligand and the dichloro ligands. The significance of the structural preferences with respect to the lower than expected enantiospecificity is discussed. Crystals of [Pt(R,R-eap)Cl2] are monoclinic; space group, P2(1)2(1)2(1); a = 7.909(5), b = 12.972(9), and c = 13.269(12) A; Z = 4; and the structure was refined to R = 0.025 (1657F).

An in vivo study for determining the toxicity and efficacy of [Pt(S,S-dach)(phen)Cl(2).1.5H(2)O.0.5HCl (PHENSS) in female Specific Pathogen Free (SPF) Swiss nude mice bearing PC3 tumour xenografts revealed PHENSS to be non-toxic and effective in decreasing tumour growth.