Alexander Hegmans

A comparison of DNA binding profiles of dinuclear platinum compounds with polyamine linkers and the trinuclear platinum phase II clinical agent BBR3464

Abstract. The DNA binding profiles of three bis Pt(II) polyamine-linked compounds, [{trans-PtCl(NH3)2}2{µ-spermine-N1,N12}]4+, [{trans-PtCl(NH3)2}2{µ-spermidine-N1,N8}]3+, and [{trans-PtCl(NH3)2}2{µ-BOC-spermidine}]2+, were compared with that of a novel trinuclear phase II clinical agent, [{trans-PtCl(NH3)2}2{µ-trans-Pt(NH3)2(H2N(CH2)6NH2)2}]4+. All of the compounds bind preferentially in a bifunctional manner, according to unwinding of supercoiled DNA circles. The kinetics of binding of these compounds corresponds to their relative charge (2+ to 4+). The preference for the formation of interstrand crosslinks, however, does not follow a charge-based pattern. By studying the results of DNA polymerase extension products on a DNA template modified by the compounds, and by incorporating the complementary method of RNA transcription mapping, it was possible to determine the nucleotide bases that are preferred sites of binding. The stop sites due to platinum adducts were determined, and some preliminary observations concerning the range and type of crosslinks were established. It can be concluded that dinuclear Pt compounds are similar to their trinuclear counterpart, and that charge differences do not contribute solely to the variances between the compounds.

Effects of geometric isomerism in dinuclear antitumor platinum complexes on their interactions with N -acetyl- L -methionine

In this study, the reactions of N-acetyl-L-methionine (AcMet) with [{trans-PtCl(NH3)2}2-μ-H2N(CH2)6NH2](NO3)2 (BBR3005: 1,1/t,t 1) and its cis analog [{cis-PtCl(NH3)2}2-μ-{H2N(CH2)6NH2}]Cl2 (1,1/c,c 2) were analyzed to determine the rate and reaction profile of chloride substitution by methionine sulfur. The reactions were studied in PBS buffer at 37°C by a combination of multinuclear (195Pt, {1H-15N} HSQC) magnetic resonance (NMR) spectroscopy and electrospray ionization time of flight mass spectrometry (ESITOFMS). The diamine linker of the 1,1/t,t trans complex was released as a result of the trans influence of the coordinated sulfur atom, producing trans-[PtCl(AcMet)(NH3)2]+ (III) and trans-[Pt(AcMet)2(NH3)2]2+ (IV). In contrast the cis geometry of the dinuclear compound maintained the diamine bridge intact and a number of novel dinuclear platinum compounds obtained by stepwise substitution of sulfur on both platinum centers were identified. These include (charges omitted for clarity): [{cis-PtCl(NH3)2}-μ-NH2(CH2)6NH2-{cis-Pt(AcMet)(NH3)2}] (V); [{cis-Pt(AcMet)(NH3)2}2-μ-NH2(CH2)6NH2] (VI); [{cis-PtCl(NH3)2}-μ-NH2(CH2)6NH2-{PtCl(AcMet)NH3] (VII); [{PtCl(AcMet)(NH3)}2-μ-NH2(CH2)6NH2] (VIII); [{trans-Pt(AcMet)2(NH3)}-μ-NH2(CH2)6NH2-{PtCl(AcMet)(NH3)] (IX) and the fully substituted [{trans-Pt(AcMet)2(NH3)}2-μ-{NH2(CH2)6NH2] (X). For both compounds the reactions with methionine were slower than those with glutathione (Inorg Chem 2003, 42:5498–5506). Further, the 1,1/c,c geometry resulted in slower reaction than the trans isomer, because of steric hindrance of the bridge, as observed previously in reactions with DNA and model nucleotides.

Pt as Mediator of Strong Antiferromagnetic Coupling between Two CuII Ions in a Heteronuclear CuIIPtIICuII Complex of the Model Nucleobase 1-Methylcytosinate

Trinuclear CuIIPtCuIIcomplexes (see scheme) are formed with four bridging 1-methylcytosinate nucleobases. These compounds are diamagnetic as a result of the strong exchange interaction (J≅1000 cm−1 (2 b)), despite a separation of approximately 5 A between the CuII centers.

Reactivity of an extremenly sterically crowded monofunctional Pt complex, [Pt(1-MeC-N3)3(H2O)]2+ (1-MeC=1-methylcytosine), toward model nucleobases and selectivity toward guanine in single- and double-stranded deoxyoligonucleotides

Abstract Reactions of [Pt(1-MeC-N3)3Cl]NO3 (1-MeC-N3=1-methylcytosine, bound to Pt via N3) and the respective aqua species [Pt(1-MeC-N3)3(H2O)]2+ with the model nucleobases 9-ethylguanine (9-EtGH), 9-methyladenine (9-MeA), single-stranded 5′d(T3GT3), and double-stranded [5′d(GAGA2GCT2CTC)]2 have been studied in solution by means of 1H NMR spectroscopy, HPLC, and electrospray ionization mass spectrometry. Reactions are generally slow, in particular with the chloro species, and guanine is the only reactive base in the oligonucleotides. However, unlike (dien)PtII, which binds randomly to the guanines in the ds dodecamer, (1-MeC-N3)3PtII binds selectively to the terminal guanine only, probably because base fraying takes place at the duplex ends. The X-ray crystal structures of [Pt(1-MeC-N3)3(9-EtG-N7)]ClO4·8H2O (1b) and of [Pt(1-MeC-N3)3(9-MeA-N7)](ClO4)2·0.5H2O as well as NMR spectroscopic studies of [Pt(1-MeC-N3)3(9-EtGH-N7)] (NO3)2·H2O (1a) are reported. The tetrakis(nucleobase) complexes adopt a head-tail-head orientation of the three 1-MeC bases and an orientation of the fourth base (purine) that permits a maximum of intracomplex H bonds between exocyclic groups. As far as the guanine adduct (1a, 1b) is concerned, relative orientations of the four bases are identical in the model and in the oligonucleotide adduct.

Tris and tetrakis(1–methylcytosine) complexes of Pt(II): Syntheses and X–ray structures of [Pt(1–MeC–N3)3Cl]+ and [Pt(1–MeC–N3)4]2+ compounds

Abstract Starting from K2PtCl4 and 1-methylcytosine (1-MeC), cationic [Pt(1-MeC)3Cl]+ (1) and [Pt(1-MeC)4]2+ (2) species have been prepared and isolated with various counter-ions. 1a (NO3−), 1b (ClO4−, 2b (NO3−), and 2c (Cl−) have been characterized by X-ray crystallography. Pt binding in 1 and 2 is through N3. The nucleobases display head-tail-head- and head-tail-head orientations in 1 and 2, respectively. The synthetic potential of the two complexes is briefly discussed.

Exocyclic oxygen atoms of platinated nucleobases as binding sites for alkali metal ions

Three complexes of model nucleobases with exocyclic oxygen atoms (1-methyluracilate, mura; 1-methylcytosine, mcyt; 9-methylguanine, Hmgua) which contain PtII bonded to a ring N atom and an alkali metal ion (Cs+, K+, Na+) bonded to a keto oxygen of the bases, trans-Cs[Pt(NH3)(mura)I2]·4H2O 1, trans-K[Pt(NH3)2(mcyt)2][PF6]3·H2O 2, and trans-[Pt(NH3)(Hmgua)2(mcyt)Na(H2O)2][ClO4]3·0.5H2O 3, have been prepared and their crystal structures determined. The compounds have been studied, among others, with regard to the role of alkali metal ions for the rotation of nucleobases when bound to PtII. While in the case of 1 the alkali metal ion is necessary for charge compensation and for this reason its binding to the platinated mura is not fully unexpected, it is surprising to see that alkali metal ions even bind to cationic complexes of PtII containing neutral nucleobases (2, 3).