Enantiomerically pure [1, 2-diamino-1-(4-fluorophenyl)butane]platinum(II) complexes: synthesis and antitumor activity against MCF-7 and MDA-MB 231 breast cancer and LnCaP/FGC prostate cancer cell lines

Enantiomerically pure 1, 2-diamino-1-(4-fluorophenyl)butanes were synthesized by stereoselective procedures. The enantiomeric purity was determined by (1)H NMR spectroscopy after derivatization with (1R)-myrtenal. For the coordination to platinum, the diamines were reacted with K(2)PtI(4). Reaction with Ag(2)SO(4) yielded the respective sulfatoplatinum(II) complexes, which were converted into the dichloroplatinum(II) complexes by treatment with 2 N HCl. The influence of the configuration and the kind of leaving group on the antitumor activity was studied on the MCF-7 and MDA-MB 231 breast cancer cell lines, as well as on the LnCaP/FGC prostate cancer cell line. It was demonstrated that the dichloroplatinum(II) complexes were more active than the respective diiodoplatinum(II) derivatives. Conversion into the sulfatoplatinum(II) complexes further enhanced the antiproliferative effects. The configuration determined the antitumor effects, dependent on the cell line used: MCF-7: (R, R) > (S, S) > (R, S) > (S, R); MDA-MB 231: (S, S) > (R, R) > (R, S) = (S, R); LnCaP/FGC: (S, S) > (R, R) > (R, S) > (S, R).     

Water-soluble third generation antitumor platinum complexes, [2,2-bis (aminomethyl)-1,3-propanediol-N,N']-[1,1-cyclobutanedicarboxylato (2-)-O,O']platinum(II) and [1,1-cyclobutanedicarboxylato(2-)-O,O'] [tetrahydro-4H-pyran-4,4-dimethanamine-N,N']platinum(II)

The synthesis, stability, and antitumor activity of a series of water-soluble third generation platinum(II) complexes have been described. Among these complexes, [2,2-bis(aminomethyl)-1,3- propanediol-N,N'] [1,1-cyclobutanedicarboxylato(2-)-O,O']platinum(II) and [1,1-cyclobutanedicarboxylate(2-)-O,O'](tetrahydro-4H-pyran-4,4- dimethanamine-N,N'-)platinum(II) have shown the greatest promise for further investigation and are currently under clinical evaluation.     

Antitumor platinum(II) complexes with substituted 2-aminomethylpyridine ligands]

Reaction of K2PtCl4 with the substituted 2-aminomethylpyridines 9, 14, and 22 affords the corresponding dichloroplatinum(II) complexes 3-5. Compounds 3 and 22 show remarkable relative binding affinities for the estrogen receptor. Towards the hormone-independent P388-tumor of the CD2F1-mouse the platinum(II) complexes 4 and 5 are weakly active, complex 3 is inactive. Towards the hormone-independent MDA-MB 231-cell line, compounds 3-5, 9, 14, and 22 exhibit no significant antitumor activity. Towards the hormone-dependent MCF-7 cell line, compounds 3-5, 9, 14 show weak antitumor activity, whereas compound 22 exhibits strong inhibition.     

Preparation and biodistribution of 1-[2-(3-[125I]iodo-4-aminophenyl)ethyl]-4-[3-(trifluoromethyl) phenyl]piperazine and 1-[2-(3-[125I]iodo-4-azidophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl] piperazine

The iodinated analogue of 1-[2-(4-aminophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl]piperazine (PAPP), IPAPP (4), and the corresponding azido compound azido-IPAPP (5) were synthesized. The corresponding no-carrier-added 125I (T1/2 = 60 days, 35-60 keV) labeled compounds were also prepared. High specific binding was observed from in vitro binding studies using rat brain tissue preparation; Ki = 20 and 17.5 nM against [3H]-5-HT. In vivo biodistribution studies in rats showed that azido-[125I]IPAPP passed through intact blood-brain barrier and localized in the brain. Ex vivo autoradiography of rat brain sections exhibited a diffuse uptake pattern, which may be due to specific and nonspecific binding. The results indicate that IPAPP and azido-IPAPP may not be suitable to image the serotonin receptor in the brain.     

Novel soluble cationic trans-diaminedichloroplatinum(II) complexes that are active against cisplatin resistant ovarian cancer cell lines

Positively charged, water soluble cis/trans-[PtCl(2)(piperazine)(Am1)] (where Am1 = NH(3), n-butylamine, isopropylamine, 4-picoline, piperidine, and piperazine) has significant cytotoxic activity against cisplatin resistant ovarian cancer cells. The charged complexes are taken up by cancer cells much more rapidly than cisplatin and bind to cellular DNA and to calf thymus DNA much faster than cisplatin or transplatin. The platinum-piperazine complexes bind proteins (ubiquitin and myoglobin) very slowly as compared to cisplatin and to their neutral piperidine analogues. Altogether, the results reported here suggest that combination of positively charged ligands with a trans-Pt(II)Cl(2) center may lead to the discovery of platinum complexes that are able to circumvent cisplatin resistance.     

顺铂处理卵巢癌细胞系OVCAR3引起Survivin表达差异的研究

的 探讨顺铂(DDP)处理卵巢癌细胞系时Sur-vivin表达是否有变化,进而探讨Survivin表达与肿瘤细胞耐药之间的关系及其在肿瘤细胞获得性耐药及细胞凋亡耐受所起的重要作用。方法 以卵巢癌细胞系OVCAR3为材料,用MTT比色法检测细胞活性,流式细胞术检测细胞凋亡。RT-PCR检测Survivin mRNA表达差异,Western blot检测Survivin蛋白表达变化。结果 顺铂抑制卵巢癌细胞生长,具有时间和浓度依赖效应,即随时间延长和浓度增加,细胞生长抑制越强,细胞凋亡率也有同样的趋势,最高达31.6％。1mg·L~(-1)DDP处理卵巢癌细胞,Survivin mRNA及蛋白表达随作用时间的增长,分别在8 h和12 h达最高,随后又降低。结论 抗凋亡蛋白Survivin在卵巢癌细胞系中呈高表达,顺铂处理卵巢癌细胞,Survivin mRNA表达随作用时间延长而增加,这可能是卵巢癌细胞对化疗药物产生耐药性的重要因素之一。     

Substituted-vinyl hydroxytriarylethylenes, 1-[4-[2-(diethylamino) ethoxy]phenyl]-1-(4-hydroxyphenyl)-2-phenylethylenes: synthesis and effects on MCF 7 breast cancer cell proliferation

A series of triarylethylene compounds related to 4-hydroxyclomiphene (2) in which the vinyl Cl substituent was replaced by ethyl (5), Br (6), H (7), CN (8), or NO2 (9) substituents were synthesized to facilitate studies of the molecular actions of synthetic nonsteroidal antiestrogens. The relative binding affinities of these compounds for the estrogen receptor (ER) and the antiestrogen binding site (AEBS) in MCF 7 human mammary carcinoma cells were measured and correlated with the effects of these drugs on cell proliferation kinetics. Affinities for ER and AEBS were highly correlated, illustrating that vinyl substituents influence binding to ER and AEBS in a parallel manner. All compounds except 7 had biphasic effects on cell proliferation kinetics, indicating the presence of at least two distinct mechanisms by which hydroxytriarylethylenes inhibit breast cancer cell proliferation. In the concentration range 10(-10)-10(-8) M, cell proliferation was inhibited by 60-70%, these effects were estrogen-reversible, and the degree of growth inhibition was in the order Cl greater than Et greater than Br greater than NO2 greater than CN greater than H, which paralleled the order of affinities for ER. There was no further inhibition of cell growth between 10(-8) and 10(-6) M, but at concentrations greater than 10(-6) M there was a further dose-dependent decrease in cell growth mediated by mechanisms yet to be defined but apparently distinct from ER-mediated events. In both concentration ranges, growth inhibition was accompanied by accumulation of cells in the G1 phase of the cell cycle. These data, obtained with a novel series of hydroxytriarylethylenes, have enabled clear definition of two distinct mechanisms of growth inhibition by triarylethylene antiestrogens. They also indicate that among the vinyl substitutions examined to date the Cl substituent yields the most active molecule both in terms of affinity for ER and AEBS and potency as a growth inhibitory agent.     

Stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine]platinum(II) complexes, Part III: Evaluation of the mammary tumor inhibiting properties.

Stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine]platinum(II) complexes produce a strong configuration-dependent inhibition of the hormone sensitive MXT-mammary carcinoma of the mouse. Besides an interference in the DNA synthesis in analogy to cisplatin an estrogen level lowering effect is supposed to be the mode of action. The new complexes show also a significant activity on the hormone-independent MXT-mammary carcinoma of the mouse.     

Synthesis of 1-(2-aminophenyl)isoquinolines and the biological activity of their cis-dichloro platinum(II) complexes.

The broad biological effects of isoquinolines prompted us to use them as chelating, nonleaving ligands in cis-platinum(II) antitumor complexes. The synthesis of several 1-(2-aminophenyl)isoquinoline derivatives with different levels of hydrogenation and varying substitution of the phenyl ring is reported. These compounds constitute a new class of ligands for the synthesis of oligocyclic platinum(II) complexes. In vitro cytotoxicity tests indicate that the most basic amine ligands afford the most effective complexes. Two of the new complexes were more potent against L1210 murine leukemia cells than the well-established antitumor compound cisplatinum.     

New synthetic route to [bis-1,2-(aminomethyl)benzene]dichloroplatinum(II) complexes, screening for cytotoxic activity in cisplatin-sensitive and resistant human cancer cell lines, and reaction with glutathione.

A new synthetic route to [bis-1,2-(aminomethyl)benzene]dichloroplatinum(II) complexes is described. o-Xylene and the 4-methoxy substituted derivative were used as starting points for the synthesis: benzylic bromination with N-bromosuccinamide/benzoylperoxide followed by the substitution of the benzyl bromides for azide and finally a catalytic hydrogenation with Pd/C of the diazides gave the desired diamines ligands. An attempt to synthesize the 4,6-dimethoxy derivative was unsuccessful due to the bromination of the aromatic ring. The diamines were complexed with K2PtCl4 to give the target Pt(II) complexes: [1,2-bis(aminomethyl)benzene]dichloroplatinum(II) (4a) and [1,2-bis(aminomethyl)-4-methoxy-benzene]dichloroplatinum(II) (4b). Screening for cytotoxic activity was done in comparison to cisplatin in a panel of eight human cancer cell lines; in all cases, the 4-methoxy derivative 4b was less active than the unsubstituted analog, 4a. In four cell lines 4a was as potent as cisplatin, while in the other four lines cisplatin was considerably more potent then 4a. The 5637 bladder cancer cell line was made 4-5 fold resistant to either cisplatin or [d,l-trans-1,2-diaminocyclohexane]dichloroplatinum(II); 4a showed some cross resistance (2-3 fold) to both resistant cell lines. The reactivity of 4a towards substitutions with glutathione (GSH), a biological thiol involved in intrinsic and acquired resistance to Pt-complexes, was measured by a RP-HPLC method. It was found that the second-order rate constant for the reaction of 4a with GSH was similar to that that reported for CDDP, indicating that reactivity towards GSH does not explain the different levels of cross resistance.     

Tumor inhibiting [1,2-bis(fluorophenyl)ethylenediamine]platinum(II) complexes. Part II: Biological evaluation-in vitro studies on the P 388 D1 leukemia cell line

Experiments on the P 388 D1 cell line (48 h exposure) demonstrate that [1,2-bis-(fluorophenyl)ethylenediamine]platinum(II) complexes are comparably active on the cell number and 3H-thymidine incorporation, irrespective of the position of the fluorine atom (ortho, meta, or para) and the nature of the "leaving group" (Cl- or H2O). However, the compounds of the R,R/S,S series are more active than those of the R,S series and comparable to cisplatin. In the "tumor colony forming assay" the R,R/S,S configurated compounds are about ten times as active as cisplatin. The R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts reach their half maximum effect more readily (t1/2 approximately equal to 1.6 h) than their R,S configurated analogues (t1/2 approximately equal to 20 h). A time limited contact of the cells with R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts (-1h) leads to a similar inhibition like a permanent drug exposure indicating a fast uptake of the complex by the tumor cell. In experiments on the Ehrlich ascites tumor of the mouse and on the L 1210 leukemia cell line R,R/S,S-[1,2-bis(4-fluorophenyl)ethylenediamine]dichloroplatinum(II) turns out to be equipotent with cisplatin.     

Synthesis and antiarrhythmic activity of new 1-[1-[2-[3-(alkylamino)-2-hydroxypropoxy]phenyl]vinyl]-1 H-imidazoles and related compounds

Various 1-[1-[2-[3-(alkylamino)-2-hydroxypropoxy]phenyl]vinyl]-1 H-azoles were synthesized and investigated for beta-adrenoceptor-blocking and antiarrhythmic activities. Although no compounds showed more potent beta-blocking effects than propranolol in the isolated guinea pig right atria, many compounds exhibited significant antiarrhythmic effects against aconitine or ischemic arrhythmia in mice or dogs. 1-[2,5-Dichloro-6-[1-(1H-imidazol-1-yl)-ethenyl] phenoxy]-3-[(1-methylethyl)amino]-2-propanol hydrochloride (48) (711389-S) was selected as a candidate for clinical evaluation in man, since its antiarrhythmic effects were superior to those of quinidine, disopyramide, or propranolol. Asymmetric synthesis of (R)-(+)- and (S)-(-)-48 is described, and it is proven that there is no stereospecificity in the antiarrhythmic effect of 48.     

An investigation into the formation of N- [2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and 6-[2-(dimethylamino)ethylamino]- 3-hydroxy-7H-indeno[2, 1-C]quinolin-7-one dihydrochloride (TAS-103) stabilised DNA topoisomerase I and II cleavable complexes in human leukaemia cells

The antitumour agents DACA (XR5000; N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) and TAS-103 (6-[2-(dimethylamino)ethylamino]-3-hydroxy-7H-indeno[2, 1-c]quinolin-7-one dihydrochloride) have been shown to inhibit two essential nuclear enzymes in vitro, DNA topoisomerase I and DNA topoisomerase (topo) II. To examine whether DACA or TAS-103 stabilise topo I, topo IIalpha, and topo IIbeta cleavable complexes in human leukaemia CCRF-CEM cells, the TARDIS assay (trapped in agarose DNA immunostaining) was used. This assay can reveal drug-stabilised topo-DNA complexes formed in situ in individual cells. The results showed that both DACA and TAS-103 can stabilise topo IIalpha cleavable complexes in these cells. Topo IIbeta cleavable complexes were also formed, but only at high concentrations of DACA and TAS-103. The effect on topo I was less clear, with TAS-103 showing only low levels of cleavable complex formation and DACA having no detectable effect under these assay conditions. This is in contrast to the purified enzyme cleavable complex assay, where both DACA and TAS-103 poisoned topo I. Although both DACA and TAS-103 show a preference for topo IIalpha in whole cells using the TARDIS assay, the formation of low levels of topo I or topo IIbeta cleavable complexes may still play a role in cell death.     

Beta 1-selective adrenoceptor antagonists: examples of the 2-[4-[3-(substituted amino)-2-hydroxypropoxy]phenyl]imidazole class. 2

An attempt to develop a highly cardioselective beta-adrenoceptor antagonist devoid of intrinsic sympathomimetic activity (ISA) focused on exploring structure-activity relationships around (S)-[p-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy] phenyl]-4-(2-thienyl)imidazole. Strategies to reduce or eliminate ISA centered on structural changes that could influence activation of the receptor by the drug itself or by a metabolite. The approaches involved (a) eliminating the acidic imidazole N-H proton, (b) incorporating substituents ortho to the beta-adrenergic blocking side chain, (c) increasing steric bulk around the N-H moiety, (d) decreasing lipophilicity, (e) introducing intramolecular hydrogen bonding involving the imidazole N-H, and (f) displacing the imidazole ring from an activating position by the incorporation of a spacer element. The compounds were investigated in vitro for beta-adrenoceptor antagonism and in vivo for ISA. From these studies, the most successful variation involved the insertion of a spacer between the imidazole and aryl rings. (S)-4-Acetyl-2-[[4-[3-[[2-(3, 4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]phenyl]methyl] imidazole (S-51) was demonstrated to be highly cardioselective (dose ratio beta 2/beta 1 greater than 9333) and devoid of ISA.     

The pharmacokinetics of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) in Sprague-Dawley rats

Using adult male Sprague-Dawley rats, we examined the blood protein binding and pharmacokinetics of the potent phencyclidine (PCP) receptor ligand 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP). The average percentage of unbound [3H]TCP in rat serum was 42 +/- 6% and the [3H]TCP blood to plasma ratio was 0.98 +/- 0.03 (mean +/- SD, n = 5 in both studies). For the pharmacokinetic studies, [3H]TCP and 1 mg/kg unlabeled TCP were administered as an iv bolus dose. The average [3H]TCP elimination half-life was 2.1 hr. In contrast, total radioactivity in the plasma had a much longer half-life, suggesting much slower metabolite elimination. The average distribution volumes were 27 +/- 17, 15.6 +/- 6.2, and 5.6 +/- 3.0 liters/kg for V beta, Vss, and Vc, respectively. Total body and renal clearance values were 132 +/- 45 and 1.1 +/- 0.4 ml/min/kg, respectively. When TCP pharmacokinetic parameters were compared to PCP pharmacokinetic data in rats from a previous study, a strikingly similar pharmacokinetic profile was found. These data indicated that TCP and PCP are equivalent, from a pharmacokinetic point of view, and that the higher pharmacological potency of TCP over PCP is probably due to receptor-mediated differences.     

Synthesis and 5-HT2A, 5-HT1A and alpha1-binding affinities of 2-[2-Hydroxy-3-(pyridin-3-yl-methyl)amino]-, 2-[2-hydroxy-3-(2-pyridin-2-yl-ethyl)amino]- and 2-[2-hydroxy-3-(4-N-methyl-piperazin-1-yl)-amino]propoxybenzaldehyde-O-(substituted) benzyl oximes

Some oxime ether-substituted aryloxypropanolamines 3-5, structurally related to the active metabolite 2 of sarpogrelate 1, were synthesized and tested for their affinities at 5-HT2A and 5-HT1A serotoninergic receptors as well as at the alpha1-adrenoceptor. The results show that the compounds possess, at least partially, the ability of the model compounds 1 and 2 to interact with the 5-HT2A-receptors; they have the same selectivity towards 5-HT2A receptors vs alpha1-adrenoceptors.     

Diamine ligand release from the cisplatin analogue [meso-1,2-bis(2,6-dichloro-4- hydroxyphenyl)ethylenediamine]dichloroplatinum(II) in cell culture medium.

The stability of the five-membered chelate ring of the cisplatin analogue [meso-1,2-bis(2,6-dichloro-4- hydroxyphenyl)ethylenediamine]dichloroplatinum(II) was investigated under typical cell culture conditions (IMEM-Richter's medium with 10% fetal calf serum, 37 degrees C). For this purpose, the platinum compound was radiolabeled with tritium in the meta position of the aromatic ring by an acid-catalyzed tritium-exchange reaction, and a reversed-phase HPLC assay with radiochemical detection was developed to monitor for the presence of the free diamine ligand in the cell culture medium. A gradual increase in radioactivity attributed to the free diamine was found in medium containing the dichloroplatinum(II) complex (ca. 25% after 24 h), indicating that the diamine ligand was being released from the metal atom. When 1 mM glutathione (GSH) was included in the incubation medium, the amount of free diamine nearly doubled after 24 h, while the amount of radioactivity attributed to serum protein-platinum adducts decreased relative to incubations without GSH. On the other hand, the omission of serum from the incubations resulted in a dramatic decrease in the amount of radioactivity eluting under the diamine peak, while the concentrations of the two methionine-Pt adducts, which formed in a 1:1 ratio, rose. Through the use of liquid secondary ion mass spectroscopy, the two methionine-Pt adducts were identified as monomethionine metabolites of the title compound, whereby the two chloride ligands have been replaced by the amino acid. These compounds are probably diastereomers since the sulfur of methionine can coordinate to platinum with equal probability either cis or trans to the R-configured benzylamine carbon. On the basis of the chemical shifts of the MeS groups in the 250-MHz 1H NMR, it is concluded that a S,N-five-membered chelate ring is present in these methionine-Pt adducts.     

Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization

The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials.     

2-Acetylpyridine thiosemicarbazones. 5. 1-[1-(2-Pyridyl)ethyl]-3-thiosemicarbazides as potential antimalarial agents

Reduction of the azomethine bond of 2-acetylpyridine thio- and selenosemicarbazones with sodium borohydride readily afforded the corresponding thio- or selenosemicarbazides when they were N4,N4-disubstituted. This conversion failed, however, when the thio- or selenosemicarbazones were N4-substituted or unsubstituted. A more general route to the desired thio- or selenosemicarbazides consisted of reduction with sodium borohydride of methyl 3-[1-(2-pyridyl)ethylidene]hydrazinecarbodithioate to give the 2-pyridylethyl derivative. Displacement of methyl mercaptan from the thio ester moiety of the latter by amines produced 1-[1-(2-pyridyl)ethyl]-3-thiosemicarbazides. These compounds were somewhat more active as antimalarial agents in Plasmodium berghei infected mice than the corresponding thiosemicarbazones; however, the enhancement of activity was accompanied by an increase in toxicity. Compound 7, 3-azabicyclo[3.2.2]nonane-3-carbothioic acid 2-[1-(2-pyridyl)ethyl]hydrazide, is the most potent derivative of 2-acetylpyridine we have evaluated to date.     

Mono- and polynuclear [alkylamine]platinum(II) complexes of [1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II): synthesis and investigations on cytotoxicity, cellular distribution, and DNA and protein binding

A series of mononuclear and dinuclear alkylamine derivatives of [meso-1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) (m-4F-PtL-R1 and (m-4F-PtL)2-R2; R(1) = alkylamine, R(2) = alkyldiamine, L = DMSO or Cl) as well as the DAB(PA)(4) polyimine dendrimer complex ((m-4F-PtDMSO)4DAB(PA)4; DAB(PA)4 = N,N,N',N'-tetrakis(3-aminopropyl)butane-1,4-diamine) were synthesized and tested for cytotoxicity, intracellular distribution, and DNA and protein binding. All compounds strongly bound to human serum albumin by hydrophobic and electrostatic interactions. These inactivation reactions hindered the uptake into tumor cells and prevented strong cytotoxic effects. If serum-free medium was used, a high accumulation grade in MCF-7 breast cancer cells and a high DNA binding was observed. As most efficient compound (m-4F-PtDMSO)4DAB(PA)4 was identified. It showed a 20-fold higher cellular uptake and an approximately 700-fold higher DNA binding than cisplatin.