Tuning of lipophilicity and cytotoxic potency by structural variation of anticancer platinum(IV) complexes

A series of bis(carboxylato)dichlorido(ethane-1,2-diamine)platinum(IV) compounds with IC₅₀ values ranging between 142 μM and 18 nM was investigated with respect to their lipophilicity (by the shake flask method as well as microemulsion electrokinetic chromatography), reduction potential, as well as their cellular accumulation in cancer cells in vitro. In general, the antiproliferative properties of the complexes correlated with their lipophilicity as well as their accumulation, whereas differences in antiproliferative potency could not be explained by reduction potentials since they do not vary significantly within the investigated series of compounds. Only minor effects for complexes featuring polar end groups were detected.     

Novel bis(carboxylato)dichlorido(ethane-1,2-diamine)platinum(IV) complexes with exceptionally high cytotoxicity

(OC-6-33)-Dichlorido(ethane-1,2-diamine)dihydroxidoplatinum(IV) (1) was carboxylated using succinic- or 3-methylglutaric anhydride. The resulting bis(carboxylato)platinum(IV) complexes display free, uncoordinated carboxylic acid groups which were further derivatized with primary aliphatic alcohols. The complexes were characterized in detail by elemental analysis, ESI-MS, FT-IR, as well as multinuclear (¹H, ¹³C, ¹⁵N, ¹⁹⁵Pt) NMR spectroscopy. Cytotoxic properties were evaluated in four human tumor cell lines originating from ovarian carcinoma (CH1, SK-OV-3), cervical carcinoma (HeLa) and colon carcinoma (SW480) by means of the MTT assay (MTT = 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide). Structure-activity relationships showed that the cytotoxicity increased with increasing lipophilicity of the alcoholate moiety yielding IC₅₀ values in the low micromolar or even low nanomolar range.     

Diamminetetrakis(carboxylato)platinum(IV) Complexes - Synthesis, Characterization, and Cytotoxicity

A series of eight novel diamminetetrakis(carboxylato)platinum(IV) complexes was synthesized and characterized by multinuclear (1) H-, (13) C-, (15) N-, and (195) Pt-NMR spectroscopy. Their antiproliferative potency was evaluated in three human cancer cell lines representing ovarian (CH1), lung (A549), and colon carcinoma (SW480). In cisplatin-sensitive CH1 cancer cells, cytotoxicity was found in the low micromolar range, whereas, in inherently cisplatin-resistant A549 and SW480 cells, the activity was very low or negligible. Astonishingly, raise in lipophilicity of the complexes, as found in the case of cisplatin analogs, did not result in a significant enhancement of the cytotoxic effect.     

Synthesis and cytotoxicity of new platinum(IV) complexes of mixed carboxylates

In order to develop new antitumor platinum(IV) complexes with highly tuned lipophilicity, a series of (diamine)Pt(IV) complexes of the formula [Pt(IV)(dach)L(3)L'] or [Pt(IV)(dach)L(2)L"(2)] (dach=trans-(+/-)-1,2-diaminocyclohexane; L=acetato, propionato; L'=acetato, propionato, valerato or pivalato; L"=trifluoroacetato) have been synthesized by electrophilic substitution of the tris(carboxylato)hydroxoplatinum(IV) complexes, [Pt(IV)(dach)L(3)OH] (L=acetato, propionato), with various carboxylic anhydrides such as acetic, trifluoroacetic, pivalic and valeric anhydrides. The present platinum(IV) complexes were fully characterized by means of elemental analyses, 1H NMR, mass and IR spectroscopies. The complexes 8 and 10, satisfying the appropriate range of lipophilicity (logP=0.18-1.54), exhibited high activity (ED(50), 5.1 and 1.3 microM, respectively) compared with other complexes, which implies that the lipophilicity is an important factor for the antitumor activity of this series of complexes.     

Heterobinuclear Zn‐Ln (Ln = La,Nd, Eu,Gd, Tb,Er and Yb) complexes based on asymmetric Schiff‐base ligand: synthesis,characterization and photophysical properties

With a novel asymmetric Schiff‐base zinc complex ZnL (H₂L = N‐(3‐methoxysalicylidene)‐N′‐(5‐bromo‐3‐methoxysalicylidene)phenylene‐1,2‐diamine), obtained from phenylene‐1,2‐diamine, 3‐methoxysalicylaldehyde and 5‐bromo‐3‐methoxysalicylaldehyde, as the precursor, a series of heterobinuclear Zn‐Ln complexes [ZnLnL(NO₃)₃(CH₃CN)] (Ln = La, 1; Ln = Nd, 2; Ln = Eu, 3; Ln = Gd, 4; Ln = Tb, 5; Ln = Er, 6; Ln = Yb, 7) were synthesized by the further reaction with Ln(NO₃)₃·6H₂O, and characterized by Fourier transform‐infrared, fast atom bombardment mass spectroscopy and elemental analysis. Photophysical studies of these complexes show that the strong and characteristic near‐infrared luminescence of Nd³⁺, Yb³⁺and Er³⁺ with emissive lifetimes in the microsecond range has been sensitized from the excited state of the asymmetric Schiff‐base ligand due to effective intramolecular energy transfer; the other complexes do not show characteristic emission due to the energy gap between the chromophore and lanthanide ions. Copyright © 2012 John Wiley & Sons, Ltd.     

The cellular distribution and oxidation state of platinum(II) and platinum(IV) antitumour complexes in cancer cells

The cellular distribution of platinum in A2780 ovarian cancer cells treated with cisplatin and platinum(IV) complexes with a range of reduction potentials has been examined using elemental analysis (synchrotron radiation-induced X-ray emission). The cellular distribution of platinum(IV) drugs after 24 h is similar to that of cisplatin, consistent with the majority of administered platinum(IV) drugs being reduced. Micro-X-ray absorption near-edge spectra of cells treated with cisplatin and platinum(IV) complexes confirmed the reduction of platinum(IV) to platinum(II). In cells treated, the most difficult to reduce complex, cis,trans,cis-[PtCl₂(OH)₂(NH₃)₂], platinum(IV) was detected in the cells along with platinum(II). The observations are in accordance with the relative ease of reduction of the platinum(IV) complexes used and support the requirement of reduction for activation of platinum(IV) complexes.Abbreviations en ethane-1,2-diamine - GM growth medium - PBS phosphate buffered saline - RPMI Roswell Park Memorial Institute - SRIXE synchrotron radiation-induced X-ray emission - XAFS X-ray absorption fine structure - XANES X-ray absorption near-edge spectroscopy     

Novel endothall-containing platinum(IV) complexes: synthesis, characterization, and cytotoxic activity

Two platinum(IV) complexes (OC-6-33)-dichlorido(ethane-1,2-diamine)dihydroxidoplatinum(IV) and (OC-6-33)-diammine(dichlorido)dihydroxidoplatinum(IV) were carboxylated using demethylcantharidin as carboxylation agent. The complexes were characterized by elemental analysis, mass spectrometry, multinuclear (1H, 13C, 15N, and 195Pt) NMR spectroscopy, and, in case of (OC-6-33)-diamminebis(3-carboxy-7exo-oxabicyclo[2.2.1]heptane-2-carboxylato)dichloridoplatinum(IV) via X-ray diffraction. Cytotoxicity of the complexes was studied in seven human cancer cell lines representing five tumor entities, i.e., ovarian carcinoma (CH1, SK-OV-3), cervical carcinoma (HeLa), colon carcinoma (SW480, HCT-116), osteosarcoma (U-2 OS), and hepatocellular carcinoma (Hep G2) by means of the MTT (=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium hydrobromide) assay.     

A turn‐on indole‐based sensor for hydrogen sulfate ion

A simple indole‐based receptor 1 was prepared by a simple Schiff‐base reaction of 1H‐indole‐3‐carbaldehyde with ethane 1,2‐diamine and its fluoroionophoric properties toward anions were investigated. Indole‐based receptor 1 acts as a selective turn‐on fluorescent sensor for HSO₄^? in methanol among a series of tested anions. Fluorescence spectroscopy, ultraviolet and nuclear magnetic resonance imaging support that the HSO₄^– indeed interacted with imine nitrogen and the proton of nitrogen in indole ring. Copyright © 2013 John Wiley & Sons, Ltd.     

Structural, magnetic, electrochemical, catalytic, DNA binding and cleavage studies of new macrocyclic binuclear copper(II) complexes

The macrocyclic symmetrical and a series of unsymmetrical binuclear copper(II) complexes have been synthesized by using mononuclear complex [CuL] [3,3′-((1E,7E)-3,6-dioxa-2,7-diazaocta-1,7-diene-1,8-diyl)bis(3-formyl-5-methyl-2-diolato)copper(II)]. Another compartment of the [CuL] have been condensed with various diamines like 1,2-bis(aminooxy)ethane (L¹), 1,2-diamino ethane(L^2a), 1,3-diamino propane(L^2b), 1,4-diamino butane(L^2c), 1,2-diamino benzene(L^2d), 1,8-diamino naphthalene(L^2e) and characterized by elemental, spectroscopic, and X-ray crystallographic methods. The influence of the coordination geometry and the ring size of the binucleating ligands on the electronic, redox, magnetic, catecholase activity, DNA binding and cleavage properties have been studied. The molecular structures of the symmetrical binuclear complex [Cu₂L¹(H₂O)₂](ClO₄)₂ (1) and unsymmetrical binuclear complex [Cu₂L^2b(ClO₄)(H₂O)]ClO₄ (2b) were determined by X-ray crystallography. Both of them were discrete binuclear species in which each Cu(II) ions are in distorted square pyramid. The Cu?Cu distances vary from 3.0308 (2b) to 3.0361 Å (1). Electrochemical studies evidenced that two quasi-reversible one electron-transfer reduction waves −0.91 to −1.01 V, −1.26 to −1.55 V) for binuclear complexes are obtained in the cathodic region. Cryomagnetic investigation of the binuclear complexes reveals a weak antiferromagnetic spin exchange interaction between the Cu(II) ions within the complexes (−2J = 104.4-127.5 cm⁻¹). The initial rate (V_in) for the oxidation of 3,5-di-tert-butylcatechol to o-quinone by the binuclear Cu(II)complexes are in the range 3.6 × 10⁻⁵ to 7.3 × 10⁻⁵ Ms⁻¹. The binuclear Cu(II) complexes are avid binders to calf thymus DNA. The complexes display significant oxidative cleavage of circular plasmid pBR322 DNA in the presence of mercaptoethanol using the singlet oxygen as a reactive species. The aromatic diamine condensed macrocyclic ligands of copper(II) complexes display better DNA interaction and significant chemical nuclease activity than the aliphatic diamine condensed macrocyclic Cu(II) complexes.     

The microwave synthesis of platinum(II) phosphine complexes

The microwave synthesis of a series of platinum(II) phosphine complexes is reported. The complexes dppePtCl₂ (dppe = bis(diphenylphosphino)ethane), dpppPtCl₂ (dppp = bis(diphenylphosphino)propane), dppmPtCl₂ (dppm = bis(diphenylphosphino)methane) and cis-(Ph₃P)₂PtCl₂ are synthesized from the reaction of potassium tetrachloroplatinate(II) and the phosphine. The isolated yields are 65% or better.     

Synthesis,Structural Characterization,and Chiroptical Studies of Bidentate Salen‐Type Lanthanide (III) Complexes

The salen‐type ligand prepared with (R,R) diphenylethan‐1,2‐diamine and salicylaldehyde provides stable and inert complexes KLnL₂ upon simple reaction with lanthanide halides or pseudohalides LnX₃ (Ln = Tb³⁺‐Lu³⁺; X = Cl^? or TfO^?) of its potassium salt. All the complexes were completely characterized through nuclear magnetic resonance (NMR), electronic circular dichroism (ECD) in the UV and some (Er³⁺, Tm³⁺, Yb³⁺) also with Near‐IR ECD (NIR‐ECD) and luminescence (Tb³⁺, Tm³⁺). Careful analysis of the NMR shifts demonstrated that the complexes are isostructural in solution and afforded an accurate geometry. This was further confirmed by means of Density Functional Theory (DFT) optimization of the Lu³⁺ complex, and by comparing the ligand‐centered experimental and time‐dependent TD‐DFT computed UV‐ECD spectra. As final validation, we used the NIR‐ECD spectrum of the Yb³⁺ derivative calculated by means of Richardson's equations. The excellent match between calculated and experimental ECD spectra confirm the quality of the NMR structure.  Chirality 27:857–863, 2015. © 2015 Wiley Periodicals, Inc.     

Synthesis, characterization and liquid-phase hydroxylation of phenol with hydrogen peroxide over host (nanopores of zeolite-Y)/guest (oxovanadium(IV) complexes of tetraaza macrocyclic ligands) nanocatalyst

Oxovanadium(IV) tetraaza complexes of [14]aneN₄: 1,5,8,12-tetraaza-2,9-dioxo-4,11-diphenylcyclotetradecane; [16]aneN₄: 1,5,9,13-tetraaza-2,10-dioxo-4,12-diphenylcyclohexadecane; Bzo₂[14]aneN₄: dibenzo-1,5,8,12-tetraaza-2,9-dioxo-4,11-diphenylcyclotetradecane and Bzo₂[16]aneN₄: dibenzo-1,5,9,13-tetraaza-2,10-dioxo-4,12-diphenylcyclohexadecane have been encapsulated in the nanopores of zeolite-Y by a two-step process in the liquid phase: (i) adsorption of [bis(diamine)VO(IV)] (diamine = 1,2-diaminoethane, 1,3-diaminopropane, 1,2-diaminobenzene, 1,3-diaminobenzene); [VO(N-N)₂]²⁺-NaY; in the nanopores of the zeolite-Y and (ii) in situ condensation of the oxovanadium(IV) precursor complex with ethylcinnamate. The new host-guest nanocatalysts were characterized by several techniques: chemical analysis and spectroscopic methods (FT-infrared (FT-IR), ultraviolet-visible (UV-Vis), X-ray diffraction (XRD), nitrogen adsorption and diffuse reflectance spectra (DRS)) technique. The analytical data indicated a composition corresponding to the mononuclear complex of tetraaza ligand. The characterization data showed the absence of extraneous complexes, retention of zeolite crystalline structure and encapsulation in the nanopores. Liquid-phase selective hydroxylation of phenol with H₂O₂ to a mixture of catechol and hydroquinone in CH₃CN have been reported using oxovanadium(IV) tetraaza complexes encapsulated in zeolite-Y as catalysts. All these catalysts are more selective toward catechol formation.     

Metallokinetic characteristics of antidiabetic bis(allixinato)oxovanadium(IV)-related complexes in the blood of rat

The antidiabetic effect of vanadium is a widely accepted phenomenon; some oxovanadium(IV) complexes have been found to normalize high blood glucose levels in both type 1 and type 2 diabetic animals. In light of the future clinical use of these complexes, the relationship among their chemical structures, physicochemical properties, metallokinetics, and antidiabetic activities must be closely investigated. Recently, we found that among bis(3-hydroxypyronato)oxovanadium(IV) [VO(3hp)₂] related complexes, bis(allixinato)oxovanadium(IV) [VO(alx)₂] exhibits a relatively strong hypoglycemic effect in diabetic animals. Next, we examined its metallokinetics in the blood of rats that received five VO(3hp)₂-related complexes by the blood circulation monitoring–electron paramagnetic resonance method. The metallokinetic parameters were obtained from the blood clearance curves based on a two-compartment model; most parameters, such as area under the concentration curve and mean residence time, correlated significantly with the in vitro insulinomimetic activity in terms of 1/IC₅₀ (IC₅₀ is the 50% inhibitory concentration of the complex required for the release of free fatty acids in adipocytes) and the lipophilicity of the complex (log P _com). The oxovanadium(IV) concentration was significantly higher and the species resided longer in the blood of rats that received VO(alx)₂ than in the blood of rats that received VO(3hp)₂ or bis(kojato)oxovanadium(IV); VO(alx)₂ also exhibited higher log P _com and 1/IC₅₀ values. On the basis of these results, we propose that the introduction of lipophilic groups at the C2 and C6 positions of the 3hp ligand is an effective method to enhance the hypoglycemic effect of the complexes, as supported by the observed in vivo exposure and residence in the blood.     

Synthesis,spectroscopic characterization,electrochemical behavior and computational analysis of mixed diamine ligand gold(III) complexes: antiproliferative and in vitro cytotoxic evaluations against human cancer cell lines

The gold(III) complexes of the type [(DACH)Au(en)]Cl₃, 1,2-Diaminocyclohexane ethylenediamine gold(III) chloride [where 1,2-DACH = cis-, trans-1,2- and S,S-1,2diaminocyclohexane and en = ethylenediamine] have been synthesized and characterized using various analytical and spectroscopic techniques including elemental analysis, UV–Vis and FTIR spectra; and solution as well as solid-state NMR measurements. The solid-state ¹³C NMR shows that 1,2-diaminocyclohexane (1,2-DACH) and ethylenediamine (en) are strongly bound to the gold(III) center via N donor atoms. The stability of the mixed diamine ligand gold(III) was determined by ¹H and ¹³C NMR spectra. Their electrochemical behavior was studied by cyclic voltammetry. The structural details and relative stabilities of the four possible isomers of the complexes were also reported at the B3LYP/LANL2DZ level of theory. The coordination sphere of these complexes around gold(III) center adopts distorted square planar geometry. The computational study also demonstrates that trans- conformations is slightly more stable than the cis-conformations. The antiproliferative effects and cytotoxic properties of the mixed diamine ligand gold(III) complexes were evaluated in vitro on human gastric SGC7901 and prostate PC3 cancer cells using MTT assay. The antiproliferative study of the gold(III) complexes on PC3 and SGC7901 cells indicate that complex 1 is the most effective antiproliferative agent among mixed ligand based gold(III) complexes 1–3. The IC₅₀ data reveal that the in vitro cytotoxicity of complexes 1 and 3 against SGC7901 cancer cells are fairly better than that of cisplatin.     

Study of SOD Mimic and Nucleic Acid Interaction Activity Exerted by Enrofloxacin‐Based Copper(II) Complexes

Five new copper(II) complexes of type [Cu(erx)( L )Cl] (erx, enrofloxacin; thiophene‐2‐carbaldehyde ( L ¹ ); pyridine‐2‐carbaldehyde ( L ² ); 2,2′‐dipyridylamine ( L ³ ); 4,5‐diazafluoren‐9‐one ( L ⁴ ); bis(3,5‐dimethyl‐1‐pyrazolyl)methane ( L ⁵ )) have been synthesized and characterized by elemental analysis, reflectance, IR, and FAB‐MS. Complexes have been investigated for their interaction with calf thymus (CT) DNA utilizing the absorption‐titration method, viscometric and DNA thermal denaturation studies. The cleavage reaction on pUC19 DNA has been monitored by agarose gel electrophoresis. The results indicated that the Cu^II complexes can more effectively promote the cleavage of plasmid DNA at physiological pH and superoxide dismutase. The (SOD) activity of the complexes has been evaluated by the nitroblue tetrazolium assay, and the complexes catalyzed the dismutation of superoxide at pH 7.8 with IC₅₀ values of 0.35–1.25 μM . The complexes have also been screened for their antibacterial activity against five pathogenic bacteria.     

Platinum(II) Complexes with 1,10‐Phenanthroline and Hydrophilic Alkoxyacetate Ligands as Potential Antitumor Agents

Four platinum complexes, formulated as [Pt(phen)(OCOCH₂OR)₂] (phen=1,10‐phenanthroline, R=Me, Et, ⁱPr, or ^tBu), have been synthesized and well characterized by elemental analysis, IR, ¹H‐NMR, ¹³C‐NMR and ESI‐MS spectroscopy. Replacing chloride groups of the precursor Pt(phen)Cl₂ with alkoxyacetate anions greatly improved the aqueous solubility and cytotoxicity of the resulting platinum complexes. The in vitro cytotoxicity study revealed that complexes 1 – 3 were active in vitro towards four human tumor cell lines, especially complex 1 which exhibited prominent in vitro cytotoxic activity against HCT‐116 cell lines comparable to cisplatin and oxaliplatin. Flow cytometry assay indicated that representative complexes 1 and 2 exerted cytotoxicity on HCT‐116 cell lines through inducing cell apoptosis and blocking cell cycle progression in the S or G2/M phases. The interaction of representative complexes with pET28a plasmid DNA was tested by agarose gel electrophoresis, which demonstrated that complexes 1 and 2 were capable of distorting plasmid DNA mainly by covalent binding and degradation effect.     

Preparation, crystal structures and spectroscopic properties of novel [MCl3 − n(P)3 + n] (M = Co, Rh; n = 0, 1, 2 or 3) series of complexes containing tripodal tridentate phosphine, 1,1,1-tris(dimethylphosphinomethyl)ethane

Cobalt(III) and rhodium(III) complexes of the series of [M^IIICl_3 − n(P)_3 + n]ⁿ⁺ (M = Co or Rh; n = 0, 1, 2 or 3) have been prepared with the use of 1,1,1-tris(dimethylphosphinomethyl)ethane (tdmme) and mono- or didentate phosphines. The single-crystal X-ray analyses of both series of complexes revealed that the M-P and M-Cl bond lengths were dependent primarily on the strong trans influence of the phosphines, and secondarily on the steric congestion around the metal center resulting from the coordination of several phosphine groups. In fact, the M-P(tdmme) bonds became longer in the order of [MCl₃(tdmme)] < [MCl₂(tdmme)(PMe₃)]⁺ < [MCl(tdmme)(dmpe)]²⁺ (dmpe = 1,2-bis(dimethylphosphino)ethane) < [M(tdmme)₂]³⁺ for both Co^III and Rh^III series of complexes, while the M-Cl bond lengths were shortened in this order (except for [M(tdmme)₂]³⁺). Such a steric congestion around the metal center can also account for the structural and spectroscopic characteristics of the series of complexes, [MCl(tdmme)(dmpm, dmpe or dmpp)]²⁺ (dmpm = bis(dimethylphosphino)methane, dmpp = 1,3-bis(dimethylphosphino)propane). The X-ray analysis for [CoCl(tdmme)(dmpm or dmpe)](BF₄)₂ showed that all Co-P bonds in the dmpm complex were shorter by 0.03-0.04 Å than those in the dmpe complex. Furthermore, the first d-d transition energy of the Co^III complexes and the ¹J_Rh-P(tdmme) coupling constants observed for the Rh^III complexes indicated an unusual order in the coordination bond strengths of the didentate diphosphines, i.e., dmpm > dmpe > dmpp.     

Syntheses, structures and bioactivities of silver(I) complexes with dithioether ligands that contain a di- or triethylene glycol chain and different terminal groups

A series of flexible dithioethyl ligands that contain ethyleneoxy segments were designed and synthesized, including bis(2-(pyridin-2-ylthio)ethyl)ether (L¹), 1,2-bis(2-(pyridin-2-ylthio)ethoxy)ethane (L²), bis(2-(benzothiazol-2-ylthio)ethyl)ether (L³) and 1,2-bis(2-(benzothiazol-2-ylthio)ethoxy)ethane (L⁴). Reactions of these ligands with AgNO₃ led to the formation of four new supramolecular coordination complexes, [Ag₂L¹(NO₃)₂]₂ (1), [Ag₂L²(NO₃)₂] (2), [AgL³(NO₃)]_∞ (3) and [AgL⁴(NO₃)] (4) in which the length of the (CH₂CH₂O)_n spacers and the terminal groups of ligands cause subtle geometrical differences. Studies of the inhibitory effect to the growth of Phaeodactylum tricornutum show that all four complexes are active and the compound 4 has the highest inhibitory activity.     

Structure-antitumor activity relationship for new analogs of thecis-dichloro(l,2-diamino cyclohexane) platinum(II) complex

In 1977, Gale and associates reported the synthesis and antitumor activity of a series of Pt(II) complexes containing 1,2-diaminocyclohexane as the ligand. Certain of these complexes showed superior activity and greater water solubility compared to cis-Pt(NH₃)₂Cl₂ complexes (“Neoplatin”). In this paper we report the synthesis and antitumor activity of some 40 new water soluble platinum(II) and platinum(IV) complexes. The following classes of the cis-Pt(L)Cl₂ complexes were obtained, where L = 1,2-diaminocyclohexane: (a) cis-Pt(L)(X), where X is a derivative of homophthalic acid or a derivative of 1,3-benzendicarboxylic acid, (b) cis-Pt(L)(X)(OH)₂ and cis-Pt(L)(X)(Cl)₂ complexes, where L and X are the above-mentioned ligands, (c) cis-Pt(L)(X)₂ complexes where X is the monoanion of an organic xanthate or dithiocarbamate and L = 1,2-diaminocyclohexane, (d) their corresponding Pt(IV) analogues, Pt(L)(X)₂(OH)₂ and Pt(L)(X)₂(Cl)₂. All complexes were assayed against P388 tumors and/or KB cell-bearing mice. The observed antitumor activities were correlated with the structures and spectra of the complexes as well as with the results of EHMO calculations performed on the leaving ligand molecules. A number of the most active complexes were also tested for activity against ADJ/PC6 Yoshida and S-180 tumors in vivo.     

Novel Oxaliplatin Derivatives with 1‐(Substituted Benzyl)azetidine‐3,3‐dicarboxylate Anions. Synthesis,Cytotoxicity, and Interaction with DNA

A series of oxaliplatin derivatives with (1R,2R)‐N¹‐alkyl‐1,2‐cyclohexane‐1,2‐diamine (alkyl=Bu or ⁱPr) as carrier ligands and 1‐(methoxy‐ or methyl‐substituted benzyl)azetidine‐3,3‐dicarboxylate anions as leaving groups were synthesized and spectrally characterized. Generally, Complexes 10 – 15 with an ⁱPr substituent at N(1) showed higher activities in vitro than carboplatin against MCF‐7 human breast carcinoma and A549 human non‐small‐cell lung cell lines, although they were less potent than oxaliplatin. The typical complex 14 exhibited cytotoxicity superior to that of carboplatin and comparable to that of oxaliplatin against two selected tumor cell lines. Additionally, agarose gel electrophoresis was applied to investigate the DNA‐cleavage ability of complex 14 , which demonstrated that it has a different mode of DNA distortion from that of oxaliplatin.