Synthesis and Characterization of New CIS-1,4-Diaminocyclohexane and Piperidine Platinum(II) Complexes Containing Disubstituted Sulfide Groups

Abstract

A series of cationic platinum(II) complexes of the type [Pt(cis-1,4-DACH)(R′R″S)Cl]NO₃ and [Pt(PIP)₂(R′R″S)Cl]NO₃ (where cis-1,4-DACH = cis-1,4-diaminocyclohexane; PIP = piperidine; and R′R″S = dimethylsulfide, diethylsulfide, dipropylsulfide, diisopropylsulfide, dibutylsulfide, diphenylsulfide, dibenzylsulfide, methylphenylsulfide, or methyl-p-tolylsulfide) have been synthesized and characterized by elemental analysis and infrared, ¹H, and ¹⁹⁵Pt nuclear magnetic resonance spectroscopy.     

Synthesis characterization and X-ray crystal structures of cis-1,4-diaminocyclohexane-platinum(II) nucleobase adducts

Platinum complexes of the type [Pt(cis-1,4-DACH)(L)₂]X, where cis-1,4-DACH = cis-1,4-diaminocyclohexane; L = adenine (ade) (1), hypoxanthine (hyp) (2), 9-methylguanine (9-megua) (3), cytosine (cyt) (4), or 1-methylcytosine (1-mecyt) (5); and X = SO₄ or Cl₂ groups, were synthesized and characterized by elemental analysis and by ¹H, ¹³C, and ¹⁹⁵Pt nuclear magnetic resonance spectroscopy. The crystals of [Pt(cis-1,4-DACH)(9-megua)₂]SO₄[9-megua-H]₂SO₄ (3) and [Pt(cis-1,4-DACH)(1-mecyt)₂]Cl₂ · 6H₂O (5) were also subjected to single-crystal X-ray diffraction. The base/PtN4 coordination plane dihedral angles were 74.55° and 85.61° in complex 3 and 78.12° and 81.80° in complex 5. The platinum had distorted square planar geometry in both complexes; the two adjacent corners were occupied by the two nitrogen atoms of cis-1,4-DACH, and the other two corners were occupied by the two N7 atoms of 9-megua in complex 3 and the two N3 atoms of 1-mecyt in complex 5. The cis-1,4-DACH, which has a unique twist-boat configuration, formed a seven-member chelating ring with platinum, which led to considerable strain during bidentate cis-1,4-DACH binding. Cations of both complexes 3 and 5 adopted C₂ molecular symmetry. These adducts were the models for the intrastand cross-links that were relevant to the binding of the Pt(II) antitumor drugs to DNA.     

SYNTHESIS AND CHARACTERIZATION OF A SERIES OF LIPOPHILIC CISPLATIN ANALOGS WITH PIPERIDINE AS NONLEAVING AMINE LIGAND

Abstract

A series of lipophilic platinum(II) complexes of the type cis-[Pt(PIP)₂ L ₂] where PIP = piperidine and L = acetate, propionate, butanoate, pentanoate, hexanoate, heptanoate, octanoate, nonanoate, decanoate, undecanoate, laurate, tridecanoate, myristate, pentadecanoate, palmitate, heptadecanoate, stearate, nonadecanoate and eicosanoate has been synthesized and characterized by elemental analysis, and by infrared, ¹³C and ¹⁹⁵Pt nuclear magnetic resonance spectroscopic techniques. The complexes have been prepared as potential antitumor agents for liposome entrapment.     

3-D frameworks assembled by lanthanide dimers with 1,4-cyclohexanedicarboxylic acid and 1,10-phenanthroline via hydrogen bonds and π–π stacking interactions

Two complexes [Ln(e,a-cis-1,4-chdc)(e,a-cis-1,4-Hchdc)(phen)(H₂O)]₂?10H₂O (Ln = Eu, 1; Tb, 2, 1,4-H₂chdc = 1,4-cyclohexanedicarboxylic acid; phen = 1,10-phenanthroline) have been synthesized and structurally characterized by single-crystal X-ray diffraction. Both complexes are doubly e,a-cis-1,4-chdc-bridged dimers. The e,a-cis-1,4-Hchdc, phen, and water molecules bond to Ln³⁺, forming nine-coordinate complexes. 3-D supramolecular frameworks are constructed by hydrogen bonds and π–π stacking interactions. Luminescence spectra exhibit the ⁵D₀ → ⁷F _J (J = 0–4) and ⁵D₄ → ⁷F _J (J = 6–3) transitions of Eu³⁺ for 1 and Tb³⁺ ion for 2, respectively.     

Tin(II) Halide Insertion or Halogen Exchange in the Reactions of Dihaloplatinum(II) Complexes with Tin(II) Halide

Reactions of SnCl₂ with the complexes cis‐[PtCl₂(P₂)] (P₂=dppf (1,1′‐bis(diphenylphosphino)ferrocene), dppp (1,3‐bis(diphenylphosphino)propane=1,1′‐(propane‐1,3‐diyl)bis[1,1‐diphenylphosphine]), dppb (1,4‐bis(diphenylphosphino)butane=1,1′‐(butane‐1,4‐diyl)bis[1,1‐diphenylphosphine]), and dpppe (1,5‐bis(diphenylphosphino)pentane=1,1′‐(pentane‐1,5‐diyl)bis[1,1‐diphenylphosphine])) resulted in the insertion of SnCl₂ into the Pt? Cl bond to afford the cis‐[PtCl(SnCl₃)(P₂)] complexes. However, the reaction of the complexes cis‐[PtCl₂(P₂)] (P₂=dppf, dppm (bis(diphenylphosphino)methane=1,1′‐methylenebis[1,1‐diphenylphosphine]), dppe (1,2‐bis(diphenylphosphino)ethane=1,1′‐(ethane‐1,2‐diyl)bis[1,1‐diphenylphosphine]), dppp, dppb, and dpppe; P=Ph₃P and (MeO)₃P) with SnX₂ (X=Br or I) resulted in the halogen exchange to yield the complexes [PtX₂(P₂)]. In contrast, treatment of cis‐[PtBr₂(dppm)] with SnBr₂ resulted in the insertion of SnBr₂ into the Pt? Br bond to form cis‐[Pt(SnBr₃)₂(dppm)], and this product was in equilibrium with the starting complex cis‐[PtBr₂(dppm)]. Moreover, the reaction of cis‐[PtCl₂(dppb)] with a mixture SnCl₂/SnI₂ in a 2 : 1 mol ratio resulted in the formation of cis‐[PtI₂(dppb)] as a consequence of the selective halogen‐exchange reaction. ³¹P‐NMR Data for all complexes are reported, and a correlation between the chemical shifts and the coupling constants was established for mono‐ and bis(trichlorostannyl)platinum complexes. The effect of the alkane chain length of the ligand and Sn^II halide is described.     

NMR and kinetic studies of the interactions of [Au(cis-DACH)Cl2]Cl and [Au(cis-DACH)2]Cl3 with potassium cyanide in aqueous solution

The interactions of [Au(cis-DACH)Cl₂]Cl and [Au(cis-DACH)₂]Cl₃ [where cis-DACH is cis-1,2-diaminocyclohexane] with enriched KCN were carried out in CD₃OD and D₂O, respectively. The reaction pathways of these complexes were studied by ¹H, ¹³C, ¹⁵N NMR, UV spectrophotometry, and electrochemistry. The kinetic data for the reaction of cyanide with [Au(cis-DACH)₂]Cl₃ are k = 18 M^?1s^?1, ?H^≠ = 11 kJ M^?1, ?S^≠ = ?185 JK^?1 M^?1, and E_a = 13 kJ M^?1 with square wave voltammetric (SWV) peak +1.35 V, whereas the kinetic data for the reaction of cyanide ion with [Au(cis-DACH)Cl₂]Cl are k = 148 M^?1s^?1, ?H^≠ = 39 kJM^?1, ?S^≠ = ?80 JK^-1 M^?1, and E_a = 42 kJM^?1 along with SWV peak +0.82 V, indicating much higher reactivity of [Au(cis-DACH)Cl₂]Cl toward cyanide than [Au(cis-DACH)₂]Cl₃. The interaction of these complexes with potassium cyanide resulted in an unstable [Au(¹³CN)₄]^? species which readily underwent reductive elimination reaction to generate [Au(¹³CN)₂]^? and cyanogen.     

New Oxaliplatin-Pyrophosphato Analogs with Improved In Vitro Cytotoxicity

Two new Pt(II)-pyrophosphato complexes containing the carrier ligands cis-1,3-diaminocyclohexane (cis-1,3-DACH) and trans-1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1R,2R-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na₂[Pt(pyrophosphato)(cis-1,3-DACH)] (1) slightly more stable than [Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (2). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site. Preliminary NMR studies indicate that 1 and 2 react slowly with 5’-GMP (used as a model of nucleic acids), releasing the pyrophosphate ligand and affording the bis 5’-GMP adduct. In vitro cytotoxicity assays performed against a panel of four human cancer cell lines have shown that both compounds are more active than oxaliplatin. Flow cytometry studies on HCT116 cells showed that the pyrophosphato compounds with the non-classical 1,3- and 1,4-diaminocyclohexane ligands (1 and 4) are the most capable to induce cells’ death by apoptosis and necrosis.     

Formation of Pt-S-Mn groups in platinum triphenylphosphine complexes with cymanthrenylthiolate ligands

Stepwise decarbonylation of the platinum complex with cymanthrenylthiolate ligands cis-(Ph₃P)₂Pt[(SC₅H₄)Mn(CO)₃]₂ (1) affords the cis-(Ph₃P)₂Pt[(SC₅H₄)Mn(CO)₃]-[(SC₅H₄)Mn(CO)₂] (2) and cis-(Ph₃P)₂Pt[(SC₅H₄)Mn(CO)₂]₂ (3) complexes. The replacement of one carbonyl group at the manganese atom with the lone electron pair of sulfur is accompanied by the formation of a new Mn-S bond giving rise to an unusual norbornane-type core. Complexes 1–3 were characterized by elemental analysis and IR spectroscopy. The structures of complexes 1–3 were established by single-crystal X-ray diffraction. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1508–1512, July, 2005.     

N-(1-亚氨基乙基)乙脒铂配合物合成、结构和性质

四氯合铂酸钾分别与邻、间、对磺基苯甲酸在乙腈和水中利用水热合成获得了3个铂的N-(1-亚氨基乙基)乙脒配合物:[Pt(NIA)_2]·(2-sb)·2H_2O(1),[Pt(NIA)_2]·(3-sb)·3H_2O(2)和[Pt(NIA)_2]·(1,4-dsb)·2H_2O(3)(NIA=N-(1-亚氨基乙基)乙脒,2-sb~2-=2-磺基苯甲酸二价阴离子、3-sb~2-=3-磺基苯甲酸二价阴离子、1,4-dsb~2-=1,4-二磺基苯二价阴离子)。合成过程中发生了乙氰三聚以及4-sb~2-转变为1,4-dsb~2-的反应。对配合物进行了元素分析、红外、紫外、荧光、热重和粉末X射线衍射表征,并利用单晶X射线衍射测定了配合物的晶体结构。3个配合物为阳离子-阴离子物种,阳离子为[Pt(NIA)_2]~(2+),中心金属离子四配位平面构型;阴离子与阳离子、水形成氢键,组成一个三维网络结构,但3个配合物的氢键模式不同。配合物在热稳定性、荧光性质上有一定差异。     

Reactions of cisplatin hydrolytes, cis-[Pt(15NH3)2(H2O) 2]2+, with N-acetyl-L-cysteine

The reaction of cis-[Pt(¹⁵NH₃)2(H₂O) ₂] ²⁺ (3) with N-acetylcysteine [H₃accys] was investigated in aqueous solution. In this reaction, the ammine in the platinum complex formed was liberated. A mono-dentate sulfur-boundplatinum(II) product cis-[Pt(¹⁵NH₃)₂(H₂O)(H2accys-S)]⁺ (7) and six-membered che-late ring complex cis-[Pt(¹⁵NH₃)₂ (Haccys-S,O)] (8) were formed in solution. The dinuclear sulfur-bridged complex 9, giving a broad peak in ¹⁵N NMR, was also observed, but only present in very tiny amounts. The mass spectrometry (ES-MS) was undertaken from this re action, and the product detected was only the dinuclear sulfur bridged platinum species and species related to it by ammine loss.     

1-β-D-呋喃核糖基-1,2,4-三唑-3-酰胺铂配合物的合成研究

cis-[Pt(DMSO)₂Cl₂], K[Pt(DMSO)Cl₃]分别与两摩尔1-β-D-呋喃核糖基-1,2,4-三唑-3-酰胺(Ribavirin)进行络合反应, 制得了高收率的二配位铂配合物; 讨论了不同摩尔的1-β-D-呋喃核糖基-1,2,4-三唑-3-酰胺与cis-[Pt(DMSO)₂Cl₂]和K[Pt(DMSO)Cl₃]进行络合反应的结果; 对[Pt (N⁴,N⁷-Ribavirin)(DMSO)Cl]配合物(1)的X衍射晶体结构进行了测定.     

On Mixed-Valence Dinuclear PtII,PtIII Nucleobase Complexes Derived from cis-Diamineplatinum(II): Effect of steric bulk of amine ligands on the Pt-oxidation state

A series of closely related dinuclear (head-head) Pt^II complexes of general composition cis-[a₂PtL₂Pta′₂]²⁺ with a,a′ = NH₃ or CH₃NH₂ and L = 1-methyluracilate-N3,O4 (1-MeU) or 1-methylthyminate-N3,O4 (1-MeT) has been prepared and the solution behavior toward Ce^IV oxidation studied. The X-ray crystal structure of a representative example cis-[(CH₃NH₂)₂Pt(1-MeU)₂Pt(CH₃NH₂)₂](ClO₄)₂ · 0.5 H₂O ( 1b ), has been determined: Monoclinic, space group P2₁/c, a = 11.907(7) Å, b = 19.087(14) Å, c = 12.525(7) Å, β = 90.49(4)°, Z = 4. Oxidation of these diplatinum(II) complexes ([Pt^2.0]₂) with Ce^IV in aqueous solution to the corresponding diplatinum(III) species ([Pt^3.0]₂) proceeds via tetranuclear [Pt^2.25]₄ or dinuclear [Pt^2.5]₂ mixed-valence state compounds, depending on the nature of the a′ ligands: with a′ = NH₃, blue green [Pt^2.25]₄ forms, whereas with a′ = CH₃NH₂, purple [Pt^2.5]₂ represents the intermediate. This difference is interpreted in terms of differences in bulk between NH₃ and CH₃NH₂ ligands trans to the O(4) positions of the bridging nucleobases which influence the ability of dinuclear species to associate via the O(4)₂ Pt a₂′ faces.     

Synthesis,structures and magnetic properties of nickel bis (dithiolene) complexes with [Fe(qsal)2]+

Two new compounds containing the possible Fe(III) spin-crossover cation, [Fe(qsal)₂]⁺ (qsalH = N-(8-quinolyl)salicylaldimine), and nickel bis(dithiolene) anions have been synthesized. Both are 1 : 1 salts [Fe(qsal)₂][Ni(dddt)₂] · CH₃CN · CH₃OH (1) and [Fe(qsal)₂][Ni(pddt)₂] (2) (dddt = 5,6-dihydro-1,4-dithiin-2,3-dithiolate; pddt = 6,7-dihydro-5H-1,4-dithiepin-2,3-dithiolate). They have been characterized by X-ray crystal structure determination, elemental analysis, UV-Vis spectra and magnetic susceptibility measurements. The UV–Vis spectra are dominated by [Ni(L)₂]^? (1, L = dddt; 2, L = pddt). Magnetic studies show antiferromagnetic interaction in 1 from intermolecular S···S contacts and π–π stacking interactions, while the antiferromagnetic interaction in 2 is very weak.     

PLATINUM(II) COMPLEXES OF P(III) CYCLOPHOSPHAMIDE DERIVATIVES

Abstract

The syntheses of the P(III) analogues of cyclophosphamide, isophosphamide and triphosphamide are reported. These compounds (4–6, respectively) polymerize easily at room temperature but are sufficiently stable in solution to react with Cl₂Pt(NCPh)₂, forming cis-Cl₂Pt(4)₂, cis-Cl₂Pt(5)₂ and cis-Cl₂Pt(6)₂ (complexes 9–11, respectively). Complex 10 can also be made by condensing cis-Cl₂Pt[ClPN(CH₂CH₂Cl)CH₂CH₂CHO]₂ with ClCH₂CH₂NH₂, while an alternate route to 9 and 11 is afforded by the condensation of cis-Cl₂Pt[Cl₂PN(CH₂CH₂Cl)₂]₂ with H₂NCH₂CH₂CH₂OH and ClCH₂CH₂NHCH₂CH₂CH₂OH, respectively. Complexes 9–11 exist in two diastereomeric configurations and these can be separated in the cases of 9 and 11 by column chromatography. ³¹P NMR spectral data for the complexes are discussed and the results of NCl antitumor screening are presented.     

Platinum(II) complexes containing the 3,3-dimethylglutarimidate ligand

Reaction of cis-[PtCl₂(PPh₃)₂] with excess 3,3-dimethylglutarimide (dmgH) and sodium chloride in refluxing methanol gives the mono-imidate complex cis-[PtCl(dmg)(PPh₃)₂], which was structurally characterized. The plane of the imidate ligand is approximately perpendicular to the platinum coordination plane which, coupled with restricted rotation about the Pt–N bond, results in inequivalent methyl groups and CH₂ protons of the dmg ligand in the room temperature ¹H NMR spectrum. These observations were corroborated by a theoretical study using density functional theory methods. The analogous bromide complex cis-[PtBr(dmg)(PPh₃)₂] can be prepared by replacing NaCl with NaBr in the reaction mixture.     

Mixed dimethyl sulfoxide-thiocarbamic ester complexes of platinum(II) halides

Summary The platinum(II) halidecis-[Pt(DMTC)(DMSO)X₂] andcis-[Pt(DETC)(DMSO)X₂](X=Cl or Br; DMSO=dimethyl sulfoxide; DMTC=EtOSCN-Me₂; DETC=EtOSCNEt₂) adducts and the platinum(II) and palladium(II) halide adducts,trans-[M(DETC)₂X₂] (M=Pt or Pd; X=Cl or Br), have been prepared. The complexes were characterized by i.r., and¹H and¹³Cn.m.r. spectroscopy. Both DMTC and DETC coordinate through the sulphur atoms. The 1:2 DETC complexes present the usualtrans configuration, whereas the presence of DMSO favourscis geometry in the mixed species.     

Experimental and quantum‐chemical studies of 1H, 13C and 15N NMR coordination shifts in Au(III), Pd(II) and Pt(II) chloride complexes with picolines

¹H, ¹³C and ¹⁵N NMR studies of gold(III), palladium(II) and platinum(II) chloride complexes with picolines, [Au(PIC)Cl₃], trans‐[Pd(PIC)₂Cl₂], trans/cis‐[Pt(PIC)₂Cl₂] and [Pt(PIC)₄]Cl₂, were performed. After complexation, the ¹H and ¹³C signals were shifted to higher frequency, whereas the ¹⁵N ones to lower (by ca 80–110 ppm), with respect to the free ligands. The ¹⁵N shielding phenomenon was enhanced in the series [Au(PIC)Cl₃] < trans‐[Pd(PIC)₂Cl₂] < cis‐[Pt(PIC)₂Cl₂] < trans‐[Pt(PIC)₂Cl₂]; it increased following the Pd(II) → Pt(II) replacement, but decreased upon the trans → cis‐transition. Experimental ¹H, ¹³C and ¹⁵N NMR chemical shifts were compared to those quantum‐chemically calculated by B3LYP/LanL2DZ + 6‐31G**//B3LYP/LanL2DZ + 6‐31G*. Copyright © 2008 John Wiley & Sons, Ltd.     

Stereochemistry of the Platinum Catalyzed Hydroformylation of Olefins

The deuterioformylation of (Z)- or (E)-2-butene catalyzed by [DIOP]Pt(SnCl₃)-Cl

1 DIOP=2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane.

gives predominantly erythro- or threo-1,3-[²H]₂-2-methylbutanal respectively. Hence, hydroformylation by this catalytic system must take place with cis-stereochemistry.     

RATES OF RING-OPENING OF 2,2,4,7,7-PENTAMETHYL-3,6-DITHIAOCTANE TETRACARBONYL TUNGSTEN (0)

Abstract

Ring displacement from η²-PDOW(CO)₄ (PDO = 2,2,4,7,7-pentamethyl-3.6-dithiaoctane) by L (L = P(0-i-Pr)₃ and P(OEt)₃) produces a mixture of cis- and trans- (L)₂W(CO)₄. Results from kinetics experiments are consistent with the results observed for the structurally-related η²-DTOW(CO)₄ complex (DTO = 2,2,7,7-tetramethyl-3,6-dithiaoc-tane). A smaller value for the rate constant (k₁) for the ring-opening step of η²-PDOW(CO)₄ reflects the shorter W-S bond distances observed in η²-PDOW(CO)₄. This observation is consistent with the trend observed for a series of η²-DTAW(CO)₄ complexes (DTA = Dithiaalkanes) in which the value of k₁ increases with the size of the chelate ring. Since the species η²-PDOW(CO)₄ and η²-DTOW(CO)₄ are five-membered chelate complexes, differences in their molecular and kinetic parameters are being ascribed to the methyl group in the chelate backbone of η²-PDOW(CO)₄. Our observations confirm earlier findings that small differences in the structure of DTA greatly affect the rates of ring-opening in η²-DTAW(CO)₄ complexes.     

Acetate platinum(II) compound with 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine that overcomes cisplatin resistance: structural characterization,in vitro cytotoxicity,and kinetic studies

The reaction of silver acetate with cis-[PtI₂(dbtp)₂], where dbtp = 5,7-ditertbutyl-1,2,4-triazolo-[1,5-a]pyrimidine, yielded cis-[Pt(OOCCH₃)₂(dbtp)₂]·dmf (1). The complex has been analyzed by multinuclear magnetic resonance (¹H, ¹³C, ¹⁵N), IR, and Raman. The compound formed two rotamers in CDCl₃ and its spatial structures have been optimized using computational calculation. It was found that head-to-tail rotamer (1a) is more stable than its head-to-head counterpart (1b). In vitro antiproliferative activity against four tumor cell lines (A549, T47D, FaDu, and A2780cis) revealed in all cases significant cytotoxicity (IC₅₀ = 0.26–1.80 μM), possessing IC₅₀ values at least fivefold lower than cisplatin, carboplatin, and oxaliplatin (except A2780cis). The remarkable in vitro activity against T47D and A2780cis suggested the ability to overcome cisplatin resistance in these types of tumor cells. In addition, in vitro toxicity was evaluated against BALB/3T3 and has shown that the lipophilic platinum(II) complex (1) inhibits cell proliferation weaker than cisplatin and oxaliplatin. Additionally, cis-[Pt(OOCCH₃)₂(dbtp)₂]·dmf exhibited selective activity, in contrast to cisplatin or oxaliplatin.