Natalia Cutillas

A Potent Ruthenium(II) Antitumor Complex Bearing a Lipophilic Levonorgestrel Group

The novel steroidal conjugate 17-α-[2-phenylpyridyl-4-ethynyl]-19-nortestosterone (LEV-ppy) (1) and the steroid-C,N-chelate ruthenium(II) conjugate [Ru(η(6)-p-cymene)(LEV-ppy)Cl] (2) have been prepared. At 48 h incubation time, complex 2 is more active than cisplatin (about 8-fold) in T47D (breast cancer) and also shows an improved efficiency when compared to its nonsteroidal analogue [Ru(η(6)-p-cymene)(ppy)Cl] (ppy = phenylpyridine) (3) in the same cell line. The act of conjugating a levonorgestrel group to a ruthenium(II) complex resulted in synergistic effects between the metallic center and the steroidal ligand, creating highly potent ruthenium(II) complexes from the inactive components. The interaction of 2 with DNA was followed by electrophoretic mobility. Theoretical density functional theory calculations on complex 2 show the metal center far away from the lipophilic steroidal moiety and a labile Ru-Cl bond that allows easy replacement of Cl by N-nucleophiles such as 9-EtG, thus forming a stronger Ru-N bond. We also found a minimum energy location for the chloride counteranion (4(+)·Cl(-)) inside the pseudocavity formed by the α side of the steroid moiety, the phenylpyridine chelating subsystem, and the guanine ligand, i.e., a host-guest species with a rich variety of nonbonding interactions that include nonclassical C-H···anion bonds, as supported by electrospray ionization mass spectra.

Structure–solid-state CPMAS 13C NMR correlation in palladacycle solvates (pseudo-polymorphs) with a transformation from Z′ = 1 to Z′ = 2

The dinuclear µ-acetato-µ-benzophenone iminato palladium complex [{(C∧N)Pd}2(µ-OAc)(µ-NCPh2)] (1) [C∧N = N,N-dimethylbenzylamine-κN,κC)] is prepared by reaction of [{(C∧N)Pd(µ-OAc)}2] with benzophenone imine and [NBu4]OH in ethanol. The dinuclear palladacycle 1 can crystallize with different solvents molecules as 1·1.5C6H5CH3, 1·0.25C6H5CH3 (Z′ = 2), 1·1.5C6H6 and 1·C6H14 (n-hexane) upon hexane diffusion into a toluene, benzene or CH2Cl2 solution, respectively. The structure of 1·0.25C6H5CH3 with two palladacycle molecules and two partly occupied toluene molecules in the asymmetric unit (Z′ = 2) is a consequence of partial toluene solvent loss from 1·1.5C6H5CH3 (Z′ = 1) as was followed by solid-state CPMAS 13C NMR. The transformation from Z′ = 1 to Z′ = 2 (crystal “on the way”?) toluene solvate can proceed in a solid-state single-crystal-to-crystal transition as evidenced from multiple single-crystal X-ray diffraction studies, also when the crystals are still in their mother liquor. During this transformation the remaining toluene crystal solvent becomes “locked in” (immobile from static 2H (D) NMR, only lost above 80° from TGA) and the crystals of 1·0.25C6H5CH3 (Z′ = 2) remain crystalline in air in the absence of mother liquor or toluene, different from the other solvates. A rotational disorder of one of the benzene molecules in 1·1.5C6H6 (Z′ = 1) around its pseudo-six-fold axis is supported by the line-shape analysis of the static 2H (D) spectrum.

Synthesis and structural study of [{Pd(C6H4CH2N(CH3)2)}2(μ-Br) (μ-X)] complexes (X = hydroxide, amide or thiolate)

Abstract The mixed hydroxo-bromo bridged complex [{Pd(C 6 H 4 CH 2 NMe 2 )} 2 (μ-Br)(μ-OH)] ( 1 ) (C 6 H 4 CH 2 NMe 2 = 2-[(dimethyl-amino)methyl]phenyl) has been prepared by addition of one equivalent of NBu 4 OH to [{Pd(C 6 H 4 CH 2 NMe 2 )(μ-O 2 CMe)} 2 ] in acetone-water solution, followed by addition of one equivalent of LiBr. Complex 1 reacts with arylamines or thiols in 1:1 mole ratio to yield the corresponding amido- or thiolato-bromo complexes [{Pd(C 6 H 4 CH 2 NMe 2 )} 2 (μ-Br)(μ-NHR)] (R = C 6 H 5 ( 2 ), p -MeOC 6 H 4 ( 3 ), p -MeOC 6 H 4 ( 4 )) or [{Pd(C 6 H 4 CH 2 NMe 2 )} 2 (μ-Br)(μ-SR)] (R = Et ( 5 ). 1 Bu ( 6 ), C 6 H 5 ( 7 ), p -MeC 6 H 4 ( 8 )). The 1 H NMR data indicate a cis arrangement of the C 6 H 4 CH 2 NMe 2 ligands. The crystal structure of compound 1 has been determined by X-ray diffraction. It crystallizes in the orthorhombic space group Pbca with a = 12.445(3), b = 18.029(3), c = 17.436(3) A . Final R = 0.039 and R n = 0.040 based on 2692 reflections.

Anticancer C,N-Cycloplatinated(II) Complexes Containing Fluorinated Phosphine Ligands: Synthesis, Structural Characterization, and Biological Activity

A series of potent C,N-cycloplatinated(II) phosphine antitumor complexes containing fluorous substituents in the cyclometalated or the ancillary phosphine ligands [Pt(C-N)(PR3)Cl] or both have been synthesized and characterized. The crystal structure of [Pt(dmba){P(C6H4CF3-p)3}Cl]·2CH2Cl2 (dmba = dimethylaminomethyl)phenyl) has been established by X-ray diffraction. Values of IC50 of the new platinum complexes were calculated toward a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR) and breast cancers (T47D). Complexes containing P(C6H4CF3-p)3 as ancillary ligand (with a bulky and electronegative CF3 substituent in para position) were the most cytotoxic compounds in all the tested cancer cell lines. In some cases, the IC50 values were 16-fold smaller than that of cisplatin and 11-fold smaller than the non-fluorous analogue [Pt(dmba)(PPh3)Cl]. On the other hand, very low resistance factors (RF) in A2780cisR (cisplatin-resistant ovarian carcinoma) at 48 h were observed (RF ≈ 1) for most of the new compounds. Analysis of cell cycle was done for the three more active compounds in A2780. They arrest cell growth in G0/G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis. They are also good cathepsin B inhibitors (an enzyme implicated in a number of cancer related events).

Acetonimine and 4-imino-2-methylpentan-2-amino platinum(II) complexes: synthesis and in vitro antitumor activity.

The reaction of [Pt(dmba)(PPh3)Cl] [where dmba = N,C-chelating 2-(dimethylaminomethyl)phenyl] with aqueous ammonia in acetone in the presence of AgClO4 gives the acetonimine complex [Pt(dmba)(PPh3)(NH=CMe2)]ClO4 (1). The reaction of [Pt(dmba)(DMSO)Cl] with aqueous ammonia in acetone in the presence of AgClO4 gives a mixture of [Pt(dmba)(NH=CMe2)2]ClO4 (2) and [Pt(dmba)(imam)]ClO4 (3a) (where imam = 4-imino-2-methylpentan-2-amino). [Pt(dmba)(DMSO)Cl] reacts with [Ag(NH=CMe2)2]ClO4 in a 1:1 molar ratio to give [Pt(dmba)(DMSO)(NH=CMe2)]ClO4 (4). The reaction of [Pt(dmba)(DMSO)Cl] with 20% aqueous ammonia in acetone at 70 degrees C in the presence of KOH gives [Pt(dmba)(CH2COMe)(NH=CMe2)] (5), whereas the reaction of [Pt(dmba)(DMSO)Cl] with 20% aqueous ammonia in acetone in the absence of KOH gives [Pt(dmba)(imam)]Cl (3b). The reaction of [NBu4]2[Pt2(C6F5)4(mu-Cl)2] with [Ag(NH=CMe2)2]ClO4 in a 1:2 molar ratio produces cis-[Pt(C6F5)2(NH=CMe2)2] (6). The crystal structures of 1 x 2 Me2CO, 2, 3a, 5, and 6 have been determined. Values of IC50 were calculated for the new platinum complexes against a panel of human tumor cell lines representative of ovarian (A2780 and A2780 cisR) and breast cancers (T47D). At 48 h incubation time complexes 1, 4, and 5 show very low resistance factors against an A2780 cell line which has acquired resistance to cisplatin. 1, 4, and 5 were more active than cisplatin in T47D (up to 30-fold in some cases). The DNA adduct formation of 1, 4, and 5 was followed by circular dichroism and electrophoretic mobility.

Synthesis and characterization of hydroxo, pyrazolato and carboxylato derivatives of the PdR(PPh3) moiety (R = C6F5 or C6Cl5)

Abstract The hydroxo-complexes [{PdR(PPh 3 )(μ-OH)} 2 ] (R  C 6 F 5 or C 6 Cl 5 ) have been obtained by reaction of the corresponding [{PdR(PPh 3 )(μ-Cl)}2] complexes with NBu 4 OH in acetone. In this solvent, the reaction of the hydroxo-bridged complexes with pyrazole (Hpz) and 3,5-dimethylpyrazole (Hdmpz) in 1:2 molar ratio leads to the formation of the new complexes [{Pd(C 5 F 5 )(PPh 3 )(μ-azolate)}2] and [{Pd(C 6 Cl 5 )(PPh 3 )} 2 (μ-OH)(μ-azolate)] (azolate = pz or dmpz). The reaction of the bis(μ-hydroxo) complexes with Hpz and Hdmpz in acetone in 1:1 molar ratio has also been studied, and the resulting product depends on the organic radical (C 6 F 5 or C 6 Cl 5 ) as well as the azolate (pz or dmpz). The identity of the isomer obtained has been established in every case by NMR ( 1 H, 19 F and 31 P) spectroscopy. The reaction of the bis(μ-hydroxo) complexes with oxalic (H 2 Ox) and acetic (HOAc) acids yields the binucle ar complexes [{PdR(PPh 3 )}2(μ-Ox)] (R  C 6 F 5 or C 6 Cl 5 ) and [{Pd(C 6 F 5 )(PPh 3 )(μ-OAc)}2], respectively. [{Pd(C 6 F 5 )(PPh 3 )(μ-OH)} 2 ] reacts with PPh 3 in acetone in 1:2 ratio giving the mononuclear complex trans -[Pd(C 6 F 5 ) (OH)(PPh 3 ) 2 ], whereas the pentachlorophenylhydroxo complex does not react with PPh 3 , even under forcing conditions.

Pentafluorophenyl derivatives of palladium(II) and platinum(II) with O-donor ligands

Abstract The preparation of trans -Pt(C 6 F 5 ) 2 (dioxan) 2 by the method previously used for the palladium analogue [1] is described. The compounds, trans -M(C 6 F 5 ) 2 )dioxan) 2 (M = Pd, Pt) have both been employed as starting materials for the preparation of related complexes with pyridine N -oxide (pyO), dimethylformamide (DMF), and dimethylsulfoxide (DMSO) ligands.

Synthesis and structural study of [{Pd(CH2C9H6N)}2(µ-O2CR)(µ-X)] complexes (R = Me or CF3; X = hydroxide, amide or thiolate)

The di-µ-carboxylato complexes [{Pd(CH2C9H6N)(µ-O2CR)}2](CH2C9H6N = 8-quinolylmethyl, R = Me or CF3) react in methanol with NaOH(aq)(1 : 1 molar ratio) to give the corresponding mixed hydroxo–carboxylato-bridged complexes [{Pd(CH2C9H6N)}2(µ-OH)(µ-O2CR)](R = Me 1 or CF32). The reactions of 1 or 2 with arylamines or thiols (1 : 1 molar ratio) yielded the corresponding amido- or thiolato-carboxylato complexes [{Pd(CH2C9H6N)}2(µ-O2CMe)(µ-NHR)](R = Ph 3, p-MeC6H44 or p-NO2C6H45) or [{Pd(CH2C9H6N)}2(µ-O2CR)(µ-SR′)](R = Me, R′= Et 6, But7, Ph 8 or p-MeC6H49; R = CF3, R′= But10). The 1H NMR data indicate a cis arrangement of the CH2C9H6N ligands. The crystal structure of complex 10 has been determined. It confirms the cis relationship of the CH2C9H6N ligands. The co-ordination at each palladium atom is approximately square planar and the oxygen atoms of the trifluoroacetate ligands are trans to carbon. The Pd2(µ-OCOCF3)(µ-SBut) core is quite bent with an angle of 55° between the two palladium co-ordination planes.

New steroidal 7-azaindole platinum(II) antitumor complexes ☆

Two new steroidal 7-azaindole-based N-donor ligands 17-α-[7-azaindole-5-ethynyl]-17-β-testosterone (ET-Haza) (1) and 17-α-[7-azaindole-5-ethynyl]-19-nortestosterone (LEV-Haza) (2), and two new DNA damaging warheads with an enhanced lipophilicity [Pt(dmba)Cl(L)] (dmba=N,N-dimethylbenzylamine-κN,κC; L=ET-Haza (3) and LEV-Haza (4)) have been prepared and characterized. Values of IC50 were calculated for complexes 3 and 4 against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cis) and breast cancers (T47D). At 48 h of incubation time 3 and 4 showed very low resistance factors (RF of 1) against an A2780 cell line which has acquired resistance to cisplatin, IC50 values of the new complexes towards normal human LLC-PK1 renal cells at 48 h being about double than that of cisplatin. 3 and 4 are able to react with 9-ethylguanine (9-EtG) yielding the corresponding monoadduct [Pt(dmba)(L)(9-EtG)](+) derivatives as followed by ESI-MS. Compound 3 interacts mainly with double-stranded (DS) oligonucleotides as shown by analysis with ESI-TOF-MS, being also able to displace ethidium bromide (EB) from DNA, as observed by an electrophoretic mobility study. 3 and 4 are good cathepsin B inhibitors. Theoretical calculations at the COSMO(CHCl3)/B3LYP-D/def2-TZVPPecp//B3LYP-D/def2-TZVPecp level and energy evaluations at the COSMO(CHCl3)/PWPB95-D3/def2-TZVPPecp level of theory on compound 4 and model systems have been done.

First complex containing a Pd2(μ2-NCPh2)2 functional group

Abstract Synthesis of the azavinylidene-bridged compound anti-[{Pd(C6F5)(t-BuNC)(μ-NCPh2)}2] is described. The molecular structure reveals that the core of the molecule is formed by a Pd2N2 skeleton in a bent configuration.