Venancio Rodríguez

Can a single C–H⋯F–C hydrogen bond make a difference? Assessing the H⋯F bond strength from 2-D 1H-19F CP/MAS NMR

Contrary to common belief a single C–H⋯F–C contact in [(η5-C5H5)Pd(C6F5)(PPh3)] is strong enough to pair two independent molecules and render them crystallographically different as suggested by its strongest 1H–19F dipole–dipole coupling in a 2-D CP/MAS PILGRIM NMR experiment together with solid state 1-D 19F{1H} and 2-D 19F RFDR NMR spectroscopy – thereby proving the power of 2-D solid-state NMR for assessing the strength of supramolecular contacts.

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.

Dual Antitumor and Antiangiogenic Activity of Organoplatinum(II) Complexes

A library of over 20 cycloplatinated compounds of the type [Pt(dmba-R)LCl] (dmba-R = C,N-dimethylbenzylamine-like ligand; R being MeO, Me, H, Br, F, CF3, and NO2 substituents in the R5 or R4 position of the phenyl ring; L = DMSO and P(C6H4CF3-p)3) has been prepared. All compounds are active in both human ovarian carcinoma A2780 cells and cisplatin-resistant A2780cisR cells, with most of the DMSO platinum complexes exhibiting IC50 values in the submicromolar range in the A2780 cell line. Interestingly, DMSO platinum complexes show low cytotoxicity in the nontumorigenic kidney cell line BGM and therefore high selectivity factors SF. In addition, some of the DMSO platinum complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926. These are the first platinum(II) complexes reported to inhibit angiogenesis at a close concentration to their IC50 in A2780 cells, turning them into dual cytotoxic and antiangiogenic compounds.

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.

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).

Synthesis of palladium(II) and platinum(II) N,N-dialkyldithiocarbamates starting from hydroxo-halophenyl complexes

Abstract In dichloromethane, the hydroxo-complexes [NBu4]2[{M(C6X5)2(μ-OH)}2] [M = Pd (X = F or Cl) or Pt (X = F)] and [{Pd(C5X5)(PPh3)(μ-OH)}2] (X = F or Cl) react with amines in the presence of carbon disulfide to give the corresponding dithiocarbamate complexes [NBu4][M(C6X5)2(S2CNR2)] [M = Pd, X = F and R Me (I), Et (II), or C4H8 (III); M = Pd, X = Cl and R = Me (IV) or Et (V); M = Pt, X = F and R = Me (VI) or Et (VII)] and [Pd(C6X5)(PPh3)(S2CNR2)] [X = F and R = Me (VIII) or Et (IX); X = Cl and R = Me (X) or Et (XI)]. Conductance measurements and spectroscopic (IR, 1H and 19F NMR) methods have been used for structural assignments.

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 heterodinuclear thiolate complexes containing the Pd(η3-allyl)+ moiety. Crystal structure of [(dppe)Pd(μ-SC6H4Me-p)2Pd(η3-C3H5)][ClO4]

Abstract Heterodinuclear complexes of the types [(dppe)M(μ-SR)2Pd(η3-allyl)][ClO4] (M=Pd or Pt) and [(dppe)Pt(μ-SC2H4S)Pd(η3-allyl)][ClO4] [dppe=1,2-bis(diphenylphosphino)ethane; allyl=C3H5 or C4H7] have been obtained by reaction of the corresponding cis-dithiolato complexes, [M(SR)2 (dppe)] or [Pt(SC2H4S)(dppe)], and [Pd(η3-allyl)(PhCN)2][ClO4]. The identity of these complexes has been established by NMR (1H and 31P) spectroscopy. The crystal structure of [(dppe)Pd(μ-SC6H4Me-p)2Pd(η3-C3H5)][ClO4] has been determined by single-crystal X-ray methods. The p-tolyl groups on the sulfur atoms adopt a syn conformation with respect to the central PdS2Pd core.

New methoxo-, hydroxo- and pyrazolate-bridged platinum(II) complexes. Crystal structure of [NBu4]2[{Pt(C6F5)2}2(µ-OH)(µ-dmpz)](dmpz = 3,5-dimethylpyrazolate)

The hydroxo complex [{Pt(C6F5)2(µ-OH)}2]2– reacts with azoles (1 : 1 molar ratio) in benzene to give the double bridged complexes [{Pt(C6F5)2}2(µ-OH)(µ-L–L)]2–[L–L = pyrazolate (pz)1, 3,5-dimethyl-pyrazolate (dmpz)2, 3-methylpyrazolate (mpz)3 or indazolate(indz)4]. When the same reaction is carried out in methanol with the reactants in 1 : 2 molar ratio the corresponding di-µ-azolate derivatives [{Pt(C6F5)2(µ-L–L)}2]2–[L–L = pz 5, dmpz 6, mpz 7 or indz 8] are obtained. On treatment of [{Pt(C6F5)2(µ-OH)}2]2– with methanol the di-µ-methoxo complex [{Pt(C6F5)2(µ-OMe)}2]2–9 was obtained. The di-µ-azolate complexes 5–8 can be alternatively prepared by treatment of 9 with the respective azoles (1 : 2 molar ratio) in methanol. Reaction of complex 1 with methanol leads to the formation of [{Pt(C6F5)2}2(µ-OMe)(µ-pz)]2–10. All the complexes have been isolated as the [NBu4]+ salts. Spectroscopic (IR, 1H and 19F NMR) data have been used for structural assignments, and an X-ray structure determination carried out for [NBu4]2[{Pt(C6F5)2}2(µ-OH)(µ-dmpz)] has established the binuclear nature of the anion. The structure was solved and refined to R= 0.057 and R′= 0.089 based on 10 057 observed reflections. The Pt atoms are four-co-ordinated, Pt(1)–O 2.113(7), Pt(1)–N(1) 2.04(1), Pt(1)–C(10) 2.02(1), Pt(1)–C(20) 1.96(2), Pt(2)–O 2.077(9), Pt(2)–N(2) 2.075(9), Pt(2)–C(30) 1.97(2), Pt(2)–C(40) 2.00(1)A, and show deviations from a square-planar arrangement towards a tetrahedral disposition.

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.