Giovanni Minghetti

Chemistry, antiproliferative properties, tumor selectivity, and molecular mechanisms of novel gold(III) compounds for cancer treatment: a systematic study

AbstractThe antiproliferative properties of a group of 13 structurally diverse gold(III) compounds, including six mononuclear gold(III) complexes, five dinuclear oxo-bridged gold(III) complexes, and two organogold(III) compounds, toward several human tumor cell lines were evaluated in vitro using a systematic screening strategy. Initially all compounds were tested against a panel of 12 human tumor cell lines, and the best performers were tested against a larger 36-cell-line panel. Very pronounced antiproliferative properties were highlighted in most cases, with cytotoxic potencies commonly falling in the low micromolar—and even nanomolar—range. Overall, good-to-excellent tumor selectivity was established for at least seven compounds, making them particularly attractive for further pharmacological evaluation. Compare analysis suggested that the observed antiproliferative effects are caused by a variety of molecular mechanisms, in most cases “DNA-independent,” and completely different from those of platinum drugs. Remarkably, some new biomolecular systems such as histone deacetylase, protein kinase C/staurosporine, mammalian target of rapamycin/rapamycin, and cyclin-dependent kinases were proposed for the first time as likely biochemical targets for the gold(III) species investigated. The results conclusively qualify gold(III) compounds as a promising class of cytotoxic agents, of outstanding interest for cancer treatment, while providing initial insight into their modes of action.Graphical AbstractA series of gold(III) compounds showed cytotoxic properties and tumor selectivity toward a panel of cancer cell lines. Compare analysis provided insight into their possible mechanisms of action.

Preparation and characterization of palladium(II) and platinum(II) complexes with bis(pyrazolyl)alkanes. crystal and molecular structures of [Pd2(pz)22][BF4]2 and of [PdCl2{(CH3)2C(pz)2}] (pzH = pyrazole), a new example of a Pd⋯HC agostic interaction

Abstract Neutral and cationic complexes of general formulae (LL)MCl 2 (M = Pd, (LL) = CH 2 (pz) 2 ( 1 ); CH 2 (3,5-Me 2 pz) 2 ( 2 ); (CH 3 ) 2 C(pz) 2 ( 3 ); M = Pt, (LL) = CH 2 (pz) 2 ( 4 ); CH 2 (3,5-Me 2 pz) 2 ( 5 ) and (LL) 2 M] 2+ (M = Pd, (LL) = CH 2 (pz) 2 ( 6 ); CH 2 (3,5-Me 2 pz) 2 ( 7 ); (CH 3 ) 2 C(pz) 2 ( 8 ); M = Pt, (LL) = CH 2 (pz) 2 ( 9 ); CH 2 (3,5-Me 2 pz) 2 ( 10 ) have been prepared and characterized by IR and 1 H NMR spectroscopy. The structures of 3 and 6 have been determined by X-ray diffraction; in both complexes the bis-(pyrazolyl)alkanes act as chelating ligands but the coordination around the palladium atom in the complex 6 is strictly square-planar whereas in 3 it is a slightly distorted towards pyramidal, with a significant Pd⋯HC agostic interaction. The six-membered rings in both the complexes adopt a boat-type conformations.

Palladium(II) and platinum(II) derivatives with chiral 2,2′-bipyridines. X-ray structure of C18H15ClN2Pd; C- and N-intramolecular coordination in a six-membered metallacycle

Abstract The reactions of (+)-( S )-5-s,butyl-2,2′-bipyridine (LH) and 6-(1-methylbenzyl)-2,2′-bipyridine (L′H) with Na 2 [PdCl 4 ] and K 2 [PtCl 4 ] give the 1 : 1 adducts (LH)MCl 2 (M = Pd, 1 ; M = Pt, 2 ) and the metallated species (L′)MCl (M = Pd, 3 ; M = Pt, 4 ), respectively. In complexes 3 and 4 , the deprotonated bipyridine behaves as a tridentate ligand; there is coordination to the metal through the two nitrogen atoms and the ortho -carbon atom of the phenyl ring to give a six-membered metallacycle. The X-ray structure of complex 3 shows that the coordination around the palladium atom is distorted towards tetrahedral from the usual square-planar geometry.

Reaction of platinum(II) derivatives with bis(pyrazolyl)propane. Cleavage of a C(sp3)-N bond in a bis(pyrazolyl)alkane promoted by platinum(II) derivatives. Crystal structure of cis-Pt(pzH)2CL2 (pzH = pyrazole)

The reactions of bis(pyrazolyl)propane (CH3)2C(pz)2, (pzH = pyrazole), with PtCl2, (RCN)2PtCl2 and K2[PtCl4 have been investigated, and the results compared with those described previously for the corresponding palladium(II) derivatives. In contrast with the behaviour of the palladium analogues, the platinum derivatives promote the rupture of the ligand: simple adducts of pyrazole, cis- or trans-Pt(pzH)2Cl2, or species containing the ligand [HNC(R)pz], formally arising from the insertion of a nitrile into the NH bond of pyrazole, are obtained. For comparison, the reaction of the platinum derivatives with pyrazole itself has been investigated under various conditions. The crystal structure of cis-Pt(pzH)2Cl2 has been determined by X-ray diffraction: monoclinic, space group C2/c, a 9.180(1), b 15.084(1), c 15.1445(9) A, β 101.536(7)°, Z - 8, R = 0.039, Rw = 0.040 for 2125 observed reflections.

Synthesis and characterization of gold(III) adducts and cyclometallated derivatives with 6-benzyl- and 6-alkyl-2,2′-bipyridines

The reaction of a series of 6-substituted-2,2′-bipyridines HL (N2C10H7R, R = CH2Ph, CHMePh, CMe2Ph, CH2Me, CMe3 or CH2CMe3) with HAuCl4 or Na[AuCl4] has been investigated. Under different experimental conditions, salts [H2L][AuCl4], adducts [Au(HL)Cl3] or cyclometallated derivatives [Au(L)Cl][X](X = AuCl4, BF4 or PF6) have been isolated. The cyclometallated species arise from direct activation of a C–H bond either of a phenyl or a methyl substituent. The structures of an adduct [Au{N2C10H7(CHMePh)-6}Cl3] and two metallated species [Au{N2C10H7(CMe2C6H4)-6}Cl][AuCl4] and [Au{N2C10H7(CMe2CH2)-6}Cl][BF4]·0.5H2O have been determined by X-ray diffraction. In the adduct the gold atom is bonded to the nitrogen atom of the unsubstituted pyridine ring: a long-range interaction with the other nitrogen atom is observed, Au ⋯ N 2.758(4)A. In the two cyclometallated species the bipyridines act as tridentate N,N,C anions, giving a [5,6] and a [5,5]-fused ring system, respectively. In [Au{N2C10H7(CMe2C6H4)-6}Cl]+ the hexaatomic N,C ring adopts a boat-like conformation: the structure reveals a rather short interaction between one hydrogen of the Me group in axial position and the gold atom, Au ⋯ H 2.62 A. The pentaatomic N,C ring in [Au{N2C10H7(CMe2CH2)-6}Cl]+ is not planar: the co-ordination around the gold atom is essentially square planar. The new cyclometallated complexes [Au(N,N,C)Cl]+ are compared with those derived from similarly substituted pyridines described previously.

New isocyanide complexes of platinum(II)

New platinum compounds, of formula [Pt(CNR)4][PtCl4] and cis-Pt(CNR)2Cl2, with R = cyclohexyl, p-tolyl, and p-anisyl, have been prepared and characterized. Reaction with stannous chloride yield trans-[(RNC)2Pt(SnCl3)2] and reaction with methanol gives the “carbene” complexes cis-[(RNHCOCH3)(RNC)PtCl2].

Carbonylrhodium(I) derivatives of 3,5-dimethyl- and 3,5-bis(trifluoromethyl)pyrazole

Abstract Binuclear pyrazolato-bridged complexes such as [(OC) 2 Rh(μ-pyrazolato- N,N ′] 2 , I or II, were obtained in alkaline solution from (OC) 4

Bis(carbene) complexes of gold(I) and gold (III)

The preparation of [(carbene)2Au]+ClO4−, [(carbene)Au(C6H11NC)]+ClO4− and of [(carbene)2AuI2]+ClO4− is reported.

Bis(alkylamino)carbene complexes of gold(I) and related compounds

Abstract Primary amines, RNH 2 react with ( p -tolyl isocyanide)chlorogold(I), to give two-coordinate [(ArNH)(RNH)C]AuCl or four-coordinate [(ArNH)(RNH)C] 2 (RNH 2 ) 2 Au 2 Cl 2 carbene complexes. Geometrical isomers are identified in solutions of the former type, by NMR spectroscopy. Both types of product react with bases to give insoluble [(ArN)(RNH)CAu] x , species, related to the known trimers, [(ArN)(RO)CAu] 3 .

Synthesis and characterization of gold(III) complexes of 1,4-benzodiazepin-2-ones. Crystal structure of trichloro-[7-chloro-1-(cyclopropylmethyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one]gold(III)

Abstract The reaction of gold(III) chloride with several 1,4-benzodiazepin-2-ones, L, gives 1:1 adducts, (L)AuCl3*, which were characterized by IR, Raman and 1H NMR spectroscopy. In the title compound the coordination of the ligand, ascertained through a X-ray structure determination, was shown to occur through the 4-nitrogen atom.