Diorganotin(IV) derivatives of arylhydroxamic acids: synthesis, properties and antitumor activity

Series of diorganotin(IV) complexes of 4-X-benzohydroxamic acid [X = NH₂ (HL₁), NO₂ (HL₂) or F (HL₃)] formulated as [R₂SnL₂] and [R₂Sn(L)]₂O (R = Me, Et, nBu or Ph) have been prepared and characterized by FT-IR, ¹H, ¹³C and ¹¹⁹Sn NMR spectroscopies, elemental analyses, FAB⁺-MS and melting point determination. They are stable in air, soluble in alcohols and in hydroalcoholic solution and, in some cases, in water. Their in vitro antitumor activity against a series of human tumor cell lines was tested and, in a few of them, is identical to, or even higher than, that of cisplatin. For the mononuclear dialkyltin compounds, the activity generally increases with the length of the carbon chain of the alkyl ligand, being higher for the complexes with benzohydroxamato ligands bearing an electron-acceptor substituent (X = NO₂ or F). No structure-activity relationship based on the Hammett’s σ_p constant, or related ones, has been recognized.     

Diorganotin(IV) and triorganotin(IV) derivatives of diphenic acid

The diorganotin(IV) and triorganotin(IV) derivatives R₂SnA (R = Me, n-Pr, n-Bu, n-Oct) and (R₃Sn)₂A [R = Me, Ph, cyclohexyl (Cyh); A = an anion of diphenic acid] have been prepared and characterized by elemental analysis, IR, ¹H and ¹³C NMR spectroscopies. Tetrahedral tin forms a part of a diphenate cyclic ring in the diorganotin complexes with unidentate carboxylates, which have further been used for the synthesis of cyclic acid anhydrides. The soluble dinuclear triorganotin complexes (Me, Ph) possess symmetrically bonded carboxylates while the less soluble compound (Cyh₃Sn)₂A has two asymmetrically bonded carboxylates. All have a trigonal bipyramidal structure with R₃Sn units remote from each other.     

Synthesis and Characterization of Diorganotin(IV) Complexes Bearing Binary Schiff‐Bases and Crystal Structure of nBu2SnL1

Four novel diorganotin(IV) complexes with general formula R₂SnL (R = nBu, PhCH₂) were synthesized from diorganotin dichlorides and binary Schiff‐bases (H₂L) containing N₂O₂ donor atoms in the presence of sodium ethoxide. The Schiff bases were prepared by reactions of o‐phenylenediamine with 3‐tert‐butyl‐2‐hydroxy‐5‐methylbenzaldehyde (H₂L¹) and salicylaldehyde (H₂L²) respectively. The compounds were characterized by elemental analyses, IR, and NMR spectroscopy. The solid‐state crystal structure of the compound nBu₂SnL¹ was determined by single‐crystal structural analysis.     

Synthesis and Analysis of the Structure,Diffusion and Cytotoxicity of Heterocyclic Platinum(IV) Complexes

We have developed six dihydroxidoplatinum(IV) compounds with cytotoxic potential. Each derived from active platinum(II) species, these complexes consist of a heterocyclic ligand (H_L) and ancillary ligand (A_L) in the form [Pt(H_L)(A_L)(OH)₂]²⁺, where H_L is a methyl‐functionalised variant of 1,10‐phenanthroline and A_L is the S,S or R,R isomer of 1,2‐diaminocyclohexane. NMR characterisation and X‐ray diffraction studies clearly confirmed the coordination geometry of the octahedral platinum(IV) complexes. The self‐stacking of these complexes was determined using pulsed gradient stimulated echo nuclear magnetic resonance. The self‐association behaviour of square planar platinum(II) complexes is largely dependent on concentration, whereas platinum(IV) complexes do not aggregate under the same conditions, possibly due to the presence of axial ligands. The cytotoxicity of the most active complex, exhibited in several cell lines, has been retained in the platinum(IV) form.     

Unique properties of DNA interstrand cross-links of antitumor oxaliplatin and the effect of chirality of the carrier ligand

The different antitumor and other biological effects of the third-generation antitumor platinum drug oxaliplatin [(1R,2R-diamminocyclohexane)oxalatoplatinum(II)] in comparison with those of conventional cisplatin [cis-diamminedichloridoplatinum(II)] are often explained by the ability of oxaliplatin to form DNA adducts of different conformation and consequently to exhibit different cytotoxic effects. This work describes, for the first time, the structural and biochemical characteristics of the interstrand cross-links of oxaliplatin. We find that: 1) DNA bending, unwinding, thermal destabilization, and delocalization of the conformational alteration induced by the cross-link of oxaliplatin are greater than those observed with the cross-link of cisplatin; 2) the affinity of high-mobility-group proteins (which are known to mediate the antitumor activity of platinum complexes) for the interstrand cross-links of oxaliplatin is markedly lower than for those of cisplatin; and 3) the chirality at the carrier 1,2-diaminocyclohexane ligand can affect some important structural properties of the interstrand cross-links of cisplatin analogues. Thus, the information contained in the present work is also useful for a better understanding of how the stereochemistry of the carrier amine ligands of cisplatin analogues can modulate their anticancer and mutagenic properties. The significance of this study is also reinforced by the fact that, in general, interstrand cross-links formed by various compounds of biological significance result in greater cytotoxicity than is expected for monofunctional adducts or other intrastrand DNA lesions. Therefore, we suggest that the unique properties of the interstrand cross-links of oxaliplatin are at least partly responsible for this drug's unique antitumor effects.     

Tributyltin(IV) Schiff base complexes with amino acid derivatives: synthesis,characterization and biological activity

The synthesis in one‐pot reactions and structural characterization of six new tri‐n‐butyltin(IV) derivatives of Schiff bases are reported. The compounds are derived from a condensation reaction between l ‐alanine, l ‐valine, l ‐isoleucine, l ‐methionine, l ‐phenylalanine or l ‐tryptophan and 3,5‐di‐tert‐butyl‐2‐hydroxybenzaldehyde. Characterization was completed using elemental analysis, infrared spectroscopy, mass spectrometry, one‐ and two‐dimensional solution NMR (¹H, ¹³C and ¹¹⁹Sn) as well as solid‐state ¹¹⁹Sn NMR. In addition, the crystal structures of three of the compounds were confirmed using single‐crystal X‐ray diffraction. Although five‐coordinated and polymeric in the solid state, the tin compounds are four‐coordinated and monomeric in solution. The coordination environment around the triorganotin units comprises three carbon atoms and two oxygen atoms from two ligands in a trigonal bipyramidal geometry. The anti‐proliferative effect of these compounds on the cervical carcinoma cell lines HeLa, CaSki and ViBo was screened in vitro, the compounds showing cytotoxic activity against all three strains and null or low cytotoxic activity (necrotic) as well. Copyright © 2016 John Wiley & Sons, Ltd.     

Crystallographic report: Ethyltriphenyltin(IV), Et(Ph)3Sn

The crystal lattice of the title compound comprises isolated molecules. The coordination polyhedron is a slightly distorted tetrahedron with C–Sn–C bond angles ranging from 106.62(17)° to 113.9(3)°. Copyright © 2004 John Wiley & Sons, Ltd.     

Crystallographic report: Crystal and molecular structure of tetramethylammoniumdiisothiocyanatotriphenyltin(IV), [NMe4SnPh3(NCS)2]

The structure of NMe₄SnPh₃(NCS)₂ is molecular, without any significant intermolecular contacts in the lattice. The trigonal plane around the tin atom is defined by three carbon atoms from the phenyl groups and the axial positions occupied by the NCS groups. Copyright © 2003 John Wiley & Sons, Ltd.     

Total synthesis of 7-ethyl-10-hydroxycamptothecin (SN38) and its application to the development of C18-functionalized camptothecin derivatives

A new chemical synthesis of SN38, the active metabolite of the camptothecin prodrug irinotecan, has been achieved in 12 steps from simple, commercially available starting materials. A mild and efficient FeCl₃‐catalyzed Friedländer condensation was successfully applied to construct the AB ring system. Functionalization of the C ring was accomplished by a vinylogous Mukaiyama reaction of an in situ generated N‐acyliminium intermediate with a silyl enol ether. An intramolecular oxa Diels–Alder reaction efficiently constructed the D and E rings in one step. Successive asymmetric dihydroxylation and I₂‐based hemiacetal oxidation furnished the stereochemistry of SN38 with high enantiopurity. Utilizing the ABC‐ring intermediate and a functionalized silyl enol ether permitted the synthesis of a number of new C18‐functionalized SN38 derivatives. Several of the novel SN38 derivatives that bore a C10 methoxy group were found to exhibit comparable or more potent inhibitory activity against the proliferation of cancer cells relative to SN38.     

The first pure LambdaHT rotamer of a complex with a cis-[metal(nucleotide)2] unit: a cis-[Pt(amine)2(nucleotide)2] LambdaHT rotamer with unique molecular structural features

cis-[PtA2(nucleotide)2] complexes (A2 stands for two amines or a diamine) have been extensively investigated as model compounds for key cisplatin-DNA adducts. All cis-[metal(nucleotide/nucleoside)2] complexes with guanine and related purines characterized in the solid state thus far have the DeltaHT conformation (head-to-tail orientation of the two bases and right-handed chirality). In sharp contrast, the LambdaHT conformation (left-handed chirality) dominates in acidic and neutral aqueous solutions of cis-[PtA2(5'-GMP)2] complexes. Molecular models and solution experiments indicate that the LambdaHT conformer is stabilized by 5'-phosphate/N1H hydrogen-bond interactions between cis nucleotides with the normal anti conformation. However, this evidence, while compelling, is indirect. At last, conditions have been defined to allow crystallization of this elusive conformer. The structure obtained reveals three unique features not present in all other cis-[PtA2(nucleotide)2] solid-state structures: a LambdaHT conformation, very strong hydrogen-bond interactions between the phosphate and N1H of cis nucleotides, and a very small dihedral angle between the planes of the two guanines lying nearly perpendicular to the coordination plane. These new results indicate that, because there are no local base-base repulsions precluding the LambdaHT conformer, global forces rather than local interactions account for the predominance of the DeltaHT conformer over the LambdaHT conformer in the solid state and in both inter- and intrastrand HT crosslinks of oligonucleotides and DNA.     

Synthesis,characterization and biological studies of alkenyl‐substituted titanocene(IV) carboxylate complexes

The carboxylate compounds [Ti(η⁵‐C₅H₅)(η⁵‐C₅H₄{CMe₂(CH₂CH₂CH?CH₂)})(O₂CCH₂SXyl)₂] (2; Xyl = 3,5‐Me₂C₆H₃) and [Ti(η⁵‐C₅H₅)(η⁵‐C₅H₄{CMe₂(CH₂CH₂CH?CH₂)})(O₂CCH₂SMesl)₂] (3; Mes 1 = 2,4,6‐Me₃C₆H₂) were synthesized by the reaction of [Ti(η⁵‐C₅H₅)(η⁵‐C₅H₄{CMe₂(CH₂CH₂CH?CH₂)})Cl₂] (1) with 2 equivalents of xylylthioacetic acid or mesitylthioacetic acid, respectively. Compounds 2 and 3 were characterized by spectroscopic methods. The cytotoxic activity of 1–3 was tested against human tumor cell lines from four different histogenic origins—8505C (anaplastic thyroid cancer), DLD‐1 (colon cancer) and the cisplatin sensitive A253 (head and neck cancer) and A549 (lung carcinoma)—and compared with those of the reference complex [Ti(η⁵‐C₅H₅)₂Cl₂] (R1) and cisplatin. Surprisingly, the cytotoxic activities of the carboxylate derivatives were lower than those of their corresponding dichloride analogue (1). However, complexes 1–3 were more active than titanocene dichloride against all the studied cells with the exception of complex 2 against A253 and A549 cell lines. DNA‐interaction tests were also carried out. Solutions of all the studied complexes were treated with different concentrations of fish sperm DNA, observing modifications of the UV spectra with intrinsic binding constants of 2.99 × 10⁵, 2.45 × 10⁵, and 2.35 × 10⁵ M ^?1 for 1–3. Structural studies based on density functional theory calculations of 2 and 3 were also carried out. Copyright © 2010 John Wiley & Sons, Ltd.     

In situ investigations of structure-activity relationships in heteropolyoxomolybdates as partial oxidation catalysts

The structural evolution of Keggin-type heteropolyoxomolybdates (HPOM) during thermal treatment in propene and in propene and oxygen in the temperature range from 300 to 773 K was investigated by in situ X-ray diffraction (XRD) and in situ X-ray absorption spectroscopy (XAS) combined with mass spectrometry. During treatment in propene or hydrogen and at reaction temperatures above 673 K, the initially triclinic H(3)[PMo(12)O(40)].13 H(2)O is transformed quantitatively into a cubic HPOM (Pn$\bar 3$m, a=11.853 A) exhibiting a long-range structure similar to that of the corresponding cesium salts. The treatment described constitutes the first readily available preparation route for a cubic HPOM without alkali metal ions in the structure. For both H(3)[PMo(12)O(40)] and Cs(2)H[PMo(12)O(40)] migration of molybdenum from the Keggin ion onto interstitial sites is proposed to occur in propene or hydrogen at temperatures above about 573 K to give thermally stable, partially reduced lacunary Keggin ions. During activation in propene and oxygen the onset of catalytic activity of H(3)[PMo(12)O(40)] and Cs(2)H[PMo(12)O(40)] at about 573 K correlates with partial reduction of Mo and characteristic changes in the local structure of the Keggin ion. The structural changes observed indicate that, similar to the treatment of the HPOM in propene, migration of molybdenum from the Keggin ions onto interstitial sites and formation of lacunary Keggin ions take place. Moreover, the formation of these partially reduced lacunary Keggin ions appears to be a prerequisite for the material to become an active heterogeneous catalyst. Evidently, the undistorted Keggin ion in the as-prepared HPOM has to be regarded as a precursor of the active catalyst.     

Synthesis,characterization and biological activity of a novel binuclear organotin complex,Ph3Sn(HL)·Ph2SnL [L = 3,5‐Br2‐2‐OC6H2CHNCH(i‐Pr)COO]

A 1:1 reaction of triphenyltin chloride with potassium N‐[(3,5‐dibromo‐2‐hydroxyphenyl)methylene] valinate in benzene under reflux leads to the formation of a novel mixed organotin binuclear complex, Ph₃Sn(HL)·Ph₂SnL [L = 3,5‐Br₂‐2‐OC₆H₂CH?NCH(i‐Pr)COO], by means of a facile phenyl–tin bond cleavage process. The X‐ray structure reveals that there are two distinct types of carboxylate coordination mode and trans‐O₂SnC₂N and trans‐O₂SnC₃ in distorted trigonal bipyramidal geometries. The complex displays good in vitro cytotoxicity and antibacterial activities. Copyright © 2005 John Wiley & Sons, Ltd.     

Cyclopentadienyl Ruthenium(II) Complexes with Bridging Alkynylphosphine Ligands: Synthesis and Electrochemical Studies

The reaction of [CpRuCl(PPh₃)₂] (Cp=cyclopentadienyl) and [CpRuCl(dppe)] (dppe=Ph₂PCH₂CH₂PPh₂) with bis‐ and tris‐phosphine ligands 1,4‐(Ph₂PC≡C)₂C₆H₄ ( 1 ) and 1,3,5‐(Ph₂PC≡C)₃C₆H₃ ( 2 ), prepared by Ni‐catalysed cross‐coupling reactions between terminal alkynes and diphenylchlorophosphine, has been investigated. Using metal‐directed self‐assembly methodologies, two linear bimetallic complexes, [{CpRuCl(PPh₃)}₂(μ‐dppab)] ( 3 ) and [{CpRu(dppe)}₂(μ‐dppab)](PF₆)₂ ( 4 ), and the mononuclear complex [CpRuCl(PPh₃)(η¹‐dppab)] ( 6 ), which contains a “dangling arm” ligand, were prepared (dppab=1,4‐bis[(diphenylphosphino)ethynyl]benzene). Moreover, by using the triphosphine 1,3,5‐tris[(diphenylphosphino)ethynyl]benzene (tppab), the trimetallic [{CpRuCl(PPh₃)}₃(μ₃‐tppab)] ( 5 ) species was synthesised, which is the first example of a chiral‐at‐ruthenium complex containing three different stereogenic centres. Besides these open‐chain complexes, the neutral cyclic species [{CpRuCl(μ‐dppab)}₂] ( 7 ) was also obtained under different experimental conditions. The coordination chemistry of such systems towards supramolecular assemblies was tested by reaction of the bimetallic precursor 3 with additional equivalents of ligand 2 . Two rigid macrocycles based on cis coordination of dppab to [CpRu(PPh₃)] were obtained, that is, the dinuclear complex [{CpRu(PPh₃)(μ‐dppab)}₂](PF₆)₂ ( 8 ) and the tetranuclear square [{CpRu(PPh₃)(μ‐dppab)}₄](PF₆)₄ ( 9 ). The solid‐state structures of 7 and 8 have been determined by X‐ray diffraction analysis and show a different arrangement of the two parallel dppab ligands. All compounds were characterised by various methods including ESIMS, electrochemistry and by X‐band ESR spectroscopy in the case of the electrogenerated paramagnetic species.     

Synthetic,Spectroscopic and Structural Studies of the Rhenium(I) Dicarbonyl Complexes of Phosphite,Phosphonite, and Phosphinite Ligands: cis,mer‐[ReBr(CO)2{PPh3‐n(OR)n}3] (R = Me,Et; n = 1—3)

The reaction of [ReBr(CO)₅] with phosphite and phosphonite ligands in toluene yielded cis, mer‐[ReBr(CO)₂L₃] ( 2 : L = P(OMe)₃ 2a : P(OEt)₃ 2b : PPh(OMe)₂ 2c : PPh(OEt)₂ 2d ). Compounds 2c and 2d were also obtained, as were the phosphinite complexes 2e [L = PPh₂(OMe)] and 2f [L = PPh₂(OEt)], by reaction of the corresponding phosphorus ligand with trans, mer‐[ReBr(CO)₃L₂]. Compounds 2 were all characterized by elemental analysis, mass spectrometry and NMR spectroscopy, and the structures of 2b , 2c and 2d were determined by X‐ray diffractometry. Compounds 2a‐d are stable in chloroform and dichloromethane, but 2e and 2f are transformed into the corresponding trans, mer‐[ReBr(CO)₃L₂] complexes by a reaction for which a partial mechanism is put forward.