Cisplatin-resistant A2780cisR Research Articles

Anticancer Diiron Vinyliminium Complexes: A Structure-Activity Relationship Study.

A series of 16 novel diiron complexes of general formula [Fe2Cp2(CO)(μ-CO){μ-η1:η3-C(R′)C(R″)CN(R)(Y)}]CF3SO3 (2–7), bearing different substituents on the bridging vinyliminium ligand, was synthesized in 69–95% yields from the reactions of diiron μ-aminocarbyne precursors with various alkynes. The products were characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy; moreover the X-ray structures of 2c (R = Y = CH2Ph, R′ = R″ = Me) and 3a (R = CH2CH=CH2, Y = R′ = Me, R″ = H) were ascertained by single-crystal X-ray diffraction studies. NMR and UV–Vis methods were used to assess the D2O solubility, the stability in aqueous solution at 37 °C and the octanol–water partition coefficients of the complexes. A screening study evidenced a potent cytotoxicity of 2–7 against the A2780 cancer cell line, with a remarkable selectivity compared to the nontumoral Balb/3T3 cell line; complex 4c (R = Cy, Y = R′ = R″ = Me) revealed as the most performant of the series. The antiproliferative activity of a selection of complexes was also assessed on the cisplatin-resistant A2780cisR cancer cell line, and these complexes were capable of inducing a significant ROS production. Moreover, ESI-MS experiments indicated the absence of interaction of selected complexes with cytochrome c and the potentiality to inhibit the thioredoxin reductase enzyme (TrxR).

Abstract 4872: Therapeutic value of BCL2 and MDM2-p53 axis in ovarian clear cell and endometrioid carcinomas with wild type TP53

Abstract Background: Apoptosis is the therapeutic goal following the administration of anti-cancer drugs. BCL2 and p53 are two important nodes in the apoptosis signaling pathway. Previous reports have shown that the anti-apoptotic protein BCL2 and p53 degrader MDM2 are overexpressed in many solid neoplasms, including ovarian cancers, and associated with poor clinical outcome. Purpose: Since monotherapy in cancer is generally not providing long-lasting clinical responses, here, we hypothesize that concomitant p53 activation (by an inhibitor of MDM2-p53 interaction, e.g. AMG232) and BCL2 inhibition (by venetoclax) induce maximum apoptosis and markedly reduce tumor cell proliferation in ovarian clear cell and endometrioid carcinomas with wild type (WT) TP53. Methods: We tested the anti-proliferative and apoptotic activity of venetoclax (V) alone, AMG 232 alone (A), and a combination of V plus A in ovarian clear cell carcinoma (OVISE cells) and ovarian endometrioid carcinoma cell lines (A2780 & isogenic Cisplatin resistant A2780CisR). Results: 1) A binds the MDM2 protein, blocks MDM2-p53 interaction, and induces p53 expression and activity, 2) p53 effector molecule p21 is robustly induced following the treatment of A, 3) the anti-proliferative activity of V or A was observed by 3D-ON-TOP clonogenic assay and real-time monitoring in an IncuCyte Zoom, 4) all three cell lines exhibited an increase in annexin V positivity (initiation of apoptotic activity) following V or A treatment, 5) importantly, a combination of V plus A robustly induced the apoptotic markers e.g. cleaved-CASPASE3/7, cleaved PARP1 and BIM protein expression in all cell lines, 6) high mitochondrial depolarization was also observed following the combination of treatment, 7) similar to protein expression data, mRNA data also showed that pro-apoptotic/cell cycle inhibitor transcripts such as p21 and PUMA mRNA expression were significantly increased and 8) normoxic HIF1α degradation is not rescued following the treatment of MDM2-p53 interacting inhibitor A however A-induced p53 activation inhibits hypoxic HIF1α accumulation. Conclusion: These data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy for ovarian clear cell and endometrioid carcinomas patients that retain WT-TP53. Citation Format: Pradip K. De, Jennifer C. Aske, Joseph P. Costello, Ethan Thompson, Nandini Dey. Therapeutic value of BCL2 and MDM2-p53 axis in ovarian clear cell and endometrioid carcinomas with wild type TP53 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4872.

Macrocyclic NHC complexes of group 10 elements with enlarged aromaticity for biological studies.

Two sets of macrocyclic, bio-inspired, non-heme ligands are utilized for the synthesis of NiII, PdII and PtII complexes. The ligands consist of a 16-atom macrocycle, formed by four methylene bridged NHC moieties, with imidazole or benzimidazole as building blocks. The complexes exhibit a square planar coordination geometry and are characterized by NMR, ESI-MS, elemental analysis, SC-XRD and UV/Vis. For complexes incorporating benzimidazole, an evaluation of luminescence properties is performed, and is found that phosphorescence is present for the PdII derivative and there is fluorescence for the PtII derivative. Stability studies in cell culture medium are performed for subsequent MTT assays. Here, the NiII complexes show low to no activity, and PdII and PtII complexes exhibit remarkable low IC50 values in cisplatin resistant A2780cisR cells.

An Unusual Benzoisoquinoline-9-one Derivative and Other Related Compounds with Antiproliferative Activity from Hawaiian Endophytic Fungus Peyronellaea sp. FT431.

A new polyketide containing the benzoisoquinoline-9-one moiety, peyronetide A (1), and three other new derivatives peyronetides B–D (2–4), as well as one known compound (5) were purified from the cultured broth of the endophytic fungus Peyronellaea sp. FT431, which was isolated from the Hawaiian indigenous plant, Verbena sp. The structures of the new compounds were determined through the analysis of HRMS and NMR spectroscopic data. Compounds 1, 2, and 5 showed cytotoxic activities against TK-10 (human kidney adenocarcinoma cells), cisplatin sensitive A2780S (human ovarian carcinoma cells), and cisplatin resistant A2780CisR cell lines, with IC50 values between 6.7 to 29.2 μM.

Search for cytotoxic compounds against ovarian cancer cells: Synthesis, characterization and assessment of the activity of new camphor carboxylate and camphor carboxamide silver complexes

Five silver camphor complexes of formulae [Ag2(L)(L′)2] (1,3,5) or [Ag(L)2(L′)] (2,4) were synthesized from silver nitrate and the suitable camphor carboxylate (L1) or camphor carboxamides (L3, L4). The complexes were characterized by elemental analysis and spectroscopic techniques (NMR, FTIR, XPS). Computational calculations support coordination of the carboxylate group to silver, in the case of complex 2 and combined mixed keto/carboxylate in the case of complex 1. The stability of the complexes highly relies on the tetrahedral geometry of the lithium ion that binds to four oxygen atoms of the camphor carboxylate ligands. The redox properties of complexes 1 and 4 studied by cyclic voltammetry confirm the facile reduction of the metal sites that depending on the experimental conditions may lead to formation of silver nanoparticles as confirmed by XPS and TEM. Complexes 1, 2 and 4 were tested for cytotoxic activities against A2780 (IC50, 11–14 μM) and A2780 cisplatin resistant (A2780cisR) (IC50, 4–7 μM) cells using the MTT assay. The result showed that the complexes have anticancer activity higher than cisplatin. Complex 1 was also probed for cytotoxicity against the non-tumoral human embryonic kidney (HEK 293, IC50, 62.2 ± 16 μM) cells showing low toxicity in agreement with the silver camphor carboxylate complexes having a considerable selectivity for the ovarian cancer cells A2780 and cisplatin resistant A2780cisR which is a key point under pharmacological uses.

Two new tricycloalternarenes from Hawaiian endophytic fungus Didymella sp. FT433

Two new compounds, tricycloalterenes M and N (1 and 2) and six known analogs were isolated from the cultured broth of Didymella sp. FT433. The structures of all the compounds were elucidated through the analysis of HRMS and NMR spectroscopic data. The absolute configurations (AC) of the new compounds were determined by CD. All compounds were tested against A2780 and cisplatin resistant A2780 (A2780CisR) cell lines, and pathogenic bacteria Staphylococcus aureus, Escherichia coli, Bacillus subtilis, and Pseudomonas aeruginosa, but none was active.

The in vitro renal cell toxicity of some unconventional anticancer phenanthroline-based platinum(II) complexes

The cytotoxicity of platinum(II) complexes coordinated to a chiral diamine, 1S,2S-diaminocyclohexane or 1R,2R-diaminocyclohexane and 1,10-phenanthroline or 3,4,7,8-tetramethyl-1,10-phenanthroline has been investigated in the renal proximal tubule HK-2 cell line. All platinum(II) complexes exhibited lower cytotoxicity in HK-2 cells (IC50 1.7–25μM) than in A2780 ovarian cancer cells or cisplatin-resistant A2780cisR cells (IC50 0.2–2.1μM) (at 48h). PHENSS ([Pt(1,10-phenanthroline)(1S,2S-dach)]2+) induced apoptosis and necrosis in ovarian cancer cells at concentrations that are relatively cytostatic to renal cells. Cisplatin was similarly or more cytotoxic to renal cells than ovarian cancer cells. Similar trends were reflected with shorter term exposure (1.5h). PHENSS demonstrated a comparatively cytostatic mode of action in renal cell cultures than cisplatin, as demonstrated by lower toxicity at higher concentrations (90μM). PHENSS induced an elongated renal cell morphology, cytoskeletal stress fibre thickening, and increased β-galactosidase activity, but no detectable change in reactive oxygen species generation or cell cycle distribution. In contrast, cisplatin treatment was associated with increased oxidative stress, cellular enlargement, G2/M arrest and apoptosis. The cytotoxicity of all platinum(II) complexes in both renal and ovarian cell lines were reduced in the presence of organic cation transporter (OCT) inhibitors cimetidine, disopyramide and amantadine. PHENSS and analogues demonstrated low level genotoxicity in an in vitro micronuclei assay compared to cisplatin or etoposide. These findings highlight PHENSS and other phen-based unconventional platinum(II) complexes as promising anticancer agents with alternative modes of action that induce lower kidney cell toxicity and genotoxicity, while demonstrating greater cisplatin-resistant ovarian cancer cell toxicity.

Anti-proliferative ambuic acid derivatives from Hawaiian endophytic fungus Pestalotiopsis sp. FT172

Five previously undescribed ambuic acid derivatives, pestallic acids A–E and three known analogs were isolated from the cultured broth of Pestalotiopsis sp. FT172. The structures of the pestallic acids A-E were determined through the analysis of HRMS and NMR spectroscopic data. The absolute configurations (ACs) of pestallic acids B–E were assigned by comparison of the experimental electric circular dichroism (ECD) spectra or the optical rotations with those in the literature. All compounds were tested against A2780 and cisplatin resistant A2780 (A2780CisR) cell lines. Pestallic acid E and (+)-ambuic acid showed potent activities with IC50 values from 3.3 to 17.0 μM.

Evaluation of cellular uptake, cytotoxicity and cellular ultrastructural effects of heteroleptic oxidovanadium(IV) complexes of salicylaldimines and polypyridyl ligands

Searching for prospective vanadium-based drugs for cancer treatment, a new series of structurally related [VIVO(L−2H)(NN)] compounds (1–8) was developed. They include a double deprotonated salicylaldimine Schiff base ligand (L-2H) and different NN-polypyridyl co-ligands having DNA intercalating capacity. Compounds were characterized in solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate and bind through both nitrogen donor atoms in an axial-equatorial mode. The cytotoxicity was evaluated in human tumoral cells (ovarian A2780, breast MCF7, prostate PC3). The cytotoxic activity was dependent on type of cell and incubation time. At 24h PC3 cells presented low sensitivity, but at 72h all complexes showed high cytotoxic activity in all cells. Human kidney HEK293 and ovarian cisplatin resistant A2780cisR cells were also included to evaluate selectivity towards cancer cells and potency to overcome cisplatin resistance, respectively. Most complexes showed no detectable interaction with plasmid DNA, except 2 and 7 which depicted low ability to induce single strand breaks in supercoiled DNA. Based on the overall cytotoxic profile, complexes with 2,2´-bipyridine and 1,10-phenanthroline ligands (1 and 2) were selected for further studies, which consisted on cellular distribution and ultrastructural analyses. In the A2780 cells both depicted different distribution profiles; the former accumulates mostly at the membrane and the latter in the cytoskeleton. Morphology of treated cells showed nuclear atypia and membrane alterations, more severe for 1. Complexes induce different cell death pathways, predominantly necrosis for 1 and apoptosis for 2. Complexes alternative mode of cell death motivates the possibility for further developments.

Synthesis of Ag(I) camphor sulphonylimine complexes and assessment of their cytotoxic properties against cisplatin-resistant A2780cisR and A2780 cell lines

Camphorsulphonylimine complexes [Ag(NO3)(IL)2] (IL=C12H19N3SO2, 1) and [(AgNO3)2(IIL)] (IIL=C22H23N3SO2, 2) were synthesized and characterized by elemental analysis, spectroscopy (IR, NMR) and cyclic voltammetry. [Ag(NO3)(IL)2] crystalizes in the monoclinic C2 space group with a triangular geometry assuming a chalice-type shape. The anti-proliferative properties of the new complexes 1 and 2 and those of the previously reported [Ag(NO3)(IIIL)] (IIIL=C16H18N3SO2, 3) were assessed against the human ovarian cancer cells (cisplatin-sensitive A2780, cisplatin-resistant A2780cisR) and the non-tumoral human HEK 293 cell line, using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The NR (3-amino-7-dimethylamino-2-methylphenazine hydrochloride) assay was alternatively used to assess the cytotoxicity on the A2780 cells. Results from the MTT assay (48h exposure) show that the complexes display IC50 values lower (by at least one order of magnitude) than cisplatin, while the cytotoxicity of AgNO3 is of the same order of cisplatin. The camphorsulphonylimine ligands display irrelevant (IL, IIIL) or no cytotoxicity (IIL). The highest cytotoxicity (lower IC50) was found for [(AgNO3)2(IIL)]. The binding ability of the complexes to calf thymus-deoxyribonucleic acid (CT-DNA) was studied by fluorescence. Constants (Ksv, Ka) and the number (n) of binding centres to DNA were calculated showing that DNA intercalation possibly occurs in the cases of complexes 2 and 3, while a more complicated process operates for 1. As expected from the cytotoxicity, [(AgNO3)2(IIL)] displays the highest binding affinity (Ka=1.61×105 M−1). No binding to DNA was detected for AgNO3 or IIL under the experimental conditions used. The binding trend to CT-DNA found by fluorescence was corroborated by cyclic voltammetry.

Cytotoxicity of arene ruthenium metalla-rectangles incorporating bis-pyridyl diimide linkers

A series of tetranuclear arene ruthenium complexes of the general formula [Ru4(p-cymene)4(μ2-L)2(μ4-OO∩OO)2][CF3SO3]4 (L1 = N,N’-bis(4-pyridylmethyl)-pyromellitic diimide, L2 = N,N’-bis(4-pyridylmethyl)-naphthalene diimide) were obtained from the corresponding dinuclear arene ruthenium complexes Ru2(p-cymene)2(μ4-OO∩OO)Cl2 (OO∩OO = oxalato (oxa), 2,5-dioxido-1,4-benzoquinonato (dobq), 2,5-dihydroxy-3-phenyl-1,4-benzoquinonato (dhpb), 2,5-dichloro-1,4-benzoquinonato (dClbq), 2,5-dioxido-3-undecyl-1,4-benzoquinonato (dubq), 2,5-dihydroxy-3,6-diphenyl-1,4-benzoquinonato (dhdb), 5,8-dioxido-1,4-naphtoquinonato (donq)) by reaction with the bidentate ligands (L1 and L2) and silver trifluoromethanesulfonate. The antiproliferative activity of the tetranuclear arene ruthenium metalla-rectangles was evaluated on cancerous (A2780 and A2780cisR) and non-cancerous (HEK293) cell lines, showing in all cases cancer cell selectivity. In general, the metalla-rectangles obtained with L2 are more potent than those incorporating L1, and with the exception of [Ru4(p-cymene)4(μ2-L1)2(μ4-dClbq)2][CF3SO3]4, they are all more active than cisplatin on the cisplatin resistant A2780cisR cell line.

Eremophilane sesquiterpenes from Hawaiian endophytic fungus Chaetoconis sp. FT087

Seven sesquiterpene derivatives, including chaetopenoids A–F and dendryphiellin A1, and 6-methyl-(2E, 4E, 6S) octadienoic acid were isolated from the culture broth of Chaetoconis sp. FT087. Their structures were determined through the analysis of HRMS and NMR spectroscopic data. The absolute configurations of chaetopenoids A–D were elucidated by comparison of their CD and optical rotation data with those in the literature. Chaetopenoids A–C and E belong to the eremophilane type of sesquiterpenoids, while chaetopenoids D and F and dendryphiellin A1 have a trinor-eremophilane skeleton. All compounds were tested against A2780 and cisplatin resistant A2780CisR cell lines, and dendryphiellin A1 was moderately active with IC50 values of 6.6 and 9.1μg/mL, respectively.

Abstract 3504: Synergism from combinations of monofunctional platinums with phytochemicals in human ovarian cancer cell lines

Abstract Aims To apply combinations of monofunctional platinums with selected phytochemicals in human ovarian tumor models towards overcoming platinum resistance. Recently research has been directed at combinations of platinum drugs with tumor active phytochemicals towards a means of overcoming platinum resistance in ovarian cancer. In this study, two designed monofunctional planaramineplatinum(II) complexes, tris(8-hydroxyquinoline)monochloroplatinum(II) chloride (LH3) and tris(benzimidazole)chloroplatinum(II) chloride (LH4), were investigated for activity against human ovarian A2780, cisplatin-resistant A2780 (A2780cisR) and ZD0473-resistant A2780 (A2780ZD0473R) cancer cell lines, alone and in combination with curcumin, genistein, querceitin, capsaicin and resveratrol. Methods LH3 and LH4 were synthesized starting with potassium tetracloroplatinate and phytochemicals were obtained from commercial sources. Cytotoxicity was determined using MTT reduction assay. Cellular levels of glutathione before and after treatment were also determined. Interaction of the designed compounds with pBR322 plasmid DNA and damage to DNA in A2780 and A2780cisR cell lines due to interaction with designed compounds alone and in combination with phytochemicals were also investigated. Proteomic studies involving 2D-gel electrophoresis and mass spectrometry were carried out to identify key proteins associated with drug resistance in A2780 and A2780cisR cell lines. Results and Discussion LH3 and LH4 were found to be much more active than cisplatin against the resistant tumour models and greatest synergism in activity was observed when combinations of LH3 and LH4 with the phytochemicals were administered as a bolus. For combinations of LH3 and LH4 with the phytochemicals, platinum accumulation and the level of Pt-DNA binding were greater in the resistant A2780cisR cell line than in the parental A2780 cell line. Proteomic studies confirmed significant changes in expression of a number of proteins in A2780cisR cell line compared to the A2780 parent cell line. Greater activity of LH3 and LH4 than cisplatin against the resistant ovarian cell lines indicates that monofunctional platinums can be novel drug candidates with different cytotoxicity profiles from those of Pt drugs currently in use. The steric properties conveyed by the heterocylic ligands play a significant role in modulating their cytotoxicities and binary combination with tumour active phytochemicals can serve to further enhance drug efficacy. Conclusion Monofunctional platinums containing bulky planaramine ligands in combination with tumor active phytochemicals have the potential of overcoming platinum resistance in ovarian cancer cell lines. Acknowledgment This research was partly supported by Biomedical Science Research Initiative Grant and Biomedical Science Cancer Research Donation Fund. Citation Format: Laila Arzuman, Fazlul Huq, Jun Qing Yu, Philip Beale. Synergism from combinations of monofunctional platinums with phytochemicals in human ovarian cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3504. doi:10.1158/1538-7445.AM2015-3504

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.

Trans-Thionate Derivatives of Pt(II) and Pd(II) with Water-Soluble Phosphane PTA and DAPTA Ligands: Antiproliferative Activity against Human Ovarian Cancer Cell Lines

A series of PTA and DAPTA platinum(II) and palladium(II) thionate complexes of the type trans-[M(SN)2P2] were prepared from the reaction of cis-[MCl2P2] [M = Pt, Pd; P = PTA (1,3,5-triaza-7-phosphaadamantane), DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane)] with the in situ generated sodium salts of the heterocyclic thiones S-m-methylpyrimidine-2-thione, S-4,6-dimethylpyrimidine-2-thione, S-4,6-dihydroxypyrimidine-2-thione, benzothiazole-2-thione, benzoxazole-2-thione, S-1,3,4,-thiadiazole-2-thione, S-4,5-H-thiazolan-2-thione, and S-pyrimidine-4(1H)-one-2-thione. The X-ray structures of six of the compounds confirm the trans disposition and, only in the case of [Pd2Cl2(S-pyrimidine-4(1H)-one-2-thionate)2(PTA)2], a dinuclear structure with a Pd-Pd distance of 3.0265(14)Å was observed. In vitro cytotoxicities against human ovarian cancer cell lines A2780 and A2780cisR were evaluated for ten complexes showing a high inhibition of cellular growth with a comparable inhibitory potency (IC50) against A2780 cells to that of cisplatin. Notably, the compounds also show significant (up to 7-fold higher) activity in cisplatin-resistant A2780cisR cell lines.

Palladium(II) and platinum(II) bis(thiosemicarbazone) complexes of the 2,6-diacetylpyridine series with high cytotoxic activity in cisplatin resistant A2780cisR tumor cells and reduced toxicity

Preparation and characterization of four novel 2,6-diacetylpyridine bis(4N-tolylthiosemicarbazonato) palladium(II) and platinum(II) complexes, [PdL1–2] and [PtL1–2], are described. All compounds have been characterized by elemental analysis and by IR and NMR spectroscopy, and the crystal and molecular structures of complexes [PdL2] and [PtL2] have been determined by a single crystal X-ray diffraction. The ligands act as dianionic tetradentate donors coordinating to the metal center in a square planar geometry through the Npyridinic atom and the Niminic and the S atoms from one thiosemicarbazone arm, the fourth coordination position is occupied by the Nhydrazinic of the other arm. The new compounds synthesized have been evaluated for antiproliferative activity in vitro against NCI-H460, HepG2, MCF-7, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that [PdL1], [PdL2] and [PtL2] may be endowed with important antitumor properties since they are capable of not only circumventing cisplatin resistance in A2780cisR cells but also exhibiting high antiproliferative activity in breast cancer MCF-7 cells. Subsequent toxicity study, in LLC-PK1 cells, has also been carried out and shows that none of these compounds are in vitro toxic in the tested concentration range.

Exploring the Versatility of Cycloplatinated Thiosemicarbazones as Antitumor and Antiparasitic Agents

Tridentate cycloplatinated thiosemicarbazone complexes have been prepared from a biologically significant ligand, 3,4-dichloroacetophenone thiosemicarbazone (1). The tetranuclear complex 2 was prepared by reaction of the ligand with K2[PtCl4]. Two mononuclear (3 and 4) and two dinuclear (5 and 6) complexes were isolated upon cleavage of the Pt–Sbridging bonds of the tetranuclear complex 2 with the appropriate phosphane ligand. Each complex was characterized using various analytical and spectroscopic techniques, and the molecular structures of 2–4 were also elucidated. The in vitro antiparasitic activities of these complexes against Plasmodium falciparum strains (D10 (chloroquine sensitive) and Dd2 (chloroquine resistant)) and Trichomonas vaginalis have been determined. Preliminary studies into their potential plasmodial target in the form of β-hematin formation inhibition assays were also completed. Preliminary results suggest that ligand 1 and complex 3 do not hinder formation of β-hematin. The antiproliferative activity of the complexes against the cisplatin-senstive A2780 and cisplatin-resistant A2780cisR human ovarian cancer cell lines has been evaluated. The complexes were found to exhibit moderate to weak inhibitory activities.

Pt(ii) complexes with bidentate and tridentate pyrazolyl-containing chelators: synthesis, structural characterization and biological studies

A series of four Pt(II) complexes anchored by bidentate or tridentate pyrazolyl-alkylamine chelators bearing different substituents at the azolyl rings has been prepared with the aim to assess their interest in the design of novel anticancer drugs. All complexes have been fully characterized by classical analytical methods and three of them were characterized also by X-ray diffraction analysis. Their solution behavior, together with lipophilicity measurements, cell uptake, antiproliferative properties, DNA interaction have been evaluated. Albeit all the complexes were less active than cisplatin on ovarian carcinoma A2780 cell line, greatly retained their activity in the cisplatin-resistant A2780cisR cell line and presented a lower resistance factor compared to cisplatin. Moreover, the Pt(II) complexes under investigation were less prone to undergo deactivation by glutathione, believed to be the major cellular target of cisplatin that inactivates the drug by binding to it irreversibly.

Anticancer activity of osmium metalla-rectangles

A series of cationic metalla-rectangles of the general formula [(p-cymene)(4)Os(4)(OO[intersection]OO)(2)(N[intersection]N)(2)](4+) have been obtained in methanol from the dinuclear arene osmium precursors [(p-cymene)(2)Os(2)(OO[intersection]OO)(2)Cl(2)] (OO[intersection]OO = 2,5-dioxydo-1,4-benzoquinonato (dhbq), 2,5-dichloro-1,4-benzoquinonato (dcbq)) by reaction with bipyridine linkers (N[intersection]N = 4,4'-bipyridine, 1,2-bis(4-pyridyl)ethylene) in the presence of AgCF(3)SO(3). All complexes were isolated as triflate salts and characterised by NMR, IR and UV-visible spectroscopy. The cytotoxicities of the dinuclear and tetranuclear osmium complexes were established using ovarian A2780 cancer cell lines. The most active metalla-rectangle, [(p-cymene)(4)Os(4)(dhbq)(2)(4,4'-bipyridine)(2)](4+), shows an IC(50) value of 5.7 microM (comparable to cisplatin) against A2780 cancer cells and 7.5 microM against the cisplatin resistant A2780cisR cells.

New cytotoxic and water-soluble bis(2-phenylazopyridine)ruthenium(II) complexes.

New water-soluble bis(2-phenylazopyridine)ruthenium(II) complexes, all derivatives of the highly cytotoxic alpha-[Ru(azpy)(2)Cl(2)] (alpha denoting the coordinating pairs Cl, N(py), and N(azo) as cis, trans, cis, respectively) have been developed. The compounds 1,1-cyclobutanedicarboxylatobis(2-phenylazopyridine)ruthenium(II), alpha-[Ru(azpy)(2)(cbdca-O,O')] (1), oxalatobis(2-phenylazopyridine)ruthenium(II), alpha-[Ru(azpy)(2)(ox)] (2), and malonatobis(2-phenylazopyridine)ruthenium(II), alpha-[Ru(azpy)(2)(mal)] (3), have been synthesized and fully characterized. X-ray analyses of 1 and 2 are reported, and compound 1 is the first example in which the cbdca ligand is coordinated to a ruthenium center. The cytotoxicity of this series of water-soluble bis(2-phenylazopyridine) complexes has been determined in A2780 human ovarian carcinoma and A2780cisR, the corresponding cisplatin-resistant cell line. For comparison reasons, the cytotoxicity of the complexes alpha-[Ru(azpy)(2)Cl(2)], alpha-[Ru(azpy)(2)(NO(3))(2)], beta-[Ru(azpy)(2)Cl(2)] (beta indicating the coordinating pairs Cl, N(py), and N(azo) as cis, cis, cis, respectively), and beta-[Ru(azpy)(2)(NO(3))(2)] have been determined in this cell line. All the bis(2-phenylazopyridine)ruthenium(II) compounds display a promising cytotoxicity in the A2780 cell line (IC(50) = 0.9-10 microM), with an activity comparable to that of cisplatin and even higher than the activity of carboplatin. Interestingly, the IC(50) values of this series of ruthenium compounds (except the beta isomeric compounds) are similar in the cisplatin-resistant A2780cisR cell line compared to the normal cell line A2780, suggesting that the activity of these compounds might not be influenced by the multifactorial resistance mechanism that affect platinum anticancer agents.