Iminophosphoranes As Useful Precursors To Potential Transition Metal-Based Cancer Chemotherapeutics

During the past two decades, gold(III), platinum(II), palladium(II) and ruthenium(II) compounds have been investigated as potential anticancer drugs. Our group at Brooklyn College reported on the cytotoxic properties of neutral and cationic gold(III), palladium(II) and platinum(II) complexes with iminophosphoranes (IM) or iminophosphine ligands of the general formula R3P=NR\u27. These IM ligands have been very useful to synthesize and stabilize compounds of d8 transition metals which displayed higher toxicity against leukemia, prostate cancer and ovarian cancer cells when compared to normal T-lymphocytes. They also seemed to have a mode of action different from that of cisplatin. This thesis describes the synthesis of coordination and organometallic, gold(III), platinum(II), palladium(II) and ruthenium(II) complexes with different iminophosphorane ligands, the study of their stability in solution by different techniques and of their interaction with biological targets (mostly DNA and HSA). I have also included data on the biological activity of these compounds (in vitro and for selected complexes in vivo) to understand their potential as cancer chemotherapeutics. Most of these compounds have displayed excellent anticancer properties by a mode of action different from that currently accepted for cisplatin and, in some cases, have displayed a lower toxicity, better activity or better permeability in vivo. These results are described in three different chapters as summarized below. In Chapter III, I describe the synthesis and characterization of a series of coordination gold(III), palladium(II), and platinum(II) complexes with a luminescent IM ligand derived from 8-aminoquinoline [Ph3P=N-C9H6N]. The coordination palladium(II) and platinum(II) compounds can evolve further, under appropriate conditions, to give stable cyclometalated endo species [Mκ3-C,N,N-C6H4(PPh2=N-8-C9H6N}Cl] (M = Pd, Pt) by C-H activation of the phenyl group of the PPh3 fragment. The compounds have been evaluated for their antiproliferative properties in a human ovarian cancer cell line (A2780S), in human lung cancer cells (A-549) and in a non-tumorigenic human embryonic kidney cell line (HEK-293T). Most compounds have been more toxic to the ovarian cancer cell line than to the non-tumorigenic cell line. The new complexes interact with human serum albumin (HSA) faster than cisplatin. Studies of the interactions of the compounds with DNA indicate that, in some cases, they exert anticancer effects in vitro based on different mechanisms of action with respect to cisplatin. The stability of cyclometallated compounds is markedly higher than that of coordination complexes. In Chapter IV, I describe the synthesis, characterization and stability studies of new organometallic gold(III) and platinum(II) complexes containing cyclometalated IM ligands. Most compounds are more cytotoxic to a number of human cancer cell lines than cisplatin. A cationic Pt(II) derivative ([Pt{κ2-C,N-C6H4(PPh2=N(C6H5)(COD)](PF6)) displays IC50 values in the sub-micromolar range. Its cell death mechanism is mainly through caspase-dependent apoptosis but it triggers caspase-independent cell death when apoptosis is blocked. Permeability studies by two different assays: in vitro caco-2 monolayers and a rat perfusion model have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100% which potentially makes it a good candidate for oral administration. Lastly in Chapter V, I describe the synthesis, characterization and stability studies of a series of organometallic ruthenium(II) complexes containing iminophosphorane ligands. These cationic compounds with chloride as counterion are highly soluble in water (70-100 mg/mL). Most compounds (especially the highly water-soluble compound- ([(η6-p-cymene)Ru{(Ph3P=N-CO-2-N-C5H4)-κ-N,O}Cl]Cl) are more cytotoxic to a number of human cancer cell lines than cisplatin. Initial mechanistic studies indicate that the cell death type for these compounds is mainly through canonical or caspase-dependent apoptosis, non-dependent on p53, and that the compounds do not interact with DNA or inhibit protease cathepsin B. In vivo experiments of ([(η6-p-cymene)Ru{(Ph3P=N-CO-2-N-C5H4)-κ-N,O}Cl]Cl) on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (shrinkage) of 56% after 28 days of treatment (14 doses of 5 mg/kg every other day) with low systemic toxicity. Pharmacokinetic studies showed a quick absorption in plasma with preferential accumulation in the breast tumor tissues when compared to kidney and liver, which may explain its high efficacy in vivo

Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties

New organometallic gold(III) and platinum(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt(II) derivatives 4 and 5, which differ only in the anion, Hg2Cl62– or PF6– respectively, display almost identical IC50 values in the sub-micromolar range (25–335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds 3, 4, and 5 can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound 5 does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of 5 by two different assays, in vitro Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration

Fishing Booths and Fishing Strategies in Medieval Iceland: An Archaeofauna from the [Site] of Akurvík, North-West Iceland

Excavations in 1990 in North-West Iceland documented a stratified series of small turf structures and associated midden deposits at the eroding beach at Akurvík which date from the 11th–13th to the 15th–16th centuries AD. The site reflects a long series of small discontinuous occupations, probably associated with seasonal fishing. The shell sand matrix had allowed excellent organic preservation, and an archaeofauna of more than 100,000 identifiable fragments was recovered. The collections are dominated by fish, mainly Atlantic cod, but substantial amounts of whale bone suggest extensive exploitation of strandings or active whaling. This paper briefly summarizes the excavation results, presents a zooarchaeological analysis of the two largest radiocarbon dated contexts, and places the Akurvík collections in the wider context of intra-Icelandic and interregional trade in preserved fish. Analysis of the Akurvík collection and comparison with other Icelandic collections from both inland and coastal sites dating from the 9th to 19th centuries AD both reinforces evidence for an early, pre-Hanseatic internal Icelandic fish trade and supports historical documentation of Icelandic participation in the growing international fish trade of the late Middle Ages

A 15th C. Archaeofauna from Akurvík, an Early Fishing Station in NW Iceland

This is a report of analysis of 15th c bone materials from the site of Akurvík in NW Iceland excavated in 1990. A small international project in Árneshreppur district recovered a series of stratified midden deposits associated with small turf structures on an eroding beachfront. Radiocarbon dates identify at least two major phases of occupation and use, one extending into the mid 13th century, and the other dating to the mid 15th century. This report documents the animal bone collection from the later 15th c occupation. Dominated by cod fish, these deposits appear to be the product of seasonal fishery carried out from small temporary “booths” and are clearly not the product of a normal medieval Icelandic farmstead. Clear zooarchaeological signatures for cod and haddock preserved fish production are evident and comparisons are drawn to later 18th c contexts. Whale bone was extensively used in construction and craftwork, but it is unclear whether active whaling was carried out from the site or if stranded carcasses were extensively scavenged. Seals and sea birds provided minor supplement to the station and shellfish were probably mainly collected for bait

Luminescent iminophosphorane gold, palladium and platinum complexes as potential anticancer agents

A series of coordination gold(III), palladium(II), and platinum(II) complexes with a luminescent iminophosphorane ligand derived from 8-aminoquinoline [Ph3P[double bond, length as m-dash]N–C9H6N] (1) have been synthesized and structurally characterized. The coordination palladium(II) and platinum(II) compounds can evolve further, under appropriate conditions, to give stable cyclometalated endo species [M{κ3-C,N,N-C6H4(PPh2[double bond, length as m-dash]N-8-C9H6N)}Cl] (M = Pd, Pt) by C–H activation of the phenyl group of the PPh3 fragment. Iminophosphorane 1 and the new metallic complexes are luminescent in DMSO or DMSO–H2O (1 : 1 mixture) solutions at RT. The compounds have been evaluated for their antiproliferative properties in a human ovarian cancer cell line (A2780S), in human lung cancer cells (A549) and in a non-tumorigenic human embryonic kidney cell line (HEK-293T). Most compounds have been more toxic to the ovarian cancer cell line than to the non-tumorigenic cell line. The new complexes interact with human serum albumin (HSA) faster than cisplatin. Studies of the interactions of the compounds with DNA indicate that, in some cases, they exert anticancer effects in vitro based on different mechanisms of action with respect to cisplatin

CCDC 977990: Experimental Crystal Structure Determination

Related Article: Malgorzata Frik, Josefina Jiménez, Vadim Vasilevski, Monica Carreira, Andreia de Almeida, Elena Gascón, Farrah Benoit, Mercedes Sanaú, Angela Casini, María Contel|2014|Inorg.Chem.Front.|1|231|doi:10.1039/C4QI00003J,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

CCDC 977991: Experimental Crystal Structure Determination

Related Article: Malgorzata Frik, Josefina Jiménez, Vadim Vasilevski, Monica Carreira, Andreia de Almeida, Elena Gascón, Farrah Benoit, Mercedes Sanaú, Angela Casini, María Contel|2014|Inorg.Chem.Front.|1|231|doi:10.1039/C4QI00003J,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties

New organometallic gold­(III) and platinum­(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt­(II) derivatives <b>4</b> and <b>5</b>, which differ only in the anion, Hg₂Cl₆^2– or PF₆^– respectively, display almost identical IC₅₀ values in the sub-micromolar range (25–335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds <b>3</b>, <b>4</b>, and <b>5</b> can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound <b>5</b> does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of <b>5</b> by two different assays, <i>in vitro</i> Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration

Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties

New organometallic gold­(III) and platinum­(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt­(II) derivatives <b>4</b> and <b>5</b>, which differ only in the anion, Hg₂Cl₆^2– or PF₆^– respectively, display almost identical IC₅₀ values in the sub-micromolar range (25–335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds <b>3</b>, <b>4</b>, and <b>5</b> can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound <b>5</b> does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of <b>5</b> by two different assays, <i>in vitro</i> Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration