1,721,099 research outputs found
Conformational isomerism of trans-[Pt(NH2C6H11)2I2] and the classical Wernerian chemistry of [Pt(NH2C6H11)4]X2 (X = Cl, Br, I)
No full textX-ray crystallographic analysis of the compound trans-[Pt(NH[subscript 2]C[subscript 6]H[subscript 11])[subscript 2]I[subscript 2]] revealed the presence of two distinct conformers within one crystal lattice. This compound was studied by variable temperature NMR spectroscopy to investigate the dynamic interconversion between these isomers. The results of this investigation were interpreted using physical (CPK) and computational (molecular mechanics and density functional theory) models. The conversion of the salts [Pt(NH[subscript 2]C[subscript 6]H[subscript 11])[subscript 4]]X[subscript 2] into trans-[Pt(NH[subscript 2]C[subscript 6]H[subscript 11])[subscript 2]Xp[subscript 2]] (X = Cl, Br, I) was also studied and is discussed here with an emphasis on parallels to the work of Alfred Werner.National Cancer Institute (U.S.) (Grant CA034992
The Effect of Ligand Lipophilicity on the Nanoparticle Encapsulation of Pt(IV) Prodrugs
No full textIn an effort to expand the therapeutic range of platinum anticancer agents, several new approaches to platinum-based therapy, including nanodelivery, are under active investigation. To better understand the effect of ligand lipophilicity on the encapsulation of Pt(IV) prodrugs within polymer nanoparticles, the series of compounds cis,cis,trans-[Pt(NH3)2Cl2L2] was prepared, where L = acetate, propanoate, butanoate, pentanoate, hexanoate, heptanoate, octanoate, nonanoate, and decanoate. The lipophilicities of these compounds, assessed by reversed-phase HPLC, correlate with the octanol/water partition coefficients of their respective free carboxylic acid ligands, which in turn affect the degree of encapsulation of the Pt(IV) complex within the hydrophobic core of poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-PEG-COOH) nanoparticles. The most lipophilic compound investigated, cis,cis,trans-[Pt(NH3)2Cl2(O2C(CH2)8CH3)2], displayed the best encapsulation. This compound was therefore selected to evaluate the effect of increased platinum concentration on encapsulation. As the platinum concentration was increased, there was an initial increase in encapsulation followed by a decrease due to macroscopic precipitation. Maximal loading occurred when the platinum complex was present at a 40% w/w ratio with respect to polymer during the nanoprecipitation step. Particles formed under these optimal conditions had diameters of approximately 50 nm, as determined by transmission electron microscopy.National Cancer Institute (U.S.) (grant CA034992)MIT-Harvard Center for Cancer Nanotechnology ExcellenceNational Institutes of Health (U.S.) (NIH Grant 5-U54-CA151884
The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding
Full text linkThe monofunctional platinum complex cis-[Pt(NH[subscript 3])[subscript 2]Cl(Am)][superscript +], also known as phenanthriplatin, where Am is the N-heterocyclic base phenanthridine, has promising anticancer activity. Unlike bifunctional compounds such as cisplatin, phenanthriplatin can form only one covalent bond to DNA. Another distinguishing feature is that phenanthriplatin is chiral. Rotation about the Pt–N bond of the phenanthridine ligand racemizes the complex, and the question arises as to whether this process is sufficiently slow under physiological conditions to impact its DNA-binding properties. Here we present the results of NMR spectroscopic, X-ray crystallographic, molecular dynamics, and density functional theoretical investigations of diastereomeric phenanthriplatin analogs in order to probe the internal dynamics of phenanthriplatin. These results reveal that phenanthriplatin rapidly racemizes under physiological conditions. The information also facilitated the interpretation of the NMR spectra of small molecule models of phenanthriplatin-platinated DNA. These studies indicate, inter alia, that one diastereomeric form of the complexes cis-[Pt(NH[subscript 3])[subscript 2](Am)(R-Gua)][superscript 2+], where R-Gua is 9-methyl- or 9-ethylguanine, is preferred over the other, the origin of which stems from an intramolecular interaction between the carbonyl oxygen of the platinated guanine base and a cis-coordinated ammine. The relevance of this finding to the DNA-damaging properties of phenanthriplatin and its biological activity is discussed.National Cancer Institute (U.S.) (Grant CA034992
Beyond iron: non-classical biological functions of bacterial siderophores
Full text linkBacteria secrete small molecules known as siderophores to acquire iron from their surroundings. For over 60 years, investigations into the bioinorganic chemistry of these molecules, including fundamental coordination chemistry studies, have provided insight into the crucial role that siderophores play in bacterial iron homeostasis. The importance of understanding the fundamental chemistry underlying bacterial life has been highlighted evermore in recent years because of the emergence of antibiotic-resistant bacteria and the need to prevent the global rise of these superbugs. Increasing reports of siderophores functioning in capacities other than iron transport have appeared recently, but reports of “non-classical” siderophore functions have long paralleled those of iron transport. One particular non-classical function of these iron chelators, namely antibiotic activity, was documented before the role of siderophores in iron transport was established. In this Perspective, we present an exposition of past and current work into non-classical functions of siderophores and highlight the directions in which we anticipate that this research is headed. Examples include the ability of siderophores to function as zincophores, chalkophores, and metallophores for a variety of other metals, sequester heavy metal toxins, transport boron, act as signalling molecules, regulate oxidative stress, and provide antibacterial activity.National Institutes of Health (U.S.) (R21 A1101784
Improvements in the synthesis and understanding of the iodo-bridged intermediate en route to the Pt(IV) prodrug satraplatin
Full text linkMixed amine/ammine motifs are important features in newer generation platinum anticancer agents, including the Pt(IV) prodrug satraplatin. One synthetic route that can be used to access platinum molecules with such structures exploits the trans effect during NH[subscript 3]-mediated cleavage of iodo-bridged platinum(II) dimers of the form [Pt(Am)I(μ-I)][subscript 2], where Am is an amine. A clear picture of the nature of these dimers that is consistent with the reactivity they exhibit has remained elusive. Moreover, technical aspects of this chemistry have impeded its more widespread use. We present here an improved strategy that permits isolation and use of [Pt(Am)I(μ-I)][subscript 2], where Am is cyclohexylamine, within minutes as opposed to weeks, as previously reported. A detailed spectroscopic, crystallographic, and chromatographic investigation of this intermediate in the synthesis of satraplatin is also presented with a discussion of the ability of both cis and trans isomers of the dimer to produce exclusively cis-[Pt(NH[subscript 2]C[subscript 6]H[subscript 11])(NH[subscript 3])I[subscript 2]] upon treatment with NH[subscript 3].National Cancer Institute (U.S.) (Grant CA034992
Reinterpretation of the vibrational spectroscopy of the medicinal bioinorganic synthon c,c,t-[Pt(NH[subscript 3])[subscript 2]Cl[subscript 2](OH)[subscript 2]]
Full text linkThe Pt(IV) complex c,c,t-[Pt(NH[subscript 3])[subscript 2]Cl[subscript 2](OH)[subscript 2]] is an important intermediate in the synthesis of Pt(IV) anticancer prodrugs and has been investigated as an anticancer agent in its own right. An analysis of the vibrational spectroscopy of this molecule was previously reported (Faggiani et al., Can. J. Chem. 60:529, 1982), in which crystallographic determination of the structure of the complex permitted a site group approach. The space group, however, was incorrectly assigned. In the present study we have redetermined at high resolution crystal structures of c,c,t-[Pt(NH[subscript 3])[subscript 2]Cl[subscript 2](OH)[subscript 2]] and c,c,t-[Pt(NH[subscript 3])[subscript 2]Cl[subscript 2](OH)[subscript 2]]·H[subscript 2]O[subscript 2], which makes possible discussion of the effect of hydrogen bonding on the N–H and O–H vibrational bands. The correct crystallographic site symmetry of the platinum complex in the c,c,t-[Pt(NH[subscript 3])[subscript 2]Cl[subscript 2](OH)[subscript 2]] structure is used to conduct a new vibrational analysis using both group-theoretical and modern density functional theory methods. This analysis reveals the nature and symmetry of the “missing band” described in the original publication and suggests a possible explanation for its disappearance.National Cancer Institute (U.S.) (Grant CA034992
A Potent Glucose-Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells
Full text linkThree rationally designed glucose–platinum conjugates (Glc–Pts) were synthesized and their biological activities evaluated. The Glc–Pts, 1–3, exhibit high levels of cytotoxicity toward a panel of cancer cells. The subcellular target and cellular uptake mechanism of the Glc–Pts were elucidated. For uptake into cells, Glc–Pt 1 exploits both glucose and organic cation transporters, both widely overexpressed in cancer. Compound 1 preferentially accumulates in and annihilates cancer, compared to normal epithelial, cells in vitro.National Cancer Institute (U.S.) (CA034992
The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs
Full text linkThe platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-threat agents, and photoactivatable platinum(IV) complexes. Nanoparticles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations, including supramolecular self-assembled structures, proteins, peptides, metal–organic frameworks, and coordination polymers, will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also will reflect our optimism that the next generation of approved platinum cancer drugs is about to arrive.National Cancer Institute (U.S.) (CA034992
Encapsulation of Pt(IV) prodrugs within a Pt(II) cage for drug delivery
Full text linkThis report presents a novel strategy that facilitates delivery of multiple, specific payloads of Pt(IV) prodrugs using a well-defined supramolecular system. This delivery system comprises a hexanuclear Pt(II) cage that can host four Pt(IV) prodrug guest molecules. Relying on host–guest interactions between adamantyl units tethered to the Pt(IV) molecules and the cage, four prodrugs could be encapsulated within one cage. This host–guest complex, exhibiting a diameter of about 3 nm, has been characterized by detailed NMR spectroscopic measurements. Owing to the high positive charge, this nanostructure exhibits high cellular uptake. Upon entering cells and reacting with biological reductants such as ascorbic acid, the host–guest complex releases cisplatin, which leads to cell cycle arrest and apoptosis. The fully assembled complex displays cytotoxicity comparable to that of cisplatin against a panel of human cancer cell lines, whereas the cage or the Pt(IV) guest alone exhibit lower cytotoxicity. These findings indicate the potential of utilising well-defined supramolecular constructs for the delivery of prodrug molecules.National Cancer Institute (U.S.) (Grant CA034992)David H. Koch Institute for Integrative Cancer Research at MIT. Frontier Research Program (Kathy and Curt Marble Cancer Research Fund)National Institutes of Health (U.S.) (Grant 1S10RR13886-01
Monofunctional and Higher-Valent Platinum Anticancer Agents
No full textPlatinum compounds represent one of the great success stories of metals in medicine. Following the serendipitous discovery of the anticancer activity of cisplatin by Rosenberg, a large number of cisplatin variants have been prepared and tested for their ability to kill cancer cells and inhibit tumor growth. These efforts continue today with increased realization that new strategies are needed to overcome issues of toxicity and resistance inherent to treatment by the approved platinum anticancer agents. One approach has been the use of so-called “non-traditional” platinum(II) and platinum(IV) compounds that violate the structure–activity relationships that governed platinum drug-development research for many years. Another is the use of specialized drug-delivery strategies. Here we describe recent developments from our laboratory involving monofunctional platinum(II) complexes together with a historical account of the manner by which we came to investigate these compounds and their relationship to previously studied molecules. We also discuss work carried out using platinum(IV) prodrugs and the development of nanoconstructs designed to deliver them in vivo.National Cancer Institute (U.S.) (Grant CA034992)National Institutes of Health (U.S.) (1S10RR13886-01)National Institutes of Health (U.S.) (MIT-Harvard Center of Cancer Nanotechnology Excellence. Grant 5-U54-CA151884)David H. Koch Graduate Fellowshi
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