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1.
Oxf Med Case Reports ; 2017(7): omx033, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28694972

ABSTRACT

We present the case of a 56-year-old man who presented with rhabdomyolysis and was found to have acute myeloid leukemia (AML). Our case is the first to show an association of rhabdomyolysis with AML. Although rhabdomyolysis is likely a very rare clinical presentation of AML, our case raises awareness for workup for AML in patients who present with rhabdomyolysis and other suspicious findings. Both conditions are medical emergencies and require immediate treatment.

2.
Chemistry ; 20(46): 15169-77, 2014 Nov 10.
Article in English | MEDLINE | ID: mdl-25178182

ABSTRACT

Amorphous silica plays an important role in heterogeneous catalysis as a support and is frequently presumed to be "inert". The structure of the supported catalyst is key to understanding the stability and reactivity of catalytic systems. To provide vital insights into the surface reactivity of silica, Polyhedral oligomeric silsesquioxanes (POSSs) can act as realistic homogeneous molecular models for silica surfaces. Here, we report novel reactivities associated with the silica surface, derived from our insights obtained by means of such model systems with potentially significant implications in catalysis when employing silica-supported catalysts. In this work, the gas-phase reactivities of two cyclohexyl-substituted POSSs, namely the completely condensed triganol prism [Si6cy6O9] (a6b0), and the incompletely-condensed partial cube [Si7cy7O9(OH)3] (a7b3), with cy = c-C6H11, were studied by using atmospheric pressure chemical ionisation (APCI) and collision-induced decomposition (CID) spectroscopies. Silsesquioxane a6b0, containing three-membered rings, was found to be much more reactive, undergoing novel CH2-insertion on reaction with gas phase molecules-a reaction not observed for a7b3, containing only four-membered rings. Both silsesquioxanes displayed the ability to trap ammonia formed in situ within the mass spectrometer from N2 in the instrument. This work also demonstrates the applicability of APCI and the role of CID in elucidating reactive POSS structures, highlighting novel gas-phase reactivities of POSS.

3.
Med Chem ; 9(4): 539-44, 2013 Jun 01.
Article in English | MEDLINE | ID: mdl-23061563

ABSTRACT

As a part of our continued studies on trans-planaramineplatinum(II) complexes, we report here the synthesis and in vitro activity in the human ovarian tumour models of trans-(4-hydroxypyridine)(ammine)dichloroplatinum(II)] (coded as DH1). Although less active than cisplatin against the parent ovarian A2780 and the resistant A2780cisR and A2780ZD0473R cell lines, it has much lower resistant factors than cisplatin. The results indicate that at the level of its activity, DH1 has been better able to overcome the mechanisms of resistance operating in the A2780cisR and A2780ZD0473R cell lines. When platinum-DNA binding levels at 24 h in the A2780, A2780cisR and A2780ZD0473R cell lines are compared it is found that DH1 has higher levels of platinum binding with the DNA than cisplatin even though it has lower activity than cisplatin. The lack of correlation between activity and the platinum-DNA binding level as applied to cisplatin and DH1 may not be so unexpected when we note that the two compounds will differ in their nature of interaction with the DNA. Whereas cisplatin binds with DNA forming mainly intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts, DH1 is expected to form more of 1,2-interstrand Pt(GG) and monofunctional Pt(G) and Pt(A) adducts, thus bringing about different conformational changes in the DNA. The results of interaction with pBR322 plasmid DNA combined with BamH1 digestion showed that DH1 was less able to prevent BamH1 digestion than cisplatin, indicating that cisplatin caused a greater conformational change in the DNA than DH1. Lower activity of DH1 as compared to analogous trans-platinums containing ligands such as 3-hydroxypyridine, 2-hydroxypyridine and imidazo(1,2-α-pyridine) can be seen to illustrate structureactivity relationships. In particular, it supports the idea that, in trans-planaramineplatinum(II) complexes, the ligands 2- hydroxypyridine, 3-hydroxypyridine and imidazo(1,2-α-pyridine) are much more activating towards antitumour activity than 4-hydroxypyrine.


Subject(s)
Antineoplastic Agents/chemical synthesis , Coordination Complexes/chemical synthesis , Organoplatinum Compounds/chemical synthesis , Ovarian Neoplasms/drug therapy , Platinum , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Coordination Complexes/pharmacology , DNA/metabolism , Drug Screening Assays, Antitumor , Female , Humans , Ligands , Organoplatinum Compounds/pharmacology , Ovarian Neoplasms/pathology , Structure-Activity Relationship
4.
Biosens Bioelectron ; 42: 447-52, 2013 Apr 15.
Article in English | MEDLINE | ID: mdl-23238317

ABSTRACT

A novel integrated biosensor methodology is proposed and demonstrated. The methodology utilizes a nitrogen-containing plasma polymer to achieve linker-free binding of a layer of biorecognition molecules. The sensor surface has been shown to maintain its performance after freeze-drying providing a long shelf life under ambient conditions. The sensor is configured for single wavelength ellipsometric detection providing a low cost, versatile, and rapid sensing and diagnosis platform suitable for a wide range of applications and end-users. The merits of the methodology are demonstrated using three antigen-antibody pairs.


Subject(s)
Biosensing Techniques/methods , Nitrogen/chemistry , Proteins/isolation & purification , Surface Properties , Animals , Antigen-Antibody Reactions , Cattle , Humans , Protein Binding , Proteins/chemistry
5.
Med Chem ; 8(3): 384-91, 2012 May.
Article in English | MEDLINE | ID: mdl-22530892

ABSTRACT

A novel trinuclear platinum compound with a cis-geometry for terminal metal centres coded as QH1 has been synthesized, characterized and investigated for activity against the human ovarian A2780, A2780cisR and A2780ZD0473R cancer cell lines. The cellular accumulation of platinum, level of platinum-DNA binding and the nature of interaction of the compound with pBR322 plasmid DNA have also been determined. QH1 is found to be more active against the resistant cell lines than the parent cell line, thus indicating that the compound has been able to overcome mechanisms of resistance operating in the A2780cisR and A2780ZD0473R cell lines. The high activity of QH1 is associated with high platinum accumulation and high level of platinum-DNA binding in all the three ovarian cancer cell lines. Provided QH1 has the right toxicity profile and its in vitro activity is matched with sufficient activity in vivo, the compound has the potential for development as a novel platinum-based anticancer drug targeted to the ovarian cancer.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/pharmacology , Ovarian Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Molecular Structure , Ovarian Neoplasms/pathology , Stereoisomerism , Structure-Activity Relationship
6.
Anticancer Res ; 32(1): 135-40, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22213298

ABSTRACT

UNLABELLED: We report the synthesis and in vitro activity of trans-bis-(2-hydroxypyridine)dichloroplatinum(II) (coded as DH3) in humour ovarian tumour models. The compound is less active than cisplatin against the parent cell line A2780 but more so against the cisplatin-resistant A2780(cisR) cell line, thus indicating that it is better able to overcome mechanisms of resistance operating in the A2780(cisR) cell line. DH3 is marginally less active than cisplatin against ZD0473-resistant A2780(ZD0473R) cell line but with a much lower resistance factor than cisplatin. DH3 has higher platinum-DNA binding levels than cisplatin in the A2780 and A2780(ZD0473) cell lines and a lower value in the A2780(cisR) cell line. Even though DH3 has a lower activity than cisplatin, the higher platinum-DNA binding levels observed for DH3 than cisplatin in A2780 and A2780(ZD0473R) cell lines may not be entirely unexpected when we note that the two compounds are likely to differ in their nature of binding with DNA. Whereas cisplatin binds with DNA forming mainly intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts, DH3 is expected to form more 1,2-interstrand Pt(GG) and monofunctional adducts. The higher activity of DH3 than cisplatin in the A2780(cisR) cell line despite its lower level of platinum-DNA binding can also be seen to indicate the complexity of the situation. Although platinum-DNA binding may be an essential requirement for apoptosis, it is not sufficient to cause cell death that is actually brought about by downstream processes in the cycle. The results of interaction with pBR322 plasmid DNA combined with BamH1 digestion show that DH3 is less able to prevent BamH1 digestion than is cisplatin, indicating that cisplatin causes a greater conformational change in the DNA than DH3. CONCLUSION: DH3 is less active than cisplatin against the parent cell line A2780, but more so against the cisplatin-resistant A2780(cisR) cell line, thus indicating that it is better able to overcome mechanisms of resistance operating in the A2780(cisR) cell line.


Subject(s)
Antineoplastic Agents/chemical synthesis , Cell Proliferation/drug effects , Cisplatin/pharmacology , Drug Resistance, Neoplasm/drug effects , Organoplatinum Compounds/chemical synthesis , Ovarian Neoplasms/drug therapy , Pyridines/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , DNA Adducts , Female , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Organoplatinum Compounds/pharmacology , Ovarian Neoplasms/pathology , Platinum/metabolism , Pyridines/pharmacology , Spectrophotometry, Infrared
7.
J Am Soc Mass Spectrom ; 22(8): 1420-31, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21953197

ABSTRACT

The reaction between CO(2) and aqueous amines to produce a charged carbamate product plays a crucial role in post-combustion capture chemistry when primary and secondary amines are used. In this paper, we report the low energy negative-ion CID results for several anionic carbamates derived from primary and secondary amines commonly used as post-combustion capture solvents. The study was performed using the modern equivalent of a triple quadrupole instrument equipped with a T-wave collision cell. Deuterium labeling of 2-aminoethanol (1,1,2,2,-d(4)-2-aminoethanol) and computations at the M06-2X/6-311++G(d,p) level were used to confirm the identity of the fragmentation products for 2-hydroxyethylcarbamate (derived from 2-aminoethanol), in particular the ions CN(-), NCO(-) and facile neutral losses of CO(2) and water; there is precedent for the latter in condensed phase isocyanate chemistry. The fragmentations of 2-hydroxyethylcarbamate were generalized for carbamate anions derived from other capture amines, including ethylenediamine, diethanolamine, and piperazine. We also report unequivocal evidence for the existence of carbamate anions derived from sterically hindered amines (Tris(2-hydroxymethyl)aminomethane and 2-methyl-2-aminopropanol). For the suite of carbamates investigated, diagnostic losses include the decarboxylation product (-CO(2), 44 mass units), loss of 46 mass units and the fragments NCO(-) (m/z 42) and CN(-) (m/z 26). We also report low energy CID results for the dicarbamate dianion ((-)O(2)CNHC(2)H(4)NHCO(2)(-)) commonly encountered in CO(2) capture solution utilizing ethylenediamine. Finally, we demonstrate a promising ion chromatography-MS based procedure for the separation and quantitation of aqueous anionic carbamates, which is based on the reported CID findings. The availability of accurate quantitation methods for ionic CO(2) capture products could lead to dynamic operational tuning of CO(2) capture-plants and, thus, cost-savings via real-time manipulation of solvent regeneration energies.

8.
Proc Natl Acad Sci U S A ; 108(35): 14405-10, 2011 Aug 30.
Article in English | MEDLINE | ID: mdl-21844370

ABSTRACT

Immobilizing a protein, that is fully compatible with the patient, on the surface of a biomedical device should make it possible to avoid adverse responses such as inflammation, rejection, or excessive fibrosis. A surface that strongly binds and does not denature the compatible protein is required. Hydrophilic surfaces do not induce denaturation of immobilized protein but exhibit a low binding affinity for protein. Here, we describe an energetic ion-assisted plasma process that can make any surface hydrophilic and at the same time enable it to covalently immobilize functional biological molecules. We show that the modification creates free radicals that migrate to the surface from a reservoir beneath. When they reach the surface, the radicals form covalent bonds with biomolecules. The kinetics and number densities of protein molecules in solution and free radicals in the reservoir control the time required to form a full protein monolayer that is covalently bound. The shelf life of the covalent binding capability is governed by the initial density of free radicals and the depth of the reservoir. We show that the high reactivity of the radicals renders the binding universal across all biological macromolecules. Because the free radical reservoir can be created on any solid material, this approach can be used in medical applications ranging from cardiovascular stents to heart-lung machines.


Subject(s)
Equipment and Supplies/adverse effects , Free Radicals , Heart-Lung Machine/adverse effects , Proteins/chemistry , Stents/adverse effects , Humans , Protein Conformation , Surface Properties
9.
Med Chem ; 7(1): 1-8, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21235513

ABSTRACT

A new trinuclear platinum compound [{trans-PtCl(NH(3))(2)}(2){trans-Pt(thiazole) (2)}{H(2)N(CH(2))(6)NH(2)}(2)]Cl(3) (NO(3)) has been synthesized and characterized. The activity of the compound against three human ovarian cancer cell lines A2780, A2780(cisR) and A2780(ZD0473R), its cell uptake and level of binding with DNA have been determined. JH5 is found to be less active than cisplatin against parent A2780 cell line but more active than cisplatin against the A2780(cisR) and A2780(ZD0473R) resistant cell lines indicated by the lower resistance factors. The results indicate that at the level of its activity JH5 has been better able to overcome mechanisms of resistance operating in A2780(cisR) and A2780(ZD0473R) cell lines. JH5 has higher cellular accumulation of platinum than cisplatin in the A2780(cisR) and A2780(ZD0473R) resistant cell lines but lower than cisplatin in the parents A2780 cell line. Cisplatin binds with DNA forming mainly bifunctional intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts that cause local bending of DNA strand. In contrast, JH5 is expected to bind with DNA to form mainly interstrand long-range G-Pt..Pt..Pt(G) adducts that would induce more of a global change in DNA conformation.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , DNA Adducts/metabolism , DNA, Neoplasm/metabolism , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/pharmacology , Ovarian Neoplasms/drug therapy , Antineoplastic Agents/metabolism , Cell Line, Tumor , Cisplatin/metabolism , Cisplatin/pharmacology , Drug Resistance, Neoplasm , Female , Humans , Organoplatinum Compounds/metabolism
10.
Med Chem ; 6(5): 321-8, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20977416

ABSTRACT

In this paper we report the synthesis and in vitro activity of two new mixed ligand platinum complexes: trans-[PtCl2(thiazole)(imidazole) [JH3] and trans-[PtCl2(thiazole)(3-hydroxypyridine) [JH4]. Although the compounds are less active than cisplatin against the parent ovarian cancer cell line A2780, they are more active than cisplatin against the resistant cell lines A2780(cisR) and A2780(ZD0473R), thus indicating that JH3 and JH4 have been better able to overcome mechanisms of resistance operating in A2780(cisR) and A2780(ZD0473R). When Pt-DNA binding levels at 24 h in A2780, A2780(cisR) and A2780(ZD0473R) cell lines are compared it is found that whereas for cisplatin the values in resistant cell lines are significantly lower than that in the parent cell line, for JH3 and JH4 Pt-DNA binding levels in the parent and resistant cell lines are comparable, thus providing an explanation for variations in activity of the compounds in the three cell lines.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Cell Line, Tumor , Cisplatin/chemistry , Cisplatin/metabolism , Cisplatin/pharmacology , DNA, Neoplasm/metabolism , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Female , Humans , Ligands , Molecular Structure , Organoplatinum Compounds/metabolism , Stereoisomerism
11.
ChemMedChem ; 4(11): 1841-9, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19746359

ABSTRACT

The present study deals with the synthesis, characterization and activity against human cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R) of three tripalladium complexes, MH3, MH4 and MH5, that each have two planaramine ligands bound to the central metal ion. Cellular uptake levels, extent of DNA binding, and nature of interaction with salmon sperm and pBR322 plasmid DNA were determined for each complex. Palladium compounds are much more reactive than their corresponding platinum derivatives, which makes them therapeutically inactive but toxic. However, the results of the present study suggest that significant antitumour activity can be introduced in palladium complexes by lessening their reactivity by the introduction of sterically hindered ligands such as 2-hydroxypyridine, 3-hydroxypyridine and 4-hydroxypyridine. When bound to the central palladium ion, 4-hydroxypyridine appears to be more activating than 2-hydroxypyridine and 3-hydroxypyridine, suggesting that noncovalent interactions, such as hydrogen bonding, may also be key determinants of antitumour activity in addition to the steric effect. While cisplatin binds with DNA to form intrastrand GG adducts that causes local bending of a DNA strand, these planaramine-derived palladium complexes are expected to bind with DNA and form a number of long-range interstrand GG adducts that would cause a global change in DNA conformation, provided the tripalladium cations in MH3, MH4 and MH5 persist under physiological conditions.


Subject(s)
Ligands , Organometallic Compounds/chemical synthesis , Palladium/chemistry , Cell Line, Tumor , Cisplatin/chemistry , Cisplatin/metabolism , DNA/chemistry , DNA/metabolism , DNA Adducts/chemistry , DNA Adducts/metabolism , Humans , Hydrogen Bonding , Organometallic Compounds/chemistry , Organometallic Compounds/toxicity , Plasmids/chemistry , Plasmids/metabolism
13.
Med Chem ; 5(4): 372-81, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19689395

ABSTRACT

This paper describes the synthesis, characterization, cytotoxicity of a new trinuclear Pt-Pd-Pt complex code named TH8 containing two 4-hydroxypyridine ligands bound to the central metal ion. In addition to its activity against human ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R), cell uptake, level of DNA-binding and nature of interaction of the compound with pBR322 plasmid DNA have also been determined. TH8 is found to be less active than cisplatin against the parent cell line A2780 but is more active against the cisplatin-resistant cell line A2780(cisR). Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780(cisR), and A2780 and A2780(ZD0473R) are 12.9 and 3.0 respectively, the corresponding values for TH8 are 1.4 and 2.1. The results suggest that TH8 has been better able to overcome the resistance operating in A2780(cisR) cell line. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH8 is expected to bind with DNA forming mainly interstrand GG adducts that would cause more of a global change in DNA conformation.


Subject(s)
Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , DNA/metabolism , Organoplatinum Compounds/metabolism , Organoplatinum Compounds/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biological Transport , Cell Line, Tumor , Deoxyribonuclease BamHI/metabolism , Humans , Inhibitory Concentration 50 , Ligands , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Plasmids/genetics , Pyridines/chemistry , Pyridones , Spectrum Analysis
14.
ChemMedChem ; 3(1): 145-51, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17963210

ABSTRACT

This paper describes the synthesis, characterisation, and cytotoxicity of a novel trinuclear platinum complex code named TH1. In addition to its activity against human ovarian cancer cell lines: A2780, A2780(cisR), and A2780(ZD0473R), cell uptake, DNA-binding, and the nature of the compound interaction with pBR322 plasmid DNA have been determined. TH1 is found to be significantly more cytotoxic than cisplatin - two times more active than cisplatin against the parent cell line A2780, thirteen times more active against the cisplatin-resistant cell line A2780(cisR) and 11.5 times more active against the cell line A2780(ZD0473R). Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780(cisR), and A2780 and A2780(ZD0473R) are 12.9 and 3.0 respectively, the corresponding values for TH1 are 1.98 and 0.5. The results suggest that TH1 has been able to significantly overcome resistance in A2780(cisR) and A2780(ZD0473R) cell lines. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH1 should bind with DNA forming mainly interstrand GG adducts that would cause more of a global change in DNA conformation. Provided it has favourable toxicity profile, TH1 has the potential to be developed into a highly active anticancer drug with a wider spectrum of activity than cisplatin.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Line, Tumor/drug effects , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/therapeutic use , Ovarian Neoplasms/pathology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Cisplatin/pharmacology , Cisplatin/therapeutic use , DNA/metabolism , Female , Humans , Inhibitory Concentration 50 , Organoplatinum Compounds/chemical synthesis , Ovarian Neoplasms/drug therapy , Plasmids/metabolism , Stereoisomerism , Structure-Activity Relationship
15.
BMC Chem Biol ; 6: 3, 2006 Mar 13.
Article in English | MEDLINE | ID: mdl-16533399

ABSTRACT

BACKGROUND: Cis-planaramineplatinum(II) complexes like their trans isomers are often found to be active against cancer cell lines. The present study deals with the synthesis, characterization and determination of activity of new cis-planaramineplatinum(II) complexes. RESULTS: Two cis-planaramineplatinum(II) complexes: cis-(3-hydroxypyridine)(ammine)dichloroplatinum(II) (code named AH3) and cis-(2,3-diaminopyridine)(ammine)dichloroplatinum(II) (code named AH7) have been prepared and characterised based on elemental analyses, IR, Raman, mass and 1H NMR spectral measurements. The interactions of the compounds with pBR322 plasmid DNA have been investigated and their activity against ovarian cancer cell lines: A2780, A2780cisR and A2780ZD047Rhave been determined. Like cisplatin, AH3 and AH7 are believed to form mainly monofunctional N7(G) and bifunctional intrastrand N7(G)N7(G) adducts with DNA, causing a local distortion of a DNA strand. As a result, gel mobility of the DNA changes. Both AH3 and AH7 are found to be less active than cisplatin against the three cell lines with AH3 being the more active compound of the two. The higher activity of AH3 is in line with its lower molar conductivity value corresponding to a lower degree of dissociation. CONCLUSION: The differences in activity of AH3, AH7 and cisplatin against the cell lines illustrate structure-activity relationship.

16.
Eur J Med Chem ; 40(8): 772-81, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16122580

ABSTRACT

The trinuclear complex: [{trans-PtCl(NH(3))}(2)mu-{trans-Pt(NH(3))(2-hydroxypyridine)-(H(2)N(CH(2))(6)NH(2))(2)]Cl(4) (code named CH9) has been synthesized and characterized. The activity of the compound against human ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R), cell up take, level of binding with DNA and nature of its interaction with pBR322 plasmid DNA have been determined. Although the compound is found to be less active (about a half time as active as cisplatin) against the parent ovary cell line A2780, it is found to be more active than cisplatin against resistant cell lines: A2780(cisR) (3.6 times more) and A2780(ZD0473R) (3.4 times more). The higher activity of CH9 against the resistant cell lines suggests that the compound has been able to overcome multiple mechanisms of resistance operating in A2780(cisR) and A2780(ZD0473R) cell lines. Like other multicentered complexes, the compound is believed to form a range of interstrand GG adducts with duplex DNA that induces permanent global changes in the DNA conformation. This binding is different from that of cisplatin and ZD0473 that form mainly intrastrand adducts, inducing a local kink in a DNA strand. Increasing prevention of BamH1 digestion of form I and form II pBR322 plasmid DNA with the increase in concentration of CH9 provides support to the idea that global changes in DNA conformation are induced as a result of its interaction with the compound.


Subject(s)
DNA/metabolism , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cisplatin/pharmacology , DNA/drug effects , Electrophoresis , Female , Humans , Mass Spectrometry , Organoplatinum Compounds/chemistry , Spectrophotometry, Infrared
17.
J Inorg Biochem ; 99(5): 1098-112, 2005 May.
Article in English | MEDLINE | ID: mdl-15833333

ABSTRACT

Four new trans-planaramineplatinum(II) complexes, three of the form: trans-PtCl2L2, code named CH1, CH2 and CH4 where L = 3-hydroxypyridine, 4-hydroxypyridine and imidazo[1,2-alpha]pyridine, respectively, and one of the form: PtClL3, code named CH3 where L = 3-hydroxypyridine, have been prepared and characterized by elemental analyses and IR, Raman, mass and 1H NMR spectral studies. The interactions of the compounds with salmon sperm and pBR322 plasmid DNAs have been investigated and their activity against human ovarian cancer cell lines: A2780, A2780cisR and A2780ZD0473R have also been determined. The compounds are believed to form mainly monofunctional N7(G) and bifunctional intrastrand N7(G)N7(G) adducts with DNA, causing a local distortion of DNA as a result of which gel mobility of the DNA changes. The compound containing three planaramine ligands per molecule (CH3) is found to be less reactive than the compounds containing two planaramine ligands per molecule (CH1, CH2 and CH4), which in turn are less reactive than compounds containing one of the same planaramine ligands per molecule. The decrease in reactivity is reflected in lower molar conductivity values (indicating lower degree of dissociation), less pronounced changes caused to DNA conformation (indicating decreased level of platinum-DNA binding) and lower activity. The decreased reactivity of the compounds is due to a greater steric crowding produced by the bulky planaramine ligands. Changes in DNA conformation are also found to be a function of the actual nature of the planaramine ligand. The results illustrate structure-activity relationship.


Subject(s)
Antineoplastic Agents/chemistry , DNA Adducts/chemistry , Organoplatinum Compounds/chemistry , Pyridines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , DNA Adducts/chemical synthesis , DNA Adducts/metabolism , Humans , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/metabolism
18.
J Phys Chem A ; 109(1): 157-64, 2005 Jan 13.
Article in English | MEDLINE | ID: mdl-16839101

ABSTRACT

Yttrium- and lanthanum-carbide cluster cations YC(n)(+) and LaC(n)(+) (n = 2, 4, and 6) are generated by laser ablation of carbonaceous material containing Y(2)O(3) or La(2)O(3). YC(2)(+), YC(4)(+), LaC(2)(+), LaC(4)(+), and LaC(6)(+) are selected to undergo gas-phase ion-molecule reactions with benzene and cyclohexane. The FTICR mass spectrometry study shows that the reactions of YC(2)(+) and LaC(2)(+) with benzene produce three main series of cluster ions. They are in the form of M(C(6)H(4))(C(6)H(6))(n)(+), M(C(8)H(4))(C(6)H(6))(n)(+), and M(C(8)H(6))(C(6)H(6))(m)(+) (M = Y and La; n = 0-3; m = 0-2). For YC(4)(+), LaC(4)(+), and LaC(6)(+), benzene addition products in the form of MC(n)(C(6)H(6))(m)(+) (M = Y and La; n = 4, 6; m = 1, 2) are observed. In the reaction with cyclohexane, all the metal-carbide cluster ions are observed to form metal-benzene complexes M(C(6)H(6))(n)(+) (M = Y and La; n= 1-3). Collision-induced-dissociation experiments were performed on the major reaction product ions, and the different levels of energy required for the fragmentation suggest that both covalent bonding and weak electrostatic interaction exist in these organometallic complexes. Several major product ions were calculated using DFT theory, and their ground-state geometries and energies were obtained.

19.
Phys Chem Chem Phys ; 7(8): 1687-93, 2005 Apr 21.
Article in English | MEDLINE | ID: mdl-19787926

ABSTRACT

The ion-molecule reactions of laser-generated radical clusters SnxO(x+1)(-) (x = 1-6), SnxO(x-1)(+) (x = 1-6) and SnxOx(+) (x = 2, 3) with the reagents H2S and CH3OH have been investigated using FTICR-MS. For the hypermetallic cations SnxO(x-1)(+), the rates of the sulfur-for-oxygen substitution reactions with H2S appear to be sensitive to LDA/DFT-predicted oxygen binding modes, with mu3-O modes relatively inert with respect to mu-O conformations. The reactions of the hypometallic anions SnxO(x+1)(-) with H2S were dominated by proton transfer, although S-for-O substitution was observed to be kinetically competitive. The rates of the proton transfer were found to vary with both the reagent and cluster anion, and an analysis of the reaction kinetics for SnxO(x+1)(-) afforded the relative cluster proton affinities: PA(Sn2O3-) > PA(SnO2-) >> PA(Sn3O4-) > PA(Sn5O6-) approximately PA(Sn6O7-) approximately PA(CH3O-) = 381 +/- 2 kcal mol(-1) > PA(Sn-) = 352 +/- 10 kcal mol(-1). Ion-molecule reaction results for the hypermetallic cations x = 2-5 with CH3OH are suggestive of gas-phase coordination chemistry, with each cluster undergoing one slow association reaction. A recurrent theme of the chemistry of ionic SnxOy is the initial activation or generation of OySnx(-/+)-OH bonds by a radical mechanism involving hydrogen or hydroxyl abstraction from the reagent. The resulting cluster-hydroxyl bonds are relatively labile with respect to conversion to alkoxy ligands.


Subject(s)
Fourier Analysis , Mass Spectrometry , Nanoparticles/chemistry , Tin/chemistry , Cyclotrons , Hydrogen Sulfide/chemistry , Methanol/chemistry
20.
Eur J Med Chem ; 39(8): 691-7, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15276302

ABSTRACT

Four trans-planaramineplatinum(II) complexes code named YH9, YH10, YH11 and YH12, each of the form trans-PtL(NH(3))Cl(2) where L = 2-hydroxypyridine and 3-hydroxypyridine, imidazole, and imidazo(1,2-alpha)pyridine for YH9, YH10, YH11 and YH12, respectively. All of the compounds have significant anticancer activity against human cancer cell lines. YH12 is found to be significantly more active than cisplatin against cisplatin-resistant ovary cell line A2780(cisR).


Subject(s)
Imidazoles/chemical synthesis , Organoplatinum Compounds/chemical synthesis , Pyridines/chemical synthesis , Pyridones/chemical synthesis , Thymine/analogs & derivatives , Thymine/chemical synthesis , Cell Line, Tumor , Humans , Imidazoles/analysis , Magnetic Resonance Spectroscopy , Organoplatinum Compounds/analysis , Pyridines/analysis , Pyridones/analysis , Spectrum Analysis, Raman , Thymine/analysis
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