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- Bjelosevic, Haris
(författare)
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BIOACTIVE ORGANOMETALLIC COMPOUNDS
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Various metal complexes have been used in medicine traditionally, although their use was often connected with mystery and with a lack of empirically (clinically) proven effect. In modern times, the development of biochemistry, bioinorganic and bioorganometallic chemistry allows us more in-depth understanding of biological action of metal containing substances. Among metal-containing drugs used today, platinum based drugs are the most common. Cisplatin, cis-Pt(NH3)2Cl2, is widely used in the clinic and it has contributed substantially to the success in treating cancer over the past three decades. However, therapy with Cisplatin often brings toxic side effects and development of drug resistance. In this thesis is presented a study of ferrocene- and ruthenocene-based bis-diphenylphosphines (with one phosphino-group on each cyclopentadienyl-ring) derivatised with an additional substituent on a metallocene ring. Synthesis, spectroscopic and electrochemical characterisation as well as X-ray crystal structure are described for some new metallocene-based phosphines and their platinum(II) and gold(I) complexes. Some of the new substances were tested for their ability to bind to sulfur-containing amino acids and selected oligonucleotides. Some complexes were even used in cytotoxicity and viral inhibition studies. These preliminary kinetic and biological studies reveal several promising candidate complexes of interest for further development.
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| 2. |
- Bjelosevic, Haris, et al.
(författare)
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Platinum(II) and gold(I) complexes based on 1,1 '-bis(diphenylphosphino)metallocene derivatives: Synthesis, characterization and biological activity of the gold complexes
- 2012
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Ingår i: Journal of Organometallic Chemistry. - : Elsevier BV. - 0022-328X. ; 720, s. 52-59
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis of series of 1,2,1' substituted bis(diphenylphosphino)- ruthenocenyl (1-4) and ferrocenyl cis-platinum(II) (5-7) and gold(I) (8-12) complexes are described. Crystal structures of 2 and 4, as well as 5, 6 and 10 confirm the molecular geometry of these ligands and their metal complexes. Preliminary investigation of four gold complexes as potential anticancer, antiHIV and antimalaria showed at least one gold compound that has excellent activity towards one of these diseases. The three gold(I) complexes, {1- [1-(dimethylamino)ethyl]-1 ,2-bis(diphenylphosphino)ruthenocene-kappa P-2,P'}bis[chlorogold(I)] (8) (IC50 = 1.40 mu M), {1-[1-(acetoxyethyl)-1',2-bis(diphenylphosphino)ferrocene-kappa P-2,P']bis[chlorogold(1)] (9) (IC50 = 0.51 mu M), {1-[1-(3-carboxypropanamido)ethyl]-1',2-bis(diphenylphosphino)-ruthenocene kappa P-2,P'} bis[chlorogold(I)] (12) (IC50 = 1.784 mu M), have the best activities against cancer, HIV and malaria respectively. (C) 2012 Elsevier B.V. All rights reserved.
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| 3. |
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| 4. |
- Bjelosevic, Haris, et al.
(författare)
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Synthesis and structural characterisation of novel platinum-based drug candidates with extended functionality by incorporation of bis(diphenylphosphino)ferrocene units as metal chelators
- 2006
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 62:18, s. 4519-4527
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Tidskriftsartikel (refereegranskat)abstract
- Among the metal-based anticancer drugs, cisplatin (cis-diaminedichloroplatinum(II)) is the most widely used species in therapy. Despite its clinical success, cisplatin still suffers in generating resistance, as well as being highly toxic due to poor selectivity between healthy and sick cells. By molecular design it ought to be possible to generate new cis-platinum compounds with increased selectivity and improved cellular behaviour. In this paper, we report a synthetic pathway for construction of derivatives of 1,1'-bis(diphenylphosphino)-ferrocene, together with their corresponding cis-platinum compounds with the aim testing them for their interaction capacity with respect to various DNA models. We also report a synthetic route for a nucleoside-based cis-platinum compound containing a bidentate ferrocenylphosphine derivative connected through a succinamic-based linker to the 5-position of the heterocyclic moiety of uridine. Our preliminary kinetic investigation of 5-{N-[1-[1',2-bis(diphenylphosphino)ferrocenyl]ethyl]1-N'-[prop-2-yn-3-y l]succinamide} uridinedichloroplatinum(II) showed that this compound reacted faster with the phosphorothioate containing oligonucleotides d(T(6)p(S)T-6), with an observed first-order rate constant k(obs) = (1.4 +/- 0.1) X 10(-4) s(-1), compared with the G-N7 target in d(T(7)GGT(7)), for which the observed first-order rate constant is k(obs) = (7.2 +/- 0.5) X 10(-4) s(-1). (c) 2006 Elsevier Ltd. All rights reserved.
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| 6. |
- Puxty, Graeme, et al.
(författare)
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A comparative kinetic study of modified Pt(dppf)Cl-2 complexes and their interactions with L-cys and L-met
- 2005
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9234 .- 1477-9226. ; 2005:18, s. 3032-3038
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Tidskriftsartikel (refereegranskat)abstract
- With the success of cisplatin (cis-diamminedichloroplatinum(II)), strong interest has developed in the application of inorganic metal complexes to the treatment of cancer. Research has focused on platinum( II) complexes with a variety of spectator ligands that provide novel physicochemical properties. In this paper we report a kinetic study of 1', 1'-bis(diphenylphosphino) ferrocenedichloroplatinum( II) and two related compounds with either an acetate or amide ester substituent attached to the cyclopentadienyl ring. For all compounds the reactivity towards L-cysteine and L-methionine in aqueous solution has been investigated (25 degrees C, I = 0.010 M and pseudo-first-order conditions). For the reactions with L-cysteine and L-methionine the reactions proceeded via a steady-state aquated intermediate to form mono (0.92(2) - 3.25( 4)) x 10(-3) s(-1)) and bis adducts (0.97( 2) - 3.67(4)) x 10(-4) s(-1)). For reactions with L- cysteine, direct reactions with the starting complex also contributed ( mono adduct: 0.36( 2) - 1.41(4) M-1 s(-1), bis adduct: 0.080(1) - 0.96(1) M-1 s(-1)). The attached substituents were found to have a significant effect upon the reaction kinetics, with the substituted complexes found to have increased reactivity. It is proposed that the increased reactivity stems from hydrogen bonding between the substituent and the entering ligand and subsequent outer-sphere complex stabilisation. Evidence in support of this theory was obtained form measurements in dichloromethane with 1-propanethiol as the entering ligand. The reactivity of the dppf containing complexes was also compared to that of cisplatin ( mono adduct: (0.170( 1) - 0.175(1)) x 10(-3) s(-1), bis adduct: (0.183( 1) - 0.397( 1)) x 10(-4) s(-1)) and found to be significantly enhanced.
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| 7. |
- Spencer, Lara C., et al.
(författare)
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{1-[1-(3-Carboxypropanamido)ethyl]-1',2-bis(diphenylphosphino)ferrocene-kappa2P,P'}dichloridoplatinum(II) dichloromethane 1.25-solvate
- 2008
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Ingår i: Acta Crystallographica Section E: Structure Reports Online. - 1600-5368. ; 64:1, s. 164-1562
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Tidskriftsartikel (refereegranskat)abstract
- The dinuclear title compound, [FePtCl2(C17H14P)(C23H23NO3P)]x1.25CH2Cl2, has a slightly distorted cis-PtCl2P2 square-planar geometry around the Pt atom, and the ferrocenylphosphine ligands are staggered at an angle of 29.4 (2) deg. about Pt. In the crystal structure, the complex forms centrosymmetric dimers via two strong intermolecular O—H-O bonds resulting in R22(8) rings. A weak intramolecular N—H-Cl bond leads to an S(8) motif. The solvent is highly disordered and has not been modelled with discrete atoms.
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