Role of lipophilicity in determining cellular uptake and antitumour activity of gold phosphine complexes

Synopsis __________________________________________________________________________Among a new series of gold(I) complexes that contain diphosphine and deprotonated N-heterocyclic ring systems as ligands, the compounds containing diphenyl(phosphino)pentane and pyrazolate (lypophilic) or 1,2,4,-triazolate (hydrophilic) have high anti-tumour specificities. They induce an apoptic cell death pathway and have the maximum tolerated dose of 1.5 μmol/kg when administered to Balb/C mice. ___________________________________________________________________ *Synopsis for the Graphical abstract  In 25 new complexes diphosphines and azolate-type ligands coordinate to gold  Solvent molecules and counterions appear within channels of a crystalline complex  Cytotoxicity is dependent upon aliphatic C chain length in the ligands  An apoptosis cell death with certain mitochondrial involvement is indicated  Tolerated doses compared to [Au(dppe) 2 ]Cl, tumour specificity is much better *Highlights A B S T R A C T ------------------------------------------------------------------------A series of new neutral mononuclear or dinuclear gold(I) complexes and a cyclic cationic tetranuclear amidogold(I) complex comprising of the phosphines 1,2-bis(dimethylphosphino)ethane (dmpe), μ-1,2-bis(diphenylphosphino)ethane (dppe), μ-1,3-bis(diphenylphosphino)propane (dppp), μ-1,5-bis(diphenylphosphino)pentane (dpppe), μ-1,6-bis(diphenylphosphino)hexane (dpph) or trimethylphosphine, and several N-heterocyclic ring systems (imidazolate, pyrazolate, 1,2,3-triazolate, 1,2,4-triazolate, pyrrolate, 9H-purine-9-ate or 9H-purine-6-amine-9-ate) as ligands, reveal intermolecular aurophilic interactions and 2D channels available for solvent molecules in some of their crystal structures. The antitumou r 2 activity of the acyclic gold(I) compounds is highly dependent on the substituents on the phosphorus atoms being highest for phenyl groups and lower for methyl groups. The activity of these compounds against selected cell lines is linked to the length of the carbon bridge between the two phosphorus atoms being highest with a bridge consisting of 5 or 6 carbons. Two compounds with the highest tumour specifities that contain dpppe and pyrazolate (a lipophilic compound) or 1,2,4-triazolate (a hydrophilic compound) induce the apoptic cell death pathway and tolerate a maximum dose of 1.5 μmol/kg when administered to Balb/C mice.

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“…Results are shown in hydrophilic]. This result is in agreement with previous studies [14], which includes HPLC analysis [35].…”

Section: Lipophilicity Assayssupporting

confidence: 92%

Amides of gold(I) diphosphines prepared from N-heterocyclic sources and their in vitro and in vivo screening for anticancer activity

Horvath

Dobrzańska

Strasser

et al. 2012

Journal of Inorganic Biochemistry

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“…34 We determined log P values for four iodido complexes 9 (2-F), 13 (2-Cl), 17 (2-Br), and 23 (3-Cl), and two chlorido complexes 19 (2-Br), and 25 (3-Cl), all biphenyl arene complexes, using the "shake tube method". The log P values for these complexes (Table S3) Relationship of Cytotoxicity to ROS.…”

Section: Stability and Hydrolysismentioning

confidence: 99%

Structure–activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity

Habtemariam

Basri

et al. 2011

Dalton Trans.

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We report the synthesis and characterisation of 32 half sandwich phenylazopyridine Os II arene complexes [Os(h 6 -arene)(phenylazopyridine)X] + in which X is chloride or iodide, the arene is p-cymene or biphenyl and the pyridine and phenyl rings contain a variety of substituents (F, Cl, Br, I, CF 3 , OH or NO 2 ). Ten X-ray crystal structures have been determined. Cytotoxicity towards A2780 human ovarian cancer cells ranges from high potency at nanomolar concentrations to inactivity. In general the introduction of an electron-withdrawing group (e.g. F, Cl, Br or I) at specific positions on the pyridine ring significantly increases cytotoxic activity and aqueous solubility. Changing the arene from p-cymene to biphenyl and the monodentate ligand X from chloride to iodide also increases the activity significantly. Activation by hydrolysis and DNA binding appears not to be the major mechanism of action since both the highly active complex [Os(h 6 -bip)(2-F-azpy)I]PF 6 (9) and the moderately active complex [Os(h 6 -bip)(3-Cl-azpy)I]PF 6 ( 23) are very stable and inert towards aquation. Studies of octanol-water partition coefficients (log P) and subcellular distributions of osmium in A2780 human ovarian cancer cells suggested that cell uptake and targeting to cellular organelles play important roles in determining activity. Although complex 9 induced the production of reactive oxygen species (ROS) in A2780 cells, the ROS level did not appear to play a role in the mechanism of anticancer activity. This class of organometallic osmium complexes has new and unusual features worthy of further exploration for the design of novel anticancer drugs.

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“…Injectible gold(I) thiolates, such as sodium aurothiomalate, aurothioglucose, and aurothiopropanol sulfonate, and the oral drug auranofin are used clinically against rheumatoid arthritis [1][2][3][4]. A large number of gold(I) compounds have also been tested for antitumor activity against various cancerous cell lines [5][6][7][8][9]. A wide variety of phosphinegold(I) thiolates display significant cytotoxicity in vitro [10,11].…”

Section: Introductionmentioning

confidence: 99%

A spectroscopic and electrochemical investigation of the oxidation pathway of glycyl-d,l-methionine and its N-acetyl derivative induced by gold(III)

et al. 2011

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Role of lipophilicity in determining cellular uptake and antitumour activity of gold phosphine complexes

Abstract: Alteration of lipophilicity of aromatic cationic antitumour drugs greatly affects cellular uptake and binding to plasma proteins. Changes in lipophilicity also affect host toxicity, and optimal lipophilicity may be a critical factor in the design of analogues with high antitumour activity.

Cited by 199 publications

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Amides of gold(I) diphosphines prepared from N-heterocyclic sources and their in vitro and in vivo screening for anticancer activity

Amides of gold(I) diphosphines prepared from N-heterocyclic sources and their in vitro and in vivo screening for anticancer activity

Structure–activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity

A spectroscopic and electrochemical investigation of the oxidation pathway of glycyl-d,l-methionine and its N-acetyl derivative induced by gold(III)

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