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Organometallic Titanocene-Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties.

ABSTRACT: Early-late transition metal TiAu₂ compounds [(?-C₅H₅)₂Ti{OC(O)CH₂PPh₂AuCl}₂] (3) and new [(?-C₅H₅)₂Ti{OC(O)-4-C₆H₄PPh₂AuCl}₂] (5) were evaluated as potential anticancer agents in vitro against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold(I) [{HOC(O)RPPh₂}AuCl] (R = -CH₂- 6, -4-C₆H₄- 7) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for 5 in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y. Initial mechanistic studies in Caki-1 cells in vitro coupled with studies of their inhibitory properties on a panel of 35 kinases of oncological interest indicate that these compounds inhibit protein kinases of the AKT and MAPKAPK families with a higher selectivity toward MAPKAPK3 (IC₅₀3 = 91 nM, IC₅₀5 = 117 nM). The selectivity of the compounds in vitro against renal cancer cell lines when compared to a nontumorigenic human embryonic kidney cell line (HEK-293T) and the favorable preliminary toxicity profile on C57black6 mice indicate that these compounds (especially 5) are excellent candidates for further development as potential renal cancer chemotherapeutics.

SUBMITTER: Fernandez-Gallardo J

PROVIDER: S-EPMC4245150 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Organometallic Titanocene-Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties.

Fernández-Gallardo Jacob J Elie Benelita T BT Sulzmaier Florian J FJ Sanaú Mercedes M Ramos Joe W JW Contel María M

Organometallics 20141030 22

Early-late transition metal TiAu2 compounds [(η-C5H5)2Ti{OC(O)CH2PPh2AuCl}2] (3) and new [(η-C5H5)2Ti{OC(O)-4-C6H4PPh2AuCl}2] (5) were evaluated as potential anticancer agents in vitro against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and go ...[more]

PMID: 25435644

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Project description:The reaction of new dinuclear gold(I) organometallic complexes containing mesityl ligands and bridging bidentate phosphanes [Au(2)(mes)(2)(?-LL)] (LL=dppe: 1,2-bis(diphenylphosphano)ethane 1a, and water-soluble dppy: 1,2-bis(di-3-pyridylphosphano)ethane 1b) with Ag(+) and Cu(+) lead to the formation of a family of heterometallic clusters with mesityl bridging ligands of the general formula [Au(2)M(?-mes)(2) (?-LL)][A] (M=Ag, A=ClO(4)(-), LL=dppe 2a, dppy 2b; M=Ag, A=SO(3)CF(3)(-), LL=dppe 3a, dppy 3b; M=Cu, A=PF(6)(-), LL=dppe 4a, dppy 4b). The new compounds were characterized by different spectroscopic techniques and mass spectrometry The crystal structures of [Au(2)(mes)(2)(?-dppy)] (1b) and [Au(2)Ag(?-mes)(2)(?-dppe)][SO(3)CF(3)] (3a) were determined by a single-crystal X-ray diffraction study. 3a in solid state is not a cyclic trinuclear Au(2)Ag derivative but it gives an open polymeric structure instead, with the {Au(2)(?-dppe)} fragments "linked" by {Ag(?-mes)(2)} units. The very short distances of 2.7559(6)?Å (Au-Ag) and 2.9229(8)?Å (Au-Au) are indicative of gold-silver (metallophilic) and aurophilic interactions. A systematic study of their luminescence properties revealed that all compounds are brightly luminescent in solid state, at room temperature (RT) and at 77?K, or in frozen DMSO solutions with lifetimes in the microsecond range and probably due to the self-aggregation of [Au(2)M(?-mes)(2)(?-LL)](+) units (M=Ag or Cu; LL=dppe or dppy) into an extended chain structure, through Au-Au and/or Au-M metallophilic interactions, as that observed for 3a. In solid state the heterometallic Au(2)M complexes with dppe (2a-4a) show a shift of emission maxima (from ca. 430 to the range of 520-540?nm) as compared to the parent dinuclear organometallic product 1a while the complexes with dppy (2b-4b) display a more moderate shift (505 for 1b to a max of 563?nm for 4b). More importantly, compound [Au(2)Ag(?-mes)(2)(?-dppy)]ClO(4) (2b) resulted luminescent in diluted DMSO solution at room temperature. Previously reported compound [Au(2)Cl(2)(?-LL)] (LL dppy 5b) was also studied for comparative purposes. The antimicrobial activity of 1-5 and Ag[A] (A=ClO(4)(-), SO(3)CF(3)(-)) against gram-positive and gram-negative bacteria and yeast was evaluated. Most tested compounds displayed moderate to high antibacterial activity while heteronuclear Au(2)M derivatives with dppe (2a-4a) were the more active (minimum inhibitory concentration 10 to 1??g?mL(-1)). Compounds containing silver were ten times more active to gram-negative bacteria than the parent dinuclear compound 1a or silver salts. Au(2)Ag compounds with dppy (2b, 3b) were also potent against fungi.

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Organometallic Titanocene-Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties.

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Organometallic Titanocene-Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties.

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