Dual Antitumor and Antiangiogenic Activity of Organoplatinum(II) Complexes

Abstract

A library of over 20 cycloplatinated compounds of the type [Pt(dmba-R)LCl] (dmba-R = C,N-dimethylbenzylamine-like ligand; R being MeO, Me, H, Br, F, CF3, and NO2 substituents in the R5 or R4 position of the phenyl ring; L = DMSO and P(C6H4CF3-p)3) has been prepared. All compounds are active in both human ovarian carcinoma A2780 cells and cisplatin-resistant A2780cisR cells, with most of the DMSO platinum complexes exhibiting IC50 values in the submicromolar range in the A2780 cell line. Interestingly, DMSO platinum complexes show low cytotoxicity in the nontumorigenic kidney cell line BGM and therefore high selectivity factors SF. In addition, some of the DMSO platinum complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926. These are the first platinum(II) complexes reported to inhibit angiogenesis at a close concentration to their IC50 in A2780 cells, turning them into dual cytotoxic and antiangiogenic compounds.

Anticancer Organometallic Osmium(II)‐p‐cymene Complexes

“…Complexes 8 and 4 exhibit ag reat vascular-disrupting activity on the CAM with perfused vasculature reductionso f5 3 and 49 %, respectively.I ntravenous administration of the ruthenium analogue of 8 at ad ose of 50 mm induced an antivascular effect represented by ad ecrease in the number of branching points per mm 2 on the CAM capillary bed by 42 %, [36] less than that observedf or 4.Asimilard ecrease in the number of branching points per mm 2 on the CAM capillaryb ed (by 39 %) was obtained after treatmentw ith sunitinib at 30 mm,t hat is, at ad ose sixfold higher (topicala dministration between EDD 7a nd 9. [50] Various other organometallic compounds, some with bioactive ligands knownt oi nhibit vascularization,h ave been shown to have antiangiogenic properties, including compounds based on titanium, [51][52][53][54] vanadium, [55,56] cobalt, [57] ruthenium, [42,44,[58][59][60][61] iridium, [62,63] platinum, [64] and gold. [65] However,d irect comparisons between these compounds tends to be problematic due to the different modelsa nd protocols used to determine antiangiogenic activity.An otable differencei nt he morphologyo ft he remaining vasculature was observed with 4,l eading to the complete disappearance of capillaries, with only smallp erfused vessels observed.…”

Toward Angiogenesis Inhibitors Based on the Conjugation of Organometallic Platinum(II) Complexes to RGD Peptides

“…Compounds 2 [24] and 5 [25,26] were synthesized and characterized as previously reported. Milli-Q water was directly obtained from aM illi-Q system equipped with a5 000 Da ultrafiltration cartridge.…”

“…In addition, the particularo verexpression of a V b 3 , a V b 5 ,a nd a 5 b 1 integrins in tumor cells offer the possibilityo fu sing RGD peptides as delivery vectors in both therapy and diagnosis. [24] Because the introduction of substituents into the C,N-chelatingl igand did not influence their dual antiangiogenic and cytotoxic activities in vitro, attachment to ac arriera gent was envisaged as ap romising strategyt oi mprove the pharmacological properties of such novel metallodrugs. In spite of the relativelyl arge number of nontoxic angiogenesis inhibitors based on Ru II ,R h II ,a nd Ir III complexes reported in recent years, [17][18][19] bioactivem etallodrugs with dual cytotoxicity and antiangiogenic properties are scarce, [20][21][22][23] particularly in the platinum field.…”

“…Herein,w ef ocus on the conjugation of ap romising organoplatinum(II) complex with dual antitumor and antiangiogenic activity,[ PtCl(dmba)(dmso)] (2;S cheme 1), [24] to c(RGDfK), a cyclic conjugatable version of the RGD motif, with the aim of exploring the antiangiogenic activity of the resulting conjugate. Solid-phase peptide synthesis (SPPS) in combination with solution-phase approaches have been used for the preparation of the bioconjugate (3;S cheme 1), and the effect of peptide conjugation on the biological activity of the parent Pt II complex has been investigated in ap anel of human cancerc ell lines that overexpress or not integrin receptors relatedt oa ngiogenesis.…”

Geometry matters: inverse cytotoxic relationship for cis/trans-Ru(ii) polypyridyl complexes from cis/trans-[PtCl2(NH3)2]

“…However, replacement of the NH 3 ligand in ineffective transplatin by planar N-heterocyclic amines produced trans -platinum complexes with significantly improved cytotoxicity due to enhanced rate of bifunctional interstrand adduct formation and altered sequence specificity. 17 Not only the geometry requirements for platinum species have been lifted; many compounds with “non-conventional” structures, including polynuclear, 18 monofunctional, 19 Pt(IV) 20 and organometallic 21 complexes have displayed anticancer potential. These findings highlighted that more chemical space is available for exploration among platinum compounds than previously thought.…”