Exploring the Influence of the Aromaticity on the Anticancer and Antivascular Activities of Organoplatinum(II) Complexes

Abstract

A series of new organometallic Pt complexes of the type [Pt(C^N)Cl(DMSO)] (C^N=N,N-dimethyl-1-(2-aryl)methanamine-κ C2,N; aryl=phenyl 2 a, biphenyl 2 b, p-terphenyl 2 c, naphthyl 2 d, anthracenyl 2 e, or pyrenyl 2 f) have been synthesized to explore the influence of the aromaticity on their anticancer activity. The best performers, 2 b and d, are more active than cisplatin (CDDP) in epithelial ovarian carcinoma cells A2780, with 2 d having a higher selectivity factor than CDDP in all the tested cell lines. In addition, all the new compounds overcome the acquired resistance in A2780cisR cells and interestingly, show low micromolar IC values towards the triple negative breast cancer cell line MDA-MB-231 and the highly metastatic 518A2 melanoma cells. This study shows that the hydrophobicity, accumulation into cells, and metal levels on nuclear DNA for the complexes are consistent with their cytotoxicity. Complexes 2 b and d induce apoptosis in a caspase-independent manner and suppress the intracellular ROS generation without modifying the mitochondria membrane potential. In addition, 2 a-f effectively inhibit angiogenesis in the endothelial cell line EA.hy926 at sub-cytotoxic concentrations and 2 b and d show in vivo antivascular effects on the chorioallantoic membrane (CAM) of fertilized SPF-eggs (SPF=specific-pathogen-free). Inhibition of tubulin polymerization and degeneration of cytoskeleton organization in 518A2 melanoma cells are presented as a preliminary mechanism of its antimetastatic activity.

Benzothiazole‐Based Cycloplatinated Chromophores: Synthetic, Optical, and Biological Studies

“…Recently, a dichloroplatinum(II) complex featuring a 4α‐ O ‐(2′′,3′′‐diaminopropanoyl)podophyllotoxin ligand has been shown to induce cycle arrest in the G 2 /M phase and inhibits the formation of microtubules in Hela cells . In a similar line, the inhibition of tubulin polymerization and the degeneration of the cytoskeleton organization in 518A2 melanoma cells have been also found for N , N ‐dimethyl‐1‐(2‐aryl)methanamine‐κ 2 C 2, N cyclometalated [Pt(C ∧ N)Cl(DMSO)] complexes …”

“…In addition to drugs that alter nuclear DNA integrity, mitostatic molecules that bind to tubulins and disrupt microtubule dynamics are widely used as anticancer drugs based on the key role of microtubules in the formation of the mitotic spindle and cytokinesis . Recently, the capability to inhibit tubulin polymerization and degenerate the cytoskeleton network in 518A2 mellanoma cells of a series of organoplatinum(II) complexes has been evaluated in vivo, thus evidencing that some of these complexes act as vascular disrupting agents . Based on the higher cytotoxic activity shown by complex 1 b and its cytoplasmic localization pattern, we explored the capacity of this complex to destabilize tubulin polymerization by immunostaining microtubules with an antitubulin antibody and analyzing the cytoskeletal morphology in A549 and HeLa cells by means of confocal microscopy.…”

“…[51] Recently,t he capability to inhibitt ubulin polymerization and degenerate the cytoskeleton network in 518A2 mellanoma cells of as eries of organoplatinum(II) complexesh as been evaluated in vivo, thus evidencingt hat some of these complexes act as vascular disrupting agents. [52] Based on the higher cytotoxic activity shown by complex 1b and its cytoplasmic localizationp attern, we explored the capacity of this complex to destabilize tubulin polymerization by immunostaining microtubulesw ith an antitubulin antibodya nd analyzing the cytoskeletal morphologyi nA 549 and HeLa cells by means of confocal microscopy.N ocodazole was used as ap ositive control that destabilizes microtubule polymerization, [53] and nontreated cells as an egative control. The exposure of cells to nocodozale-inducedm icrotubule depolymerization in both cell lines, althoughw ith more efficiency in the A549 cells, led to complete disorganization and depolymerization of the microtubules after 30 min treatment, thus generating rounded cells (Figure 12), as previously reported.…”

“…[56] In as imilarl ine, the inhibition of tubulin polymerization and the degenerationo ft he cytoskeleton organization in 518A2 melanoma cells have been also found for N,N-dimethyl-1-(2-aryl)methanamine-k 2 C2,N cyclometalated [Pt(C 6 N)Cl(DMSO)] complexes. [52]…”

A new parameter of growth inhibition for cell proliferation assays

“…We emphasize that, using these parameters to compare drug efficacy between distinct cell populations (such as cell lines), cells that grow “faster” in culture will be inferred more sensitive than “slower” ones, and therefore these parameters lead to a misinterpretation of the results because of their dependency to the unique growth properties of each cell population. Despite PG partially overcomes this limitation, we provide in the first section of the results a detailed description of the dependency of R , and consequently the IC 50 , to cell proliferation rate because of its frequent usage in current anticancer drug discovery research (as few recent examples (Ben et al, ; Cabrera et al, ; Esposito et al, ; Hamed, Darwish, Herrmann, Abadi, & Engel, ; Indovina et al, ; Koul et al, ; Mathema, Chaijaroenkul, Karbwang, & Na‐Bangchang, ; Menderes et al, ; Mukunthan, Satyan, & Patel, ; Muñoz, Rosso, & Coveñas, ; Potenza et al, ; Ravi, Ramesh, & Pattabhi, ; Rimoldi et al, ; Said, Brouard, Quintana, & Estévez, ; Venkataramana Reddy et al, ; Wehbe et al, ; Zamora et al, ; Zhu et al, )). Subsequently, in the second section of the results, we show that PG is also dependent on the growth properties of the cells, because of their exponential and not linear proliferation in culture.…”