Ein Organoruthenium‐Tumortherapeutikum mit unerwartet hoher Selektivität für Plectin

Abstract

Metallorganische Tumortherapeutika werden durch Ligandenaustauscha ktiviert, und es wird gemeinhin angenommen, dass die resultierenden aktivierten Spezies geringe Selektivitätf ürp otenzielle zelluläre Ziele zeigen.D urche in Proteomik-basiertes Ziel-Antwort-Profiling konnte jedoch nachgewiesen werden, dass ein Ruthenium-Aren-Pyridincarbothioamid (Plecstatin) eine unerwartet hohe Selektivitätf ür Plectin, ein Strukturprotein und Vernetzer des Zytoskeletts, zeigt, was in einem Plectin-Knock-out-Modell in vitro validiert wurde.I nS phäroidkulturen konnte gezeigt werden, dass die gezielten Wechselwirkungen mit Plectin das Potenzial haben, den invasiven Charakter von Tumoren zu inhibieren. Nach oraler Gabe wirkte Plecstatin-1 im invasiven B16-Melanom stärker tumorinhibierend als im CT-26-Kolonkarzinom-Tumormodell.

Organoruthenium and Organoosmium Complexes of 2‐Pyridinecarbothioamides Functionalized with a Sulfonamide Motif: Synthesis, Cytotoxicity and Biomolecule Interactions

“…The Ru–cym and Os–cym complexes were inactive in all tested cancer cell lines. This is surprising given the fact that plecstatin‐1 and other related derivatives were highly cytotoxic (Table ) . The low potency might be related to the comparatively low lipophilicity of ligand 1 (clog P =0.92) as compared to the N ‐(4‐fluorophenyl)pyridine‐2‐carbothioamide (F‐SN) ligand in Plecstatin‐1 (clog P =2.88), possibly interfering with efficient accumulation in cancer cells.…”

“…This is surprising given the fact that plecstatin-1a nd other relatedderivatives were highly cytotoxic ( Table 2). [25,27,28] The low potency might be relatedt ot he comparatively low lipophilicity of ligand 1 (clogP = 0.92) as comparedt ot he N-(4-fluorophenyl)pyridine-2-carbothioamide (F-SN) ligand in Plecstatin-1 (clogP = 2.88), [27] possibly interfering with efficient accumulation in cancerc ells. Another explanation might be that the sulfonamide substituent hinders the interaction of the complex with plectin, which was identified as the targetf or plecstatin-1.…”

“…Another explanation might be that the sulfonamide substituent hinders the interaction of the complex with plectin, which was identified as the targetf or plecstatin-1. [28]…”

“…[24] We have recently developed organometallic anticancer complexes of 2-pyridinecarbothioamide (PCA) ligands. [25][26][27][28][29] The Ru complex, termed plecstatin-1, demonstrated target selectivity for plectin in an invasive B16 melanoma tumor model. [28] Herein, we report the functionalization of the PCAs caffold with the sulfonamide pharmacophore and its coordination to Ru II /Os II -cym (cym = h 6 -p-cymene) organometallics.…”

“…[25][26][27][28][29] The Ru complex, termed plecstatin-1, demonstrated target selectivity for plectin in an invasive B16 melanoma tumor model. [28] Herein, we report the functionalization of the PCAs caffold with the sulfonamide pharmacophore and its coordination to Ru II /Os II -cym (cym = h 6 -p-cymene) organometallics. The compounds weree valuated for their potential tumor inhibition against ap anel of human cancer cell lines and their stability in solution,a sw ell as their reactivity toward small biomolecules.…”