One concept of improving anticancer effects of conventional platinum-based antitumor drugs consists of conjugating these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, physicochemical characterization, biological effects, and mechanisms of action of four new analogs of conventional cisplatin, namely, cis-Pt(II) complexes containing either methyl or ethyl pyrazole N-donor ligands and chlorido or iodido ligands. It is noteworthy that while chlorido complexes display activity in a variety of cancer cell lines comparable to cisplatin, iodido complexes are considerably more potent due to their enhanced hydrophobicity and consequently enhanced cellular accumulation. Moreover, all of the studied Pt(II) alkylpyrazole complexes display a higher selectivity for tumor cells and effectively overcome the acquired resistance to cisplatin. Further results focused on the mechanism of action of the studied complexes and showed that in contrast to cisplatin and several platinum-based antitumor drugs, DNA damage by the investigated Pt(II)-alkylpyrazole complexes does not play a major role in their mechanism of action. Our findings demonstrate that inhibition of the tubulin kinesin Eg5, which is essential for forming a functional mitotic spindle, plays an important role in their mechanism of antiproliferative action.

• Publikační typ
• časopisecké články MeSH

4-Azaindole (1H-pyrrolo[3,2-b]pyridine; 4aza) and its N1-alkylated derivative N1-isopropyl-4-azaindole (1-(propan-2-yl)-1H-pyrrolo[3,2-b]pyridine; ip4aza) have been used for the preparation of the cis-diiodido-platinum(II) complexes cis-[Pt(4aza)2I2] (1), cis-[PtI2(ip4aza)2] (2), cis-[Pt(4aza)I2(NH3)] (3) and cis-[PtI2(ip4aza)(NH3)] (4). The prepared complexes were thoroughly characterized (e.g., multinuclear NMR spectroscopy and ESI mass spectrometry) and their in vitro cytotoxicity was assessed at human ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R) and colon carcinoma (HT-29) cell lines, where they showed, in some cases, significantly higher activity than the used reference-drug cisplatin. The results of in vitro cytotoxicity testing at the A2780 and A2780R cells indicated that alkylation of the 4-azaindole moiety at the position of the N1 atom had a positive biological effect, because the ip4aza-containing complexes 2 and 4 showed significantly (p < 0.005) higher cytotoxicity than 4aza-containing analogues 1 and 3. The resistance factors (A2780R/A2780 model) equalled 0.8-1.4, indicating the ability of complexes 1-4 to overcome the acquired resistance of the A2780 cells against cisplatin. Complexes 1 and 2 revealed low toxicity against primary culture of human hepatocytes. The flow cytometry studies of the A2780 cell cycle modification showed that complexes 1-4 induce different cell cycle perturbations as compared with cisplatin, thus suggesting a different mechanism of their antitumor action.

• Klíčová slova
• 4-Azaindole, Cytotoxicity, In vitro, Iodido, Platinum(II) complexes,
• MeSH
• buněčný cyklus účinky léků   MeSH
• hydrofobní a hydrofilní interakce MeSH
• indoly chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buňky kultivované MeSH
• organoplatinové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 4-azaindole MeSH Prohlížeč
• indoly MeSH
• organoplatinové sloučeniny MeSH
• protinádorové látky MeSH