New heteronuclear Pt(II)-L-Zn(II) complexes: testing of antitumor activity on colorectal cancer cells, in vitro

[S. A. Vučelj]

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Uvod: Sintetisana je i okarakterisana serija mono- i heteronuklaeranih komleksa platine(II) i cinka(II) sa inertnim ligandom 4,4′,4-tri-tert-butil-2,2′:6′2′′- terpiridinom. Materijal i metode: DNK i protein-vezujuća svojstva [ZnCl2(terpytBu)] (C1), [{cis- PtCl(NH3)2(μ-pirazin)ZnCl(terpytBu)}](ClO4)2 (C2), [{trans-PtCl(NH3)2(μ-pirazine)ZnCl (terpytBu)}](ClO4)2 (C3), [{cis-PtCl(NH3)2(μ-4,4’-bipiridil)ZnCl(terpytBu)}](CIO4)2 (C4), [{trans-PtCl(NH3)2(μ-4,4’-bipiridil)ZnCl(terpytBu)}](CIO4)2 (C5) kompleksa (gde je terpytBu=4,4′,4-tri-tert-butil-2,2′:6′2′′-terpiridin) ispitana su putem elektronske apsorpcije, fluorescencije i metodom molekuluskog dokinga. Antikancerogena aktivnost kompleksa platine(II) i cinka(II) je ispitivana na ćelijskim linijama mišijeg karcinoma kolorektuma, kao i n a zdravoj liniji mezenhimalnih matičnih ćelija miša, korišćenjem MTT testa. Rezultati: Kompleksi koji sadrže transplatinu pokazali su niže vrednosti konstanti Kb i Ksv u poređenju sa cisplatinskim analozima. Najnižu vrednost Ksv imao je kompleks C1, dok je C4 pokazao najvišu. Molekulske doking studije su pokazale da je veza kompleksa C1 sa DNK posledica van der Valsovih sila, dok su veze C2-C5 konvencionalne vodonične veze i van der Valsovih sile. Testirani kompleksi pokazali su varijabilnu citotoksičnost prema mišjem kolorektalnom karcinomu (CT26), ljudskom kolorektalnom karcinomu (HCT116 i SW480) i normalnim mišjim mezenhimalnim matičnim ćelijama (mMSC). Posebno, mononuklearni kompleks C1 pokazao je izraženu selektivnost prema kancerogenim ćelijama u odnosu na nekancerogene mMSC. Kompleks C1 značajno je izazvao apoptozu u CT26 ćelijama, efikasno zaustavio ćelijski ciklus u fazi G0/G1, i selektivno smanjio izražaj ciklina D. Zaključak: Dobijeni rezultati ukazuju da novosintetisani mono- i heteronuklerani komleksi platine(II) i cinka(II) pokazuju antitumorsku aktivnost na tumorskim ćelijama kolorektalnog karcinoma i imaju potencijal da postanu mogući kandidati u antikancerskoj terapiji.

Introduction: A series of mono- and heteronuclear platinum(II) and zinc(II) complexes with 4,4,4-tri-tert-butyl-2,2′:6′,2″-terpyridine ligand were synthesized, and characterized. Material and methods: The DNА and protein binding properties of [ZnCl2(terpytBu)] (C1), [{cis-PtCl(NH3)2(μ-pyrazine)ZnCl(terpytBu)}](ClO4)2 (C2), [{trans-PtCl(NH3)2(μ-pyrazine) ZnCl(terpytBu)}](ClO4)2 (C3), [{cis-PtCl(NH3)2(μ-4,4'-bipyridyl)ZnCl(terpytBu)}](CIO4)2 (C4) and [{trans-PtCl(NH3)2(μ-4,4'-bipyridyl)ZnCl(terpytBu)}](CIO4)2 (C5) (terpytBu = 4,4′,4″-tritert- butyl-2,2′:6′,2″-terpyridine), were investigated by electronic absorption, fluorescence spectroscopic, and molecular docking methods. The in vitro anticancer activity of the complexes was investigated in murine cancer cell lines and a normal murine cell line by MTT assay. Results: Complexes featuring transplatin exhibited a lower Kb and Ksv constant values compared to cisplatin analogues. The lowest Ksv value belonged to complex C1, while C4 exhibited the highest. Molecular docking studies reveal that the binding of complex C1 to DNA is due to van der Waals forces while, that of C2-C5 is due to conventional hydrogen bonds and van der Waals forces. The tested complexes exhibited variable cytotoxicity toward mouse colorectal carcinoma (CT26), human colorectal carcinoma (HCT116 and SW480), and noncancerous mouse mesenchymal stem cells (mMSC). Particularly, mononuclear C1 complex showed pronounced selectivity towards cancer cells over non-cancerous mMSC. The C1 complex notably induced apoptosis in CT26 cells and effectively arrested the cell cycle in the G0/G1 phase and selectively down-regulated Cyclin D. Conclusion: Obtained results indicate that these novel mono- and heteronuclear platinum(II) and zinc(II) complexes revealed activity in colorectal cancer and have the potential to become possible candidates for cancer treatment.

heteronuklaerani komleks; 4,4′,4-tri-tert-butil-2,2′:6′2′′-terpiridin; korelacija struktura-reaktivnost; citotoksična aktivnost; kolonrektalni karcinom

heteronuclear complexes; 4,4′,4′′-tri-tert-butyl-2,2′:6′,2′′-terpyridine; structure– reactivity correlation; cytotoxic activity; colorectal cancers

579(043.3) 616-097(043.3)

karcinom, lečenje

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