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Updated: May 21, 2025
Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
Published on: May 28, 2014
The anti-neoplastic potency of epoxy-substituted polyaromatic platinum(II) and platinum(IV) complexes against A549
Rouba Al Sayegh1, Aleen Khoury2, Maria George Elias3
1School of Arts and Sciences, Natural Sciences Department, Lebanese American University, Byblos, Mount Lebanon, Lebanon.
Abstract:
A novel platinum(II) complex, PtII56OSS, coordinated to 5,6-epoxy-5,6-dihydro-1,10-phenanthroline and its platinum(IV) di-hydroxido derivative (PtIV56OSS) were synthesized and successfully characterised via NMR spectroscopy, HPLC, ESI-MS, UV, and CD spectroscopy. The cytotoxic activity of PtII56OSS and PtIV56OSS against A549, A375 and MDA-MB-231 cancer cells was investigated, and the results showed that both complexes exhibit dose dependent growth inhibition against all three cancer cell lines. In addition, PtIV56OSS displayed significantly less toxicity against mesenchymal cells (MCs; >100 microM) compared to both PtII56OSS (6.5 microM) and cisplatin (2.0 microM). A Dose Escalation Study on Balb/c mice showed that the most tolerated dose (MTD) for PtII56OSS and PtIV56OSS were 140 and 200 mg/kg.b.w., respectively (which were ∼23-fold and 33-fold more tolerated than cisplatin). Cellular uptake experiments in A549 cells after 1, 3, 6, 12, 24 and 30 h of incubation, showed that both complexes are actively transported into the cells with PtII56OSS exhibiting a similar uptake rate to cisplatin and approximately a 3-fold higher uptake than PtIV56OSS. Intracellular distribution showed that while PtII56OSS resides primarily in the Cytoplasmic Fraction) while (CF), the PtIV56OSS resides heavily in the nucleus and cytoskeleton (NC) fraction. A549 cells treated with PtII56OSS and PtIV56OSS also showed a significant increase in the production of cellular ROS at all-time points (24, 48 and 72 h). Flow cytometry results demonstrated that PtII56OSS and PtIV56OSS caused significant increase in apoptotic cell death. Western blot assays exhibited an upregulation of cytochrome c, cleaved Parp, and the ratio of Bax/Bcl-2 when A549 cells were treated with either PtII56OSS and PtIV56OSS. These results distinguish PtII56OSS and PtIV56OSS as promising candidates for further investigation both in vitro and in vivo against several cancer models with the platinum(IV) analogue showing more promise due to its low cytotoxicity against normal cells coupled with its high in vivo tolerability.
