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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
Published on: May 28, 2014
A Pt(IV)-based mononitro-naphthalimide conjugate with minimized side-effects targeting DNA damage response via a
Yingguang Li1, Kexin Yue1, Linrong Li1
1School of Pharmacy, Institute for Innovative Drug Design and Evaluation, Henan University, N. Jinming Ave, 475004 Kaifeng, China.
Abstract:
Platinum(Pt)(II) drugs and new Pt(IV) agents behave the dysregulation of apoptosis as the result of DNA damage repair and thus, are less effective in the treatment of resistant tumors. Herein, mononitro-naphthalimide Pt(IV) complex 10b with minimized side-effects was reported targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance. 10b displayed remarkably evaluated antitumor (70.10%) activities in vivo compared to that of cisplatin (52.88%). The highest fold increase (FI) (5.08) for A549cisR cells and the lowest (0.72) for A549 indicated 10b preferentially accumulated in resistant cell lines. The possible molecular mechanism indicates that 10b targets resistant cells in a totally different way from the existing Pt drugs. The cell accumulation and the Pt levels in genomic DNA from 10b is almost 5 folds higher than that of cisplatin and oxaliplatin, indicating the naphthalimide moiety in 10b exhibits preferentially DNA damage. Using 5'-dGMP as a DNA model, the DNA-binding properties of 10b (1 mM) with 5'-dGMP (3 mM) in the presence of ascorbic acid (5 mM) deduced that 10b was generated by the combination of cisplatin with 5'-dGMP after reduction by ascorbic acid. Moreover, 10b promoted the expression of p53 gene and protein more effectively than cisplatin, leading to the increased anticancer activity. The up-regulated γH2A.X and down-regulated RAD51 indicates that 10b not only induced severe DNA damage but also inhibited the DNA damage repair, thus resulting in its higher cytotoxicity in comparison to that of cisplatin. Their preferential accumulation in cancer cells (SMMC-7721) compared to the matched normal cells (HL-7702 cells) demonstrated that they were potentially safe for clinical therapeutic use. In addition, the higher therapeutic indices of 10b for 4T1 cells in vivo indicated that naphthalimide-Pt(IV) conjugates behaved a vital function in the treatment of breast cancer. For the first time, our study implies a significant strategy for Pt drugs to treat resistance cancer targeting DNA damage repair via dual DNA damage mechanism in a totally new field.
Insights
A novel platinum(IV) complex, 10b, overcomes cisplatin resistance by dual DNA damage, showing superior antitumor activity and preferential accumulation in resistant cancer cells. This platinum drug offers a promising strategy for treating resistant tumors with minimized side effects.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Drug Development
Background:
- Platinum(II) and platinum(IV) drugs are less effective against resistant tumors due to DNA damage repair mechanisms.
- Cisplatin resistance remains a significant challenge in cancer chemotherapy.
Purpose of the Study:
- To develop a novel platinum(IV) complex, 10b, targeting DNA damage response to overcome cisplatin resistance.
- To evaluate the efficacy and mechanism of action of 10b in resistant cancer models.
Main Methods:
- Synthesis and characterization of mononitro-naphthalimide Pt(IV) complex 10b.
- In vivo antitumor activity evaluation and comparison with cisplatin.
- Cellular uptake studies in cisplatin-resistant and sensitive cell lines.
- DNA binding studies using 5'-dGMP and ascorbic acid.
- Analysis of DNA damage and repair markers (p53, γH2A.X, RAD51).
- In vitro and in vivo safety assessments.
Main Results:
- Complex 10b exhibited significantly higher in vivo antitumor activity (70.10%) than cisplatin (52.88%).
- 10b showed preferential accumulation in resistant A549cisR cells (FI=5.08) compared to sensitive A549 cells (FI=0.72).
- 10b demonstrated 5-fold higher cellular and genomic DNA platinum levels than cisplatin and oxaliplatin, indicating enhanced DNA damage.
- 10b promoted p53 expression and induced DNA damage (γH2A.X) while inhibiting repair (RAD51), leading to increased cytotoxicity.
- Preferential accumulation in cancer cells over normal cells and higher therapeutic indices suggest potential safety and efficacy in breast cancer treatment.
Conclusions:
- Mononitro-naphthalimide Pt(IV) complex 10b effectively overcomes cisplatin resistance via a dual DNA damage mechanism.
- 10b exhibits enhanced antitumor activity, preferential targeting of resistant cells, and a favorable safety profile.
- This study presents a novel strategy for developing platinum-based drugs against resistant cancers by targeting DNA damage repair pathways.
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