26035-31-4Relevant articles and documents
A Pt(IV)-based mononitro-naphthalimide conjugate with minimized side-effects targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance
Li, Linrong,Li, Yingguang,Liu, Hanfang,Ma, Jing,Niu, Jie,Xie, Songqiang,Yue, Kexin
, (2020/07/03)
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 (70.10percent) activities in vivo compared to that of cisplatin (52.88percent). 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.
trans-Platinum(iv) pro-drugs that exhibit unusual resistance to reduction by endogenous reductants and blood serum but are rapidly activated inside cells:1H NMR and XANES spectroscopy study
Chen, Catherine K. J.,Gibson, Dan,Hambley, Trevor W.,Kappen, Peter
supporting information, p. 7722 - 7736 (2020/06/26)
Recent results have confirmed that protection of transplatin from reactions on the path to cancer cells substantially increases their activity, suggesting that such complexes have greater potential than previously thought. In this study we have investigated the use of the platinum(iv) oxidation state and the tetracarboxylate coordination sphere to determine whether these features could impart the same stability totrans-diammineplatinum complexes that they do tocis-diam(m)ineplatinum complexes. Theciscomplexes exhibit resistance to reduction byl-ascorbate and human blood serum, but are readily reduced inside cancer cells. Studies of reduction monitored by1H NMR revealed that oxidation oftrans-diammineplatinum(ii) complexes does not always result in significant stabilisation, but the complexestrans, trans, trans-[Pt(OAc)4(NH3)2] (OAc = acetate) andtrans, trans, trans-[Pt(OPr)2(OAc)2(NH3)2] (OPr = propionate) exhibit second order half-lives of 33 h and 5.9 days respectively in the presence of a ten-fold excess ofl-ascorbate. XANES spectroscopy studies of reduction in blood models showed thattrans, trans, trans-[Pt(OAc)4(NH3)2] is stable in blood serum for at least 24 hours, but is reduced rapidly in whole blood and was observed to have a half-life of approximately 4 hours in DLD-1 colon cancer cells. Consequently, the tetracarboxylatoplatinum(iv) moiety has the properties required to enable the delivery oftrans-diammine platinum complexes to cancer cells.
Development of an Efficient Dual-Action GST-Inhibiting Anticancer Platinum(IV) Prodrug
Lee, Keefe Guang Zhi,Babak, Maria V.,Weiss, Andrea,Dyson, Paul J.,Nowak-Sliwinska, Patrycja,Montagner, Diego,Ang, Wee Han
, p. 1210 - 1217 (2018/06/04)
The cytotoxicity of cisplatin (cDDP) is enhanced when co-administered with ethacrynic acid (EA), a glutathione S-transferase (GST) inhibitor. A PtIV–EA conjugate containing a cDDP core and two axial ethacrynate ligands (compound 1) was shown to be an excellent inhibitor of GST, but did not readily release a PtII species to exert a synergistic cytotoxic effect. In this study, a redesigned PtIV construct composed of a cDDP core with one axial ethacrynate ligand and one axial hydroxido ligand (compound 2) was prepared and shown to overcome the limitations of compound 1. The EA ligand in 2 is readily released in vitro together with a cytotoxic PtII species derived from cisplatin, working together to inhibit cell proliferation in cDDP-resistant human ovarian cancer cells. The in vitro activity translates well in vivo with 2, showing effective (～80 %) inhibition of tumor growth in a human ovarian carcinoma A2780 tumor model, while showing considerably lower toxicity than cisplatin, thus validating the new design strategy.
