Discovery of Platinum^IV–Artesunate Multiaction Prodrugs as Potent Antitumor and Antimalarial Agents

Abstract

Recently, artemisinin and derivatives have been revealed to possess encouraging antitumor activity. Herein, we integrated the antitumor advantages of artesunate and platinum drugs to construct novel Pt IV −artesunate dual-action and tripleaction complexes. Most derivatives, especially 10f, displayed broadspectrum and potent in vitro antitumor activities against a number of cancer cell lines. Compound 10f displayed potent antimetastasis and anticlonogenic activities, efficiently induced autophagic cell death and apoptosis, and arrested the cell cycle at both S and G2/M phases. More importantly, it displayed remarkable in vivo antitumor efficacy in the A549 xenograft model (TGI = 53.4%; 6 μmol/kg) with low toxicity. In addition to the antitumor application, 10f showed potent in vivo antimalarial activity in malarial-infected mice model and obviously alleviated malarial-related multiorgan injury. This conjugation greatly improved safety, especially reducing the platinum drugs' nephrotoxicity. Taken together, this study highlighted the therapeutic potential of Pt IV −artesunate complexes as antitumor and antimalarial agents.

Discovery of Novel p53-MDM2 Inhibitor (RG7388)-Conjugated PlatinumIV Complexes as Potent Antitumor Agents

“…CDDP treatment notably arrested the cell cycle at the S phase (56.55%). RG7388-treated cells showed modest increases in the G0/G1 (51.4%) and G2/M phase ratios (37.75%), consistent with the reported MDM2 inhibitors. ,, In the group treated with 5a , the percentage of cells in the S phase was 49.21%, similar to that of the CDDP group, while 5a also effectively hindered cells at the G2/M phase with a ratio of 34.39%. These findings reveal the remarkable ability of 5a , combining the effects of CDDP and RG7388, to arrest the cell cycle of A549 cells in the S and G2/M phases.…”

“…RG7388 was attached at one axial position of Pt IV -RG7388 complexes, and an innocent group (hydroxyl or ester side chain), RG7388, or naproxen (a representative nonsteroidal anti-inflammatory drug) was attached at the second axial position to construct dual-action or triple-action prodrugs. According to our previous report, 50 CDDP was reacted with 30% hydrogen peroxide to afford Pt IV oxoplatin (3). Using TBTU and Et 3 N as the coupling reagent, oxoplatin (3) was reacted with RG7388 to afford compound 4a bearing one RG7388 moiety and compound 4b bearing two RG7388 moieties at the axial positions.…”

“…Oxoplatin ( 3 ) was obtained as a yellow solid according to our previous report . RG7388 (60 mg, 0.096 mmol), oxoplatin (33 mg, 0.096 mmol), TBTU (39 mg, 0.125 mmol), and triethylamine (12.6 mg, 0.126 mmol) were added to 3 mL of DMF, and the mixture was stirred at room temperature overnight.…”

“…commonly considered to be more stable than platinum(II) drugs in the bloodstream and can be reduced within the reduction environment inside cancer cells to release platinum-(II) drugs and bioactive molecules. 50 To investigate the stability, compound 5a was dissolved in a phosphate-buffered saline (PBS, 100 mM, pH 7.4) solution or cell culture medium (RPMI 1640 medium with fetal calf serum) at 37 °C in the presence or absence of ascorbic acid (1 mM) to calculate the half-life (t 1/2 ) using reverse phase high-performance liquid chromatography (RP-HPLC) (Figure 2). RG7388 was used to match the peak exhibited by 5a under reduction.…”

Series of Desloratadine Platinum(IV) Hybrids Displaying Potent Antimetastatic Competence by Inhibiting Epithelial–Mesenchymal Transition and Arousing Immune Response

“…Platinum­(II) drugs as the cornerstone of chemotherapies display fascinating antitumor performance in clinics by inducing serious DNA lesions. , Nevertheless, their effectiveness against metastatic cancers was rather plagued by severe side effects, drug resistance, and the immune suppressive TME. − The exploration of multifunctional platinum­(IV) hybrids by incorporating diverse functional ligands supplies a promising strategy to discover novel antimetastatic platinum drugs. − Inspired by these observations, DLT was incorporated into the platinum­(IV) system for the first time in this work with the aim of exploring novel platinum drugs with potent antiproliferative and antimetastatic properties.…”