Ptxplatin: a multifunctional Pt(iv) antitumor prodrug

Abstract

A series of Pt(IV) prodrugs containing a microtubule inhibitor paclitaxel (PTX) were synthesized, characterized and antitumor activity evaluated. The prodrugs 5-12 exhibited the most potent antitumor activity against the tested...

Novel Indole–Chalcone Derivative-Ligated Platinum(IV) Prodrugs Attenuate Cisplatin Resistance in Lung Cancer through ROS/ER Stress and Mitochondrial Dysfunction

“…17,18 ER stress occurs when unfolded or misfolded proteins accumulate and overwhelm the ER's capacity for protein folding. 19 Under normal physiological conditions, moderate ER stress normally promotes cell survival at a low level. 20 However, if induced in excess, severe ER stress can initiate apoptosis to remove unwanted cells.…”

“…The endoplasmic reticulum (ER) modifies secreted proteins and regulates their traffic and cellular response to stress and intracellular homeostasis. , ER stress occurs when unfolded or misfolded proteins accumulate and overwhelm the ER’s capacity for protein folding . Under normal physiological conditions, moderate ER stress normally promotes cell survival at a low level .…”

Novel NF-κB Inhibitor-Conjugated Pt(IV) Prodrug to Enable Cancer Therapy through ROS/ER Stress and Mitochondrial Dysfunction and Overcome Multidrug Resistance

“…It is commonly believed that Pt(IV) complexes are usually investigated as prodrugs because they could be significantly reduced to corresponding Pt(II) drugs, resulting in cell apoptosis or cell death in the presence of overexpressed reductants, such as glutathione (GSH) or ascorbic acid (AsA), respectively. , To simulate the intracellular environment, the reduction behavior of complex 9 was investigated by incubating it with the superfluous reductant AsA (5.0 equiv) at 37 °C in the dark and monitoring via RP-HPLC. The results in Figures S1–S3 indicate that the retention times of standards AsA, 6 , and complex 9 were 2.21, 9.60, and 7.00 min, respectively.…”

Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance

“…18 More importantly, the two axial ligands introduced in platinum(IV) complexes could be used to promote tumor-targeting ability or bioavailability and enhance cellular uptake, respectively. 19,20 Therefore, multifunctional platinum(IV) complexes are an effective strategy to enhance antitumor efficacy, overcome the drug resistance, and reduce the side effects of the conventional platinum(II)-based drugs because of the different mechanism of antitumor action. For example, multifunctional platinum(IV) complexes (Figure 1), such as CX-4945-platinum(IV), 21 chalcone-platinum(IV), 22,23 chlorambucil-platinum(IV), 24 BBI-608-platinum(IV), 25 pterostilbene-platinum(IV), 26 evodiamine-platinum(IV), 27 fenofibric acid-platinum(IV), 28 ketoprofen-platinum(IV), 29 platinum(IV), 30 and so on, not only displayed stronger antitumor activity than that of cisplatin both in vitro and in vivo but also exhibited low toxicity toward normal tissue in cisplatin-sensitive or -resistant tumor xenograft models.…”

“…Recently, in order to overcome the shortcomings and improve the curative effect, increasing attention has been paid to platinum(IV) complexes as potential antitumor agents. − It is widely believed that platinum(IV) complexes are often considered as prodrugs because they could be effectively converted to the cytotoxic platinum(II) component through bioreduction in the presence of intracellular reductants. − Furthermore, platinum(IV) complexes are more stable kinetically than that of platinum(II)-based drugs owing to the low-spin d 6 octahedral geometry center, preventing many side reactions with biological substances before attacking DNA double strands . More importantly, the two axial ligands introduced in platinum(IV) complexes could be used to promote tumor-targeting ability or bioavailability and enhance cellular uptake, respectively. , Therefore, multifunctional platinum(IV) complexes are an effective strategy to enhance antitumor efficacy, overcome the drug resistance, and reduce the side effects of the conventional platinum(II)-based drugs because of the different mechanism of antitumor action. For example, multifunctional platinum(IV) complexes (Figure ), such as CX-4945-platinum(IV), chalcone-platinum(IV), , chlorambucil-platinum(IV), BBI-608-platinum(IV), pterostilbene-platinum(IV), evodiamine-platinum(IV), fenofibric acid-platinum(IV), ketoprofen-platinum(IV), PARPis-platinum(IV), and so on, not only displayed stronger antitumor activity than that of cisplatin both in vitro and in vivo but also exhibited low toxicity toward normal tissue in cisplatin-sensitive or -resistant tumor xenograft models.…”