Fuplatin: An Efficient and Low-Toxic Dual-Prodrug

Abstract

As FDA-approved chemotherapeutic agents, cisplatin, oxaliplatin, and 5-fluorouracil are widely used in clinic but limited by severe side-effects. To ameliorate their respective defects, a series of "dual-prodrug" by linking oxoplatin and 5-FU were designed and synthesized. The assembled compounds 10−17, named Fuplatin, exhibited much higher cytotoxicity against the tested cancer cells while lower cytotoxicity toward the human normal lung cells than free drugs or their combinations. Among them, 14 enhanced cellular accumulation with 62-and 825-fold amount of oxaliplatin and 8 at 9 h, respectively, significantly induced DNA damage and cell apoptosis, and inhibited migration and invasion in HCT-116 cells. Compound 14 arrested the cell cycle at S and G2 phases and up-regulated thymidylate synthase and p53, consistent with the results of the combination, suggesting 14 adopted a collaborative mode of 5-FU and oxaliplatin to kill cancer cells. In vivo, compound 14 showed high antitumor effect and no observable toxicity in NOD/SCID mice bearing HCT-116 tumors.

Novel mutual prodrug of 5-fluorouracil and heme oxygenase-1 inhibitor (5-FU/HO-1 hybrid): design and preliminary in vitro evaluation

“…The imidazole-based derivative 1 reacted with succinic anhydride under basic condition to give 4–(1-(3-bromophenyl)-2-(1 H -imidazol-1-yl)ethoxy)-4-oxobutanoic acid ( 2 ). Intermediate 2 was then coupled with 1-hydroxymethyl-5-fluorouracil, which was prepared based on a known method 35 , and using EDC·HCl as a carboxylic acid activator and DMAP as a catalyst 36 .…”

Mutual Prodrugs of 5‐Fluorouracil: From a Classic Chemotherapeutic Agent to Novel Potential Anticancer Drugs

“…Platinum (IV) compounds showed desirable properties in comparison with platinum (II) drugs because the two additional axial ligands in platinum (IV) complexes, which are released on reduction in cancer tissues, and may provide several pharmacokinetic advantages, such as kinetic stability, lipophilicity, tumor‐targeting or synergistic effect [70] . In an effort to overcome the pharmacokinetic limits of oxaliplatin in combination with 5‐FU, a series of platinum (IV)/5‐FU codrugs have been synthesized and evaluated in vitro and in vivo [71] . The chemical structures of the potential low‐toxic mutual prodrugs 11 a – d, 12 a – d , named fuplatin, are shown in Figure 5.…”

Cyanide Bridged Platinum‐Iron Complexes as Cisplatin Prodrug Systems: Design and Computational Study

“…Cisplatin is a venerable and mature anticancer agent [1] included in the list of essential medications by the world health organization, and is still the most administered anticancer agent of all the clinical chemotherapeutic drugs [2] . Therefore, research efforts to find new and improved anti cancer active agents based on platinum remain intense [3–8] . The widely accepted mechanism of the cisplatin functionality that leads to apoptotic cell death is through cross linking of the DNA base pair by binding to guanine bases [4,9,10] …”

“…Insight gained by computational investigations inspires new strategies and methods addressing the structure, reactivity and mechanism of various novel drug or prodrug molecules [3,8,18] . More recently, several prodrug molecules based on Pt(IV) centers were designed to present a dual‐threat mechanism where upon reduction cisplatin and additional biologically active ligands are released [5,20–22] …”