Abstract
SN‐38, the active metabolite of irinotecan, is released upon liver hydrolysis to mediate potent antitumor activity. Systemic exposure to SN‐38, however, also leads to serious side effects. To reduce systemic toxicity by controlling where and when SN‐38 is generated, a new prodrug was specifically designed to be metabolically stable and undergo rapid palladium‐mediated activation. Blocking the phenolic OH of SN‐38 with a 2,6‐bis(propargyloxy)benzyl group led to significant reduction of cytotoxic activity (up to 44‐fold). Anticancer properties were swiftly restored in the presence of heterogeneous palladium (Pd) catalysts to kill colorectal cancer and glioma cells, proving the efficacy of this novel masking strategy for aromatic hydroxyls. Combination with a Pd‐activated 5FU prodrug augmented the antiproliferative potency of the treatment, while displaying no activity in the absence of the Pd source, which illustrates the benefit of achieving controlled release of multiple approved therapeutics—sequentially or simultaneously—by the same bioorthogonal catalyst to increase anticancer activity.
Highlights
Bioorthogonal reactions are designed to take place in cells and organisms without interfering with biological functions.[1]
Building on previous success in the development and bio-independent release of caged drugs with catalyst-loaded devices,[7,8,9,10,11] we report the design, synthesis and screening of a novel class of inactive camptothecin derivatives that are selectively converted into cytotoxic 1 by bioorthogonal Palladium chemistry
Topotecan has lower potency against the HCT116 cell line and, to a lesser extent, U-251 when compared to 1 (Figure 1 c), but the activity gap is not as prominent as in irinotecan, which has greater than 80-fold difference in EC50 (Table S1 in the Supporting Information)
Summary
Bioorthogonal reactions are designed to take place in cells and organisms without interfering with biological functions.[1]. Irinotecan crosses the blood brain barrier[26] and displays high cytotoxic activity against glioblastoma cells with multi-drug resistance to other therapies.[27] In addition, several Phase II clinical trials have reported that the combination of bevacizumab and irinotecan shows promising activity in recurrent malignant glioma with a modest increment in median survival.[28,29,30] The side effects of irinotecan treatments are, a major concern that limits its therapeutic dose and significantly impacts patient’s quality of life To circumvent this issue, the intratumoral implantation of irinotecan-loaded drug-eluting beads has been investigated in patients with recurrent glioblastoma[31] and colorectal liver metastasis.[32] While these treatments are well tolerated, the drug is fully cleared from the organism within hours of implantation, reducing its anticancer effect.[31,32] Of note, irinotecan is an orallybioavailable prodrug that requires enzymatic conversion into its active metabolite SN-38 (1) to reach its full cytotoxic potential (Figure 1 a).[33] glioma cells have been shown to partly metabolize irinotecan, the drug is primarily metabolized into 1 in the liver, from where it distributes throughout the organism. Building on previous success in the development and bio-independent release of caged drugs with catalyst-loaded devices,[7,8,9,10,11] we report the design, synthesis and screening of a novel class of inactive camptothecin derivatives that are selectively converted into cytotoxic 1 by bioorthogonal Palladium chemistry
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