Are Pt(IV) Prodrugs That Release Combretastatin A4 True Multi-action Prodrugs?

Abstract

Metrics & MoreArticle Recommendations * sı Supporting Information ABSTRACT: "Multi-action" Pt(IV) derivatives of cisplatin with combretastatin A4 (CA4) bioactive ligands that are conjugated to Pt(IV) by carbonate are unique because the ligand (IC 50 < 10 nM) is dramatically 1000-folds more cytotoxic than cisplatin in vitro. The Pt(IV)-CA4 prodrugs were as cytotoxic as CA4 itself, indicating that the platinum moiety probably plays an insignificant role in triggering cytotoxicity, suggesting that the Pt(IV)-CA4 complexes act as prodrugs for CA4 rather than as true multi-action prodrugs. In vivo tests (Lewis lung carcinoma) show that ctc-[Pt(NH 3 ) 2 (PhB)(CA4)Cl 2 ] inhibited tumor growth by 93% compared to CA4 (67%), cisplatin (84%), and 1:1:1 cisplatin/CA4/PhB (85%) while displaying <5% body weight loss compared to cisplatin (20%) or CA4 (10%). In this case, and perhaps with other extremely potent bioactive ligands, platinum(IV) acts merely as a self-immolative carrier triggered by reduction in the cancer cell with only a minor contribution to cytotoxicity.

Metallodrugs in cancer nanomedicine

“…This has for instance been observed for some Pt( iv ) derivatives with combretastatin A4 bioactive ligands, where the metal was a thousand fold less cytotoxic than the organic moiety. 371 This, and the usually complex synthesis, overall limits the efficacy and clinical translation of multi-action complexes. By employing nanocarriers for combination therapies, these challenges can be addressed to some extent.…”

Stimuli-responsive platinum and ruthenium complexes for lung cancer therapy

“…Combretastatin A-4 (CA4), an tubulin polymerization inhibitor that exhibits dramatically 1000-folds more cytotoxic than cisplatin, was conjugated with Pt(IV) ( 14 ). CA4 showed higher cytotoxicity than Pt(IV)-CA4 conjugates in vitro , while in vivo test showed that Pt(IV)-CA4 conjugates exhibited significantly enhanced tumor suppression and reduced acute toxicity (weight loss) in LLC-bearing mice ( Schmidt et al, 2021 ). Pt(IV)-bioactive ligand conjugates usually exerted synergistic anticancer activity via multi-action.…”

Pt(IV) Prodrug as a Potential Antitumor Agent with APE1 Inhibitory Activity

“…1 H NMR (400 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 6.55−5.92 (m, 6H). 13 Commercial Compounds. Cisplatin (S1166) and CRT0044876 (S7449) were purchased from Selleck Co., Ltd.…”

“…1 H NMR (600 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 8.19 (dd, J = 19.6, 7.9 Hz, 2H), 7.30 (t, J = 7.9 Hz, 1H), 7.16 (s, 1H), 6.23−5.92 (m, 6H) 13. C NMR (101 MHz, DMSOd 6 ) δ 167.69, 135.11, 133.22, 131.61, 131.28, 128.62, 121.36, 120.27, 107.10.…”