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Design, Synthesis, and Evaluation of Prodrug–Payloads for the Targeted Delivery of Platinum–Acridine Anticancer Agents

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title
Design, Synthesis, and Evaluation of Prodrug–Payloads for the Targeted Delivery of Platinum–Acridine Anticancer Agents
author
Chen, Jiangxue
abstract
Platinum-acridines (PAs) are a class of DNA-targeted hybrid anticancer agents used to treat cancers that do not respond well to conventional chemotherapies. Cell culture and animal studies indicate that PAs show potent activity at low-nanomolar concentrations in various solid tumors but show suboptimal pharmacological properties in vivo. The goal of the research described in this thesis was to design ADC payloads of platinum acridine anticancer agents for targeted antigen-specific delivery to tumor tissue. Chemically robust, azide-modified Pt(IV) analogues of PAs were designed that are compatible with efficient strain-promoted azide-alkyne cycloaddition (SPAAC) approach/click chemistry and allow the introduction of thiol-reactive linkers. Several payloads of the most cytotoxic analog, [PtCl(pn)(N-(2-(acridin-9-ylamino)ethyl)-N-methylacetimidamide)(NO3)2 (Compound 1, P8-A1, pn = 1,3-diaminopropane) were synthesized and fully characterized. In pH neutral aqueous media, the conjugates are highly stable but undergo rapid and complete reduction in less than 30 minutes in the presence of sodium ascorbate to release the intact, active Pt(II) form of the prodrug. Preliminary data from model reactions is presented, demonstrating that the payloads are (i) compatible with maleimide-thiol bioconjugation, (ii) exquisitely stable under conditions mimicking circulation, and (iii) reductively activatable to trigger release of P8-A1. Confocal microscopy experiments were designed to demonstrate intracellular reduction using a fluorescently labeled Pt(IV) prodrug derivative. PA prodrug-payloads may open new strategies for targeting aggressive cancers susceptible to the unique DNA damage caused by PAs.
subject
Antibody Drug Conjugates
Anticancer Agents
Click Chemistry
Platinum(IV) Prodrugs
Platinum–Acridine
Prodrug–Payloads
contributor
Bierbach , Ulrich (committee chair)
Alexander , Rebecca W. (committee member)
Hinze , Willie L. (committee member)
date
2022-01-15T09:35:37Z (accessioned)
2024-01-14T09:30:05Z (available)
2021 (issued)
degree
Chemistry (discipline)
embargo
2024-01-14 (terms)
identifier
http://hdl.handle.net/10339/99398 (uri)
language
en (iso)
publisher
Wake Forest University
type
Thesis

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