Stimuli-Responsive Prodrug Linkers That Simultaneously Release Cargo and Neutralize In Situ Generated (Aza)Quinone...

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Chemical Biology

Background:

• Self-immolative linkers, such as p-amino/hydroxy-benzyloxycarbonyl (PABC/PHBC) spacers, are crucial in prodrug design.
• A major limitation is the generation of reactive (aza)quinone methide byproducts, posing potential toxicity risks.

Purpose of the Study:

• To develop a novel tripartite prodrug strategy that integrates a self-quenching mechanism for (aza)quinone methide byproducts.
• To create prodrugs with tunable triggers and a PABC/PHBC-type self-immolative spacer containing an integrated nucleophile.

Main Methods:

• Synthesis of novel tripartite prodrugs with diverse triggers (nitro, amide, azide, boronate) and a nucleophile-integrated self-immolative spacer.
• Activation of prodrugs via reductive, hydrolytic, or oxidative stimuli.
• Analysis of the self-quenching mechanism and the resulting tetrahydroisoquinolines (THIQs).

Main Results:

• The integrated nucleophile effectively quenched the reactive (aza)quinone methide, forming stable tetrahydroisoquinolines (THIQs).
• One synthesized THIQ derivative showed no anti-proliferative effects on the A431 mammalian tumor cell line.
• The prodrug strategy demonstrated broad scope, accommodating various triggers and drug/cargo attachments.

Conclusions:

• This new prodrug strategy provides a method to mitigate the toxicity associated with (aza)quinone methide intermediates in self-immolative systems.
• The approach offers versatility in designing prodrugs and antibody-drug conjugates by allowing trigger-specific activation and diverse cargo conjugation.
• The developed linker strategy represents a significant advancement for chemical biology probes and therapeutic delivery systems.