A novel bioresponsive self-immolative spacer based on aza-quinone methide reactivity for the controlled release of thiols, phenols, amines, sulfonamides or amides

• Published in: Chemical science (Cambridge) Vol. 15; no. 16; pp. 6168 - 6177
• Main Authors: Ermini, Elena, Brai, Annalaura, Cini, Elena, Finetti, Federica, Giannini, Giuseppe, Padula, Daniele, Paradisi, Lucrezia, Poggialini, Federica, Trabalzini, Lorenza, Tolu, Paola, Taddei, Maurizio
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 24.04.2024; Royal Society of Chemistry; The Royal Society of Chemistry
• Subjects: Alcohols; Alkylation; Amides; Amines; Aqueous environments; Cancer; Carbamates (tradename); Carbonates; Chemistry; Chemistry, Multidisciplinary; Colchicine; Conjugation; Controlled release; Drugs; Functional groups; Hypoxia; Iron; Nanoparticles; Nicotinamide adenine dinucleotide; Phenols; Physical Sciences; Quinones; Science & Technology; Sulfonamides; Thiols; REDUCTIONS; TARGET; AROMATICITY; STRATEGY; ST7612AA1; HYPOXIA; DELIVERY; PROSTAGLANDIN-E2; WATER
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d4sc01576b

A stimuli-sensitive linker is one of the indispensable components of prodrugs for cancer therapy as it covalently binds the drug and releases it upon external stimulation at the tumour site. Quinone methide elimination has been widely used as the key transformation to release drugs based on their nucleofugacity. The usual approach is to bind the drug to the linker as a carbamate and release it as a free amine after a self-immolative 1,6-elimination. Although this approach is very efficient, it is limited to amines (as carbamates), alcohols or phenols (as carbonates) or other acidic functional groups. We report here a self-immolative spacer capable of directly linking and releasing amines, phenols, thiols, sulfonamides and carboxyamides after a reductive stimulus. The spacer is based on the structure of (5-nitro-2-pyrrolyl)methanol (NPYM-OH), which was used for the direct alkylation of the functional groups mentioned above. The spacer is metabolically stable and has three indispensable sites for bioconjugation: the bioresponsive trigger, the conjugated 1,6 self-immolative system and a third arm suitable for conjugation with a carrier or other modifiers. Release was achieved by selective reduction of the nitro group over Fe/Pd nanoparticles (NPs) in a micellar aqueous environment (H 2 O/TPGS-750-M), or by NADH mediated nitroreductase activation. A DFT study demonstrates that, during the 1,6 elimination, the transition state formed from 5-aminopyrrole has a lower activation energy compared to other 5-membered heterocycles or p -aminobenzyl derivatives. The NPYM scaffold was validated by late-stage functionalisation of approved drugs such as celecoxib, colchicine, vorinostat or ciprofloxacin. A hypoxia-activated NPYM-based prodrug (HAP) derived from HDAC inhibitor ST7612AA1 was also produced, which was active in cancer cells under hypoxic conditions. The power of pyrrole: a 1,6-self-immolative spacer designed on the pyrrole structure enables direct late-stage functionalisation of drugs and their traceless release under enzymatic or reductive micellar catalysis in water.