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HomeChemistryMasking and focused launch of redox-cycling ortho-quinones through a C–C bond-cleaving 1,6-elimination

Masking and focused launch of redox-cycling ortho-quinones through a C–C bond-cleaving 1,6-elimination


Redox-cycling happens as a result of the ortho-quinone is well decreased by mobile enzymes (e.g., NAD(P)H Quinone Oxidoreductase 1, NQO1) however the ensuing ortho-hydroquinone, not like a para-quinone, isn’t steady and auto-oxidises quickly, decreasing oxygen to superoxide. A big enhance in reactive oxygen species and consumption of NAD(P)H reserves promotes mobile disaster.

The cell-killing mechanism of ortho-quinones requires an preliminary enyzmatic discount, which present selective toxicity to most cancers cells overexpressing reductases, reminiscent of NQO1. A notable instance is β-lapachone, a compound derived from the bark of the South American ‘Lapacho’ tree, which was investigated within the early 2000s by the late David Boothman and associates as a ‘Kiss of Demise’ remedy for therapy of NQO1+ strong tumours. Nonetheless, NQO1+ selectivity isn’t adequate, and that is conceivably the explanation why, regardless of excessive curiosity, no ortho-quinone has but reached additional than Section II scientific research. Certainly, the quinone could also be decreased by different reductive enzymes, reminiscent of these at mitochondrial membranes, and it’s difficult to realize adequate doses for efficacy with out harmful haematological side-effects appreciated to the redox mechanism, notably methemoglobinemia.

We initially got interested within the concept of focusing on β-lapachone as a most cancers remedy. We realised {that a} chemical technique to stop redox-cycling in circulation can be key for purposes of any ortho-quinone. We have been struck by the restricted safety methods which might be described for the compounds. For instance, classical methodologies are described that shield the quinone as a hydroquinone ester, an imine or a hydrazone. We imagined that safety of ortho-quinones with a self-immolative benzyl linker may open-up the potential of extra steady protease-cleavable pro-moieties. Comparable techniques have been utilized efficiently for focused therapies of amine- and alcohol- containing medicine through benzyl carbamate and benzyl ether linkers, respectively.

We tried to synthesise O-benzyl hydroquinone derivatives, however we rapidly realised that O-benzyl ortho-hydroquinones are unstable and rearrange to their C-benzyl ketol isomers, as additionally described by Shurygina and associates. As a substitute of discarding the benzyl ketol merchandise we, considerably fortunately (!), determined to analyze their properties. Surprisingly, we noticed that deprotected para-aminobenzyl ketols additionally endure self-immolative elimination, with their C–C bond breaking in a 1,6-elimination to reform the hydroquinone and launch an aza-quinone methide aspect product. This was a brand new technique for ortho-quinone safety.

In our article, we reveal this safety technique with a number of ortho-quinones. The benzyl ketol derivatives are redox-inactive, which is vital for ortho-quinone focused therapies. We carried out modelling to know our outcomes and work out the energetic fragmenting species liable for the elimination. In contrast to para-aminobenzyl ethers, para-aminobenzyl ketols have an acidic rate-pH dependence. The speed-pH dependence is modulated relying on the construction and digital atmosphere of quinone species protected, which may result in future tuning of launch charges and kinetics.

We additionally present how our technique could also be utilized. Dipeptide prodrugs of β-lapachone are cleavable by protease cathepsin B, with drug elimination occurring through the para-aminobenzyl intermediate. Moreover, an antibody-drug conjugate with protected β‑lapachone demonstrated an anti-tumour impact in an in vivo mannequin of acute myeloid leukemia, with β‑lapachone detected in tumour tissue by LC MS/MS, which reveals the potential of the expertise for quinone-tumour focusing on.

With this new safety technique, managed masking of ortho-quinones is now extra viable. We hope that this chemistry that can allow extra purposes of ortho-quinone containing compounds in drugs and different areas.

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