Cleavable conjugates of functionalized platinum-acridine and platinum-benzacridine agents and methods thereof
US9765103B2 · kind B2 · utility
Inventors
Key dates
| Filing date | Jun 22, 2015 |
| Grant date | Sep 19, 2017 |
| Priority date | — |
| Expiry date | Jun 22, 2035 |
Classification
- Technology area (CPC C)Chemistry; Metallurgy
- CPC primaryC07D487/06
- WIPO fieldOrganic fine chemistry
- WIPO sectorChemistry
Abstract
The present invention relates to using a versatile synthetic approach to generate a new class of ester, amido, or carbamate prodrugs of highly potent, but systemically too toxic, platinum-acridine anticancer agents. The new hybrids contain a hydroxyl group, which has been masked with a cleavable lipophilic acyl moiety. Both butanoic (butyric) and bulkier 2-propanepentanoic (valproic) esters were introduced to these compounds. The goal of this design was to improve the drug-like properties of the pharmacophore (e. g., log D) without compromising its DNA-mediated cell kill potential. Two distinct pathways by which the target compounds undergo effective ester hydrolysis, the proposed activating step, have been confirmed: platinum-mediated, self-immolative ester cleavage in a low-chloride environment (LC-ESMS, NMR spectroscopy) and enzymatic cleavage by human carboxylesterase-2 (hCES-2) (LC-ESMS). Several of the new compounds show excellent stability, reduced systemic toxicity, and favorable activation profiles while maintaining submicromolar cytotoxicity in various cancers, such as lung adenocarcinoma cell lines (A549, NCI-H1435). The results suggest that the novel dual-mode prodrug c…
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