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  • 5- and 6-membered (thio)lactones are prodrug type carbonic anhydrase inhibitors.

5- and 6-membered (thio)lactones are prodrug type carbonic anhydrase inhibitors.

Bioorganic & medicinal chemistry letters (2011-12-06)
Fabrizio Carta, Alfonso Maresca, Andrea Scozzafava, Claudiu T Supuran
ABSTRACT

The inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) with (thio)coumarins has been recently reported (Maresca et al., J. Am. Chem. Soc. 2009, 131, 3057). Here we demonstrate that a series of γ- and δ-(thio)lactones also act as mechanism based, prodrug type CA inhibitors, similar to the (thio)coumarins. Through the esterase activity of CA, these compounds are hydrolyzed in situ to the corresponding hydroxy/keto/mercapto acids which thereafter act as inhibitors. CA isoforms I and IX were efficiently inhibited by simple such compounds, with K(I)s in the range of 0.92-19.1μM, whereas CA II was not inhibited at all. Isoform-selective CA inhibitors which spare the ubiquitous off-target CA II may have interesting applications for example for selectively inhibiting the tumor-associated CA IX, a validated anticancer target.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
5,6-Dihydro-2H-pyran-2-one, technical grade, 90%
Sigma-Aldrich
2H-Pyran-2-one, 90%
Sigma-Aldrich
δ-Valerolactone, technical grade
Sigma-Aldrich
Coumarin, ≥99% (HPLC)
Sigma-Aldrich
γ-Valerolactone, ≥99%, FCC, FG
Sigma-Aldrich
2(5H)-Furanone, 98%