Synthesis, computational studies and assessment of in vitro inhibitory activity of umbelliferon-based compounds against tumour-associated carbonic anhydrase isoforms IX and XII

Abstract

Coumarins are widely diffused secondary metabolites possessing a plethora of biological activities. It has been established that coumarins represent a peculiar class of human carbonic anhydrase (hCA) inhibitors having a distinct mechanism of action involving a non-classical binding with amino acid residues paving the entrance of hCA catalytic site. Herein, we report the synthesis of a small series of new coumarin derivatives 7-11, 15, 17 prepared via classical Pechmann condensation starting from resorcinol derivatives and suitable b-ketoesters. The evaluation of inhibitory activity revealed that these compounds possessed nanomolar affinity and high selectivity towards tumour-associated hCA IX and XII over cytosolic hCA I and hCA II isoforms. To investigate the binding mode of these new coumarin-inspired inhibitors, the most active compounds 10 and 17 were docked within hCA XII catalytic cleft.

Selective inhibition of carbonic anhydrase IX and XII by coumarin and psoralen derivatives

“…On the contrary, all of them are submicromolar inhibitors of the hCA membrane isoforms IX and XII. This behaviour is in agreement with our previous findings and with the generally observed selectivity profile of coumarin derivatives 32 , 33 , 35 , 37 , 38 , 63 .…”

2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases

“…As aforementioned, CAs can also exert an esterase activity; the water molecule coordinated to the Zn 2+ ion is activated by the metal, thus allowing it to act as a strong nucleophile 56 . Upon hydrolysis of the lactone functionality 39 , the corresponding 2-hydroxycinnamic acid might be isomerised to the most stable E -configuration, depending on the sterical hindrance of the substituents on the coumarin core ( Scheme 4 ).…”

Synthesis and biological evaluation of coumarin‐thiazole hybrids as selective carbonic anhydrase IX and XII inhibitors

“…[9,10] After Supuran and coworkers reported coumarins as novel suicidal inhibitors of CA, especially CAs IX and XII, [11,12] several groups including ours have worked on the development of selective and potent inhibitors of both these isoforms. [13][14][15][16][17] The five-membered heterocycle, 1,3-thiazole as well as its derivatives have also shown a multitude of biological profiles like antitumor activity, anti-inflammatory activity, anticonvulsant activity, antibacterial activity, and antifungal activity. [18] Several hCAs, including hCAs IX and XII, have also been found to be effectively inhibited by compounds incorporating the 1,3-thiazole moiety.…”