Abstract
In this study a novel silicon(iv) phthalocyanine bearing [(2E)-3-[4-(dimethylamino)phenyl]-1-(4-phenoxy)prop-2-en-1-one] group and its quaternized derivative at their axial positions were synthesized for the first time. Axially disubstituted silicon(iv) phthalocyanines were also characterized by various spectroscopic techniques. The inhibition of two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II, with axially disubstituted silicon phthalocyanines and their quaternized derivatives were investigated by using the esterase assay, with 4-nitrophenyl acetate as substrate. Silicon phthalocyanines ZM-1-Si, ZM-5-Si, ZT-Si and their quaternized derivatives ZM-1-SiQ, ZM-5-SiQ, ZT-SiQ showed IC50 values in the range of 0.0178–0.1653 μM for hCA I and of 0.0172–0.1212 μM against hCA II, respectively. This study is the first example of carbonic anhydrase enzyme inhibition of phthalocyanines.
Highlights
IntroductionCarbonic anhydrase (EC 4.2.1.1, CA) is a metalloenzymes family that catalyzes the rapid conversion of CO2 to HCO3À and H+.1 CA isoforms are found in a variety of tissues where they participate in several important biological processes such as acid–base balance, respiration, carbon dioxide and ion transport, bone resorption, ureagenesis, gluconeogenesis, lipogenesis and electrolyte secretion.[2,3,4,5,6] Many CA isozymes involved in these processes are important therapeutic targets with the potential to be inhibited/activated for the treatment of a range of disorders such as edema, glaucoma, obesity, cancer, epilepsy and osteoporosis.[2,4] Our groups recently investigated the interaction of 12 mammalian CA isozymes with several types of phenolic compounds, such as catechol and a series of phenols and phenolic acids, e.g., catechol, resorcinol, salicyclates and some of their derivatives
The inhibition of two human cytosolic carbonic anhydrase isozymes I and II, with axially disubstituted silicon phthalocyanines and their quaternized derivatives were investigated by using the esterase assay, with 4-nitrophenyl acetate as substrate
Phenol binds to CA in a diverse manner compared to the classical inhibitors of the sulfonamides/sulfamates/ sulfamides, which coordinate to the Zn2+ ion from the enzyme active site by substituting the fourth, non-protein ligand, a water molecule or hydroxide ion.[10]
Summary
Carbonic anhydrase (EC 4.2.1.1, CA) is a metalloenzymes family that catalyzes the rapid conversion of CO2 to HCO3À and H+.1 CA isoforms are found in a variety of tissues where they participate in several important biological processes such as acid–base balance, respiration, carbon dioxide and ion transport, bone resorption, ureagenesis, gluconeogenesis, lipogenesis and electrolyte secretion.[2,3,4,5,6] Many CA isozymes involved in these processes are important therapeutic targets with the potential to be inhibited/activated for the treatment of a range of disorders such as edema, glaucoma, obesity, cancer, epilepsy and osteoporosis.[2,4] Our groups recently investigated the interaction of 12 mammalian CA isozymes with several types of phenolic compounds, such as catechol and a series of phenols and phenolic acids, e.g., catechol, resorcinol, salicyclates and some of their derivatives. CA isoforms are found in a variety of tissues where they participate in several important biological processes such as acid–base balance, respiration, carbon dioxide and ion transport, bone resorption, ureagenesis, gluconeogenesis, lipogenesis and electrolyte secretion.[2,3,4,5,6] Many CA isozymes involved in these processes are important therapeutic targets with the potential to be inhibited/activated for the treatment of a range of disorders such as edema, glaucoma, obesity, cancer, epilepsy and osteoporosis.[2,4] Our groups recently investigated the interaction of 12 mammalian CA isozymes with several types of phenolic compounds, such as catechol and a series of phenols and phenolic acids, e.g., catechol, resorcinol, salicyclates and some of their derivatives They are reported to possess anticancer, anti-carcinogenic, antimutagenic, antibacterial, antiviral or anti-in ammatory activities. The phenyl moiety of this inhibitor was found to lay in the hydrophobic part of the hCA II active site, where presumably CO2, the physiologic substrate of the CAs, binds in the precatalytic complex, explaining the behaviour of phenol as a unique CO2 competitive inhibitor.[10]
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