Synthesis, Computational Studies and Assessment of in Vitro Activity of Squalene Derivatives as Carbonic Anhydrase Inhibitors

Abstract

We report novel molecules incorporating the nontoxic squalene scaffold and different carbonic anhydrase inhibitors (CAIs). Potent inhibitory action, in the low‐nanomolar range, was detected against isoforms hCA II for sulfonamide derivatives, which proved to be selective against this isoform over the tumor‐associate hCA IX and XII isoforms. On the other hand, coumarin derivatives showed weak potency but high selectivity against the tumor‐associated isoform CA IX. These compounds are interesting candidates for preclinical evaluation in glaucoma or various tumors in which the two enzymes are involved. In addition, an in silico study of inhibitor‐bound hCA II revealed extensive interactions with the hydrophobic pocket of the active site and provided molecular insights into the binding properties of these new inhibitors.

Chromene-Containing Aromatic Sulfonamides with Carbonic Anhydrase Inhibitory Properties

“…The classical CA inhibitors (CAIs) are the primary sulfonamides, which coordinate the zinc ion with their terminal deprotonated nitrogen atom and have been in clinical use for more than 70 years as diuretics and systemically acting antiglaucoma drugs [ 10 ]. Chromenes have attracted the interest of the scientific community due to their wide range of biological activities, such as antimicrobial [ 11 , 12 ], anticancer [ 13 , 14 ], anti-inflammatory [ 15 , 16 ], and CA inhibitors [ 17 , 18 , 19 , 20 , 21 ], nematicidal [ 22 ], antiallergic [ 23 ] Some sulfonamides also show antimicrobial [ 24 , 25 ], anticancer [ 26 , 27 ], antidiabetic [ 28 ], anti-inflammatory [ 15 , 29 ], and antitubercular [ 30 ] activities. Taking into account all of the above-mentioned, here we report the synthesis of (4-sulfamoylphenyl)-4 H -chromene-2-carboxamide derivatives for its incorporation into one scaffold chromene and sulfonamide moieties.…”

Novel Nanotherapeutic Systems Based on PEGylated Squalene Micelles for Enhanced In Vitro Activity of Methotrexate and Cytarabine

“…The synthesis of the PEGylated squalene was accomplished using a slightly modified version of our previously reported protocol [58]. Briefly, in the first step, SQ-COOH (200 mg, 0.5 mmol) was solubilized in anhydrous DMF (3 mL), and the flask was flushed and kept under dried nitrogen.…”

Synthetic Approaches to Novel Human Carbonic Anhydrase Isoform Inhibitors Based on Pyrrol-2-one Moiety

“…23 A widespread family of metalloenzymes called carbonic anhydrases (CAs) catalyzes the reversible transformation of carbon dioxide to H + and HCO 3− . 24,25 Many biosynthetic processes, like respiration, photosynthesis, pH regulation, and electrolyte secretion, are carried out by CA enzymes. 26,27 In humans, there are currently 15 known isoforms, of which only 12 are catalytically active.…”

“…A widespread family of metalloenzymes called carbonic anhydrases (CAs) catalyzes the reversible transformation of carbon dioxide to H + and HCO 3– . , …”

“…Aiming to produce new derivatives in light of all of the above, our current work was a continuation of our earlier investigation into N -heterocycle systems − and as part of our interest in the field of physiologically active chemicals, − with a focus on carbonic anhydrase inhibitors. ,,,− The synthesis, structure, and evaluation of several novel dihydro-pyrrol-2-one derivatives as inhibitors of tumor-associated human CA are thus reported here.…”