Exploring the potency of diazo‐coumarin containing hybrid molecules: Selective inhibition of tumor‐associated carbonic anhydrase isoforms IX and XII

Abstract

This study introduces a series of ten hybrid molecules DK(1‐10), which combine diazo and coumarin moieties along with diverse aromatic substitutions. The primary objective was to evaluate the inhibitory capabilities of these compounds against four prominent isoforms: the cytosolic hCA I and II, as well as the tumor‐associated membrane‐bound hCA IX and XII. Impressively, the majority of the tested compounds exhibited significant inhibition activity against the tumor‐associated isoforms hCA IX and XII, with KI values ranging from 29.2 to 293.3 nM. Notably, compound DK‐8 displayed particularly robust inhibitory activity against the tumor‐associated membrane‐bound isoforms, hCA IX and XII, yielding KI values of 32.5 and 29.2 nM, respectively. Additionally, another derivative, DK‐9, containing a primary sulfonamide, exhibited notable inhibition against hCA XII with a KI value of 36.4 nM. This investigation aimed to explore the structure‐activity relationships within these compounds, shedding light on how various substitutions and structural components influence their inhibitory potential. As a result, these compounds present promising candidates for further exploration in medicinal and pharmacological research. Their ability to selectively inhibit specific isoforms, particularly those associated with hypoxic tumors, suggests their potential as foundational compounds for the development of novel therapeutic agents.

New Structural Features of Isatin Dihydrothiazole Hybrids for Selective Carbonic Anhydrase Inhibitors

“…In the human body, members of the carbonic anhydrase enzyme family are involved in pH regulation and other physiological functions. , These proteins are ubiquitous metalloenzymes that contain a zinc ion in the active site, where the reversible hydration of carbon dioxide into bicarbonate ions and protons is catalyzed. , In mammals more than 16 different isoforms of hCAs are found, differing in their sequence, tissue localization, expression, and activity. − Since these enzymes are involved in several physiological and pathological metabolic pathways, their role as drug targets has been investigated. ,, In particular, isoforms IX and XII play key roles in proliferation, cell differentiation, and pH regulation. Furthermore, isoform IX is overexpressed in different types of tumors. , For this reason, hCA IX and XII inhibitors have been deeply explored as anticancer agents. ,− Both represent attractive targets for selective inhibition compared with other hCA isoforms due to their relatively limited expression in normal tissues. These two isoforms are transmembrane and not cytosolic.…”