Human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms IX and XII are overexpressed in solid hypoxic tumors, and they are considered as prognostic tools and therapeutic targets for cancer. Based on a molecular simplification of the well-known coumarin scaffold, we developed a new series of derivatives of the pyran-2-one core. The new compounds are endowed with potent and selective inhibitory activity against the tumor-related hCA isoforms IX and XII, in the low nanomolar range, whereas they are inactive against the two cytosolic off-targets hCA I and II. The compounds exhibiting the best hCA inhibition were further investigated against the breast adenocarcinoma cell line (MCF7) in hypoxic conditions, evaluating their ability to eventually synergize with doxorubicin. The compounds’ biocompatibility on healthy cells was also tested and confirmed on Human Gingival Fibroblasts (HGFs). Furthermore, the possible binding mode of all compounds to the active site of the tumor-associated human CA IX was investigated by computational techniques which predicted the binding conformations and the persistency of binding poses within the active site of the enzyme, furnishing relevant data for the design of tight binding inhibitors.
<div>Continuous efforts in the development of monoamine oxidase inhibitors</div><div>prompted the search for effective strategies for the design of novel drugs candidate.</div><div>Thankfully, nature often provides scaffolds useful for the promotion of novel</div><div>exploitable chemical entities. In this regard, aurones (a class of uncommon flavonoids)</div><div>and their structural related analogues may play an important role in the development of</div><div>monoamine oxidase inhibitors. The target prediction of the simplest aurone (2-</div><div>benzylidenebenzofuran-3(2H)-one) clearly suggests that this compound probably</div><div>affects MAO (monoamine oxidase) enzymes, which is in accordance with the recently</div><div>reported literature. The current chapter reports the recent discoveries involving aurones</div><div>and their structurally related analogues as MAO inhibitors, describing detailed</div><div>structure-activity relationships (SARs) for each subgroup of compounds.</div>
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.