9h0w
Human Carbonic Anhydrase II in complex with B-Thujaplicin (2-hydroxy-4-(propan-2-yl)cyclohepta-2,4,6-trien-1-one)
Structural highlights
DiseaseCAH2_HUMAN Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:259730; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.[1] [2] [3] [4] [5] FunctionCAH2_HUMAN Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.[6] [7] Publication Abstract from PubMedHerein we report the chemical derivatization of the naturally occurring Tropolone (TRP) and its related compound beta-Thujaplicin (beta-TJP) as well as their in vitro assessment for inhibition of the physio/pathologically relevant hCAs isoforms I, II, VA; VII, IX and XII to obtain a first set of inhibition data useful for driving selected derivatives towards appropriate biomedical exploitation. The selected compound 17beta was characterized for its chemical stability and assessed for its antiproliferative activity on a multiple myeloma model and showed potent pro-apoptotic features jointly with a safe toxicity profile on healthy cells. The binding mode of beta-TJP within the hCA II was assessed by means of X-ray crystallography of the hCA II/beta-TJP complex and showed almost complete superposition with the hCA II/TRP adduct reported in the literature. The data produced were used to elaborate a binding prediction model of such compounds on the hCAs VA, IX, and XII which are directly connected to important diseases. Overall, the achievements reported in this work are in the sustainment of the exploitation of naturally occurring troponoloid-based structures for biomedical purposes and thus contribute to the field in extending the variety of available chemical features. O-derivatization of natural tropolone and beta-thujaplicin leading to effective inhibitors of human carbonic anhydrases IX and XII.,Melfi F, D'Agostino I, Carradori S, Carta F, Angeli A, Costa G, Renzi G, Cikos A, Vullo D, Resetar J, Ferraroni M, Baroni C, Mancuso F, Gitto R, Ambrosio FA, Marchese E, Torcasio R, Amodio N, Capasso C, Alcaro S, Supuran CT Eur J Med Chem. 2025 Jun 5;290:117552. doi: 10.1016/j.ejmech.2025.117552. Epub , 2025 Mar 27. PMID:40179613[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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