6yo7 | pdb_00006yo7
Ortho-Carborane di-propyl-sulfonamide in complex with CA IX mimic
Structural highlights
Disease[CAH2_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] Function[CAH2_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 PubMedCarbonic Anhydrase IX (CA IX), a tumor-associated metalloenzyme, represents a validated target for cancer therapy and diagnostics. Herein, we report the inhibition properties of isomeric families of sulfonamidopropyl-dicarba- closo -dodecaboranes group(s) prepared using a new direct five-step synthesis from the corresponding parent cages. The protocol offers a reliable solution for synthesis of singly and doubly substituted dicarba- closo -dodecaboranes with a different geometric position of carbon atoms. The closo - compounds from the ortho - and meta - series were then degraded to corresponding 11-vertex dicarba- nido -undecaborate(1-) anions. All the compounds show in vitro enzymatic activity against CA IX in the low nanomolar or subnanomolar range. This is accompanied by clear isomer dependence of the inhibition constant ( K i) and selectivity towards CA IX. Decreasing trends in K i and selectivity index (S I ) values are observed with increasing separation of the cage carbon atoms. Interactions of compounds with the active sites of CA IX were explored with X-ray crystallography, and eight high-resolution crystal structures uncovered the structural basis of inhibition potency and selectivity. Direct Introduction of an Alkylsulfonamido Group on C-sites of Isomeric Carboranes; the Influence of Stereochemistry on Inhibitory Activity Against Cancer-associated Carbonic Anhydrase IX Isoenzyme.,Nekvinda J, Kugler M, Holub J, El Anwar S, Brynda J, Pospisilova K, Ruzickova Z, Rezacova P, Gruner B Chemistry. 2020 Aug 5. doi: 10.1002/chem.202002809. PMID:32757220[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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