An asiatic acid derived trisulfamate acts as a nanomolar inhibitor of human carbonic anhydrase VA

• Published in: Steroids 2024-05, Vol.205, p.109381-109381, Article 109381
• Main Authors: Denner, Toni C., Heise, Niels V., Serbian, Immo, Angeli, Andrea, Supuran, Claudiu T., Csuk, René
• Format: Article
• Language: English
• Subjects: Acetazolamide - pharmacology; Asiatic acid; Betulinic Acid; Carbonic Anhydrase I - metabolism; Carbonic Anhydrase II - metabolism; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; carbonic anhydrase VA; Carbonic Anhydrases - chemistry; Carbonic Anhydrases - metabolism; Humans; Inhibitor; Molecular Structure; Oleanolic Acid - chemistry; Oleanolic Acid - metabolism; Pentacyclic Triterpenes; Protein Isoforms; Structure-Activity Relationship; Sulfamates; Triterpenes
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2024.109381

[Display omitted] •Triterpenoic acids benzylamides were synthesized and sulfamoylated.•These compounds were tested as inhibitors of carbonic anhydrases (CA) I, II, VA and IX.•An Asiatic acid derived trisulfamate held strong inhibitory effects for CA VA.•This compound showed a Ki = 36.2 nM thus outperforming standard acetalzolamide. This investigation delves into the inhibitory capabilities of a specific set of triterpenoic acids on diverse isoforms of human carbonic anhydrase (hCA). Oleanolic acid (1), maslinic acid (2), betulinic acid (3), platanic acid (4), and asiatic acid (5) were chosen as representative triterpenoids for evaluation. The synthesis involved acetylation of parent triterpenoic acids 1–5, followed by sequential reactions with oxalyl chloride and benzylamine, de-acetylation of the amides, and subsequent treatment with sodium hydride and sulfamoyl chloride, leading to the formation of final compounds 21–25. Inhibition assays against hCAs I, II, VA, and IX demonstrated noteworthy outcomes. A derivative of betulinic acid, compound 23, exhibited a Ki value of 88.1 nM for hCA VA, and a derivative of asiatic acid, compound 25, displayed an even lower Ki value of 36.2 nM for the same isoform. Notably, the latter compound displayed enhanced inhibitory activity against hCA VA when compared to the benchmark compound acetazolamide (AAZ), which had a Ki value of 63.0 nM. Thus, this compound surpasses the inhibitory potency and isoform selectivity of the standard compound acetazolamide (AAZ). In conclusion, the research offers insights into the inhibitory potential of selected triterpenoic acids across diverse hCA isoforms, emphasizing the pivotal role of structural attributes in determining isoform-specific inhibitory activity. The identification of compound 25 as a robust and selective hCA VA inhibitor prompts further exploration of its therapeutic applications.