(+)-Ascosalitoxin and Vermelhotin, a Calmodulin Inhibitor, from an Endophytic Fungus Isolated from Hintonia latiflora

• Published in: Journal of natural products (Washington, D.C.) Vol. 75; no. 9; pp. 1571 - 1577
• Main Authors: Leyte-Lugo, Martha, González-Andrade, Martín, González, María del Carmen, Glenn, Anthony E, Cerda-García-Rojas, Carlos M, Mata, Rachel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society and American Society of Pharmacognosy 28.09.2012; Amer Chemical Soc
• Subjects: aldehydes; calmodulin; Calmodulin - antagonists & inhibitors; Chemistry, Medicinal; chlorpromazine; Crystallography, X-Ray; dissociation; endophytes; Endophytes - chemistry; fungi; Life Sciences & Biomedicine; medicinal plants; Mexico; Molecular Conformation; molecular models; Molecular Structure; nuclear magnetic resonance spectroscopy; Nuclear Magnetic Resonance, Biomolecular; Pharmacology & Pharmacy; Plant Leaves - microbiology; Plant Sciences; Plants, Medicinal - microbiology; Pyrrolidines - chemistry; Pyrrolidines - isolation & purification; Pyrrolidines - pharmacology; Salicylates - chemistry; Salicylates - isolation & purification; Salicylates - pharmacology; Science & Technology; Stereoisomerism; stoichiometry; Mexico; DOCKING; TOOL
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np300327y

Chemical investigation of the endophytic MEXU 26343, isolated from the medicinal plant Hintonia latiflora, yielded the known polyketide vermelhotin (1) and a new salicylic aldehyde derivative, namely, 9S,11R-(+)-ascosalitoxin (2). The structure and absolute configuration of the new compound were established through extensive NMR spectroscopy and molecular modeling calculations at the DFT B3LYP/DGDZVP level, which included the comparison between theoretical and experimental optical rotation values. In addition, chemical transformations of 2 yielded suitable derivatives for NOESY and 1H–1H NMR coupling constant analyses, which reinforce the stereochemical assignment. The potential affinity of 1 and 2 with (Ca2+)4-hCaM in solution was measured using the fluorescent biosensor hCaM M124C-mBBr. The results showed that 1 bound to the protein with a dissociation constant (K d) of 0.25 ± 0.04 μM, close to that of chlorpromazine (K d = 0.64 ± 0.03 μM), a classical CaM inhibitor. The stoichiometry ratio of 1 to (Ca2+)4-hCaM was 1:4, similar to other well-known CaM ligands.