title: X-ray diffraction, solution structure, and computational studies on derivatives of (3-sec-butyl-2,3-dihydro-1H-isoquinolin-4-ylidene)acetic acid: compounds with activity as calpain inhibitors.
abstract: A thorough experimental and computational study of derivatives of (3-sec-butyl-2,3-dihydroisoquinolin-4-ylidene)acetic acid was performed. Some of these compounds are calpain inhibitors and could be useful as therapeutic agents, since this enzyme is a Ca(2+)-dependent cysteine protease involved in a wide variety of metabolic and physiological processes, whose over-activation is associated to several pathological conditions. To gain a better understanding of the structure-activity relationships, a structural analysis was carried out with (1)H and (13)C NMR spectroscopy and DFT calculations together with the X-ray diffraction data of three compounds. The solid state structures showed that the crystal packing as well as the intermolecular interactions depend on the substituent nature of the COOR group. Also, the reactivity of the exocyclic double bond was theoretically evaluated, finding that the more reactive compound is the most potent inhibitor of calpain (IC(50) = 25 nM).
authors.affiliation: Instituto de Química Orgánica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Alonso
authors.forename: Roberto
authors.initials: R
authors.lastname: Chicharro
authors.forename: Carlos
authors.initials: C
authors.lastname: Miranda
authors.forename: Vicente J
authors.initials: VJ
authors.lastname: Arán
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Maestro
authors.forename: Bernardo
authors.initials: B
authors.lastname: Herradón
mesh_terms: D000085:Acetates / Q000737:chemistry* / Q000494:pharmacology*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006023:Glycoproteins / Q000737:chemistry* / Q000494:pharmacology*; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: C548111:(3-sec-butyl-2,3-dihydro-1H-isoquinolin-4-ylidene)acetic acid; D000085:Acetates; D006023:Glycoproteins; D007546:Isoquinolines; C039304:calpain inhibitors