Synthesis and biological evaluation of chalcones as inhibitors of the voltage-gated potassium channel Kv1.3

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 6, 2008, Pages 2055-2061

  Cianci, Julia ^a,b   Baell, Jonathan B ^a   Flynn, Bernard L ^c   Gable, Robert, W ^b   Mould, Jorgen A ^c   Paul, Dharam ^c   Harvey, Andrew J ^a  

^a WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

^c Bionomics Ltd   (Australia)

Author keywords

Chalcones; Conformational analysis; Electrophysiology; Ion channel blockers; Kv1.3; Molecular modelling; Natural product derivatives; X ray crystallography

Indexed keywords

CHALCONE DERIVATIVE; KHELLINONE; NATURAL PRODUCT; POTASSIUM CHANNEL KV1.3; POTASSIUM CHANNEL KV1.3 INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; DRUG SCREENING; DRUG SYNTHESIS; EVALUATION; MEDICINAL PLANT; NONHUMAN; POTASSIUM TRANSPORT; STRUCTURE ACTIVITY RELATION; VOLTAGE CLAMP; X RAY CRYSTALLOGRAPHY;

BENZOFURANS; CHALCONES; CRYSTALLOGRAPHY, X-RAY; ELECTROPHYSIOLOGY; HUMANS; KV1.3 POTASSIUM CHANNEL; MODELS, CHEMICAL; MOLECULAR STRUCTURE; POTASSIUM CHANNEL BLOCKERS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 40849089294     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.01.099     Document Type: Article

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27. Minimisation was performed using the Tripos forcefield, with Gasteiger-Huckel charges, using default values as implemented in sybyl7.3 (Tripos Associates, Missouri). This included the use of a distance-dependent dielectric of 1 using a non-bonded cutoff distance of 8 Å. The α-enone hydrogen atom in the solid-state structure of 5b was changed to a methyl group. The resulting compound, the s-cis form of 11, was allowed to minimize but force constants of 5 were applied to each of the four torsion angles in the enone in order to maintain the s-cis conformation. The same restraints were applied to the s-trans form of 11, which was built in an identical conformation to the solid-state conformation of 16. The s-trans form of 11 thus obtained was calculated to be 7.4 kcal/mol lower in energy to the s-cis form.
28. The above s-trans model of 11 was superimposed on the solid-state structure of 5b, using the two benzene rings as the templates for superimposition, resulting in a 12 atom rmsd of 0.59 Å and which is shown in Figure 3C (note in Fig. 4 the mirror image of 5b is represented relative to Fig. 3).