Design, synthesis, and biological evaluation of novel T-Type calcium channel antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 14, 2004, Pages 3691-3695

  McCalmont, William F ^a   Heady, Tiffany N ^a   Patterson, Jaclyn R ^a   Lindenmuth, Michael A ^a   Haverstick, Doris M ^b   Gray, Lloyd S ^b   Macdonald, Timothy L ^a  

^a UNIVERSITY OF VIRGINIA   (United States)

^b UNIVERSITY OF VIRGINIA   (United States)

Author keywords

Calcium channel blockers; Cancer; Cellular proliferation; T type calcium channels

Indexed keywords

CALCIUM CHANNEL BLOCKING AGENT; CALCIUM CHANNEL T TYPE; CHLORCYCLIZINE; CINNARIZINE; DILTIAZEM; FENDILINE; FLUNARIZINE; ISRADIPINE; LIDOFLAZINE; MECLOZINE; NICARDIPINE; PRENYLAMINE; PROFENAMINE; VERAPAMIL;

ARTICLE; CALCIUM TRANSPORT; CANCER CELL CULTURE; CELL CYCLE; CONTROLLED STUDY; DRUG DESIGN; DRUG IDENTIFICATION; DRUG SCREENING; DRUG SYNTHESIS; HUMAN; HUMAN CELL; INTRACELLULAR SPACE; REGULATORY MECHANISM; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTINEOPLASTIC AGENTS; BEPRIDIL; CALCIUM CHANNEL BLOCKERS; CALCIUM CHANNELS, T-TYPE; CELL DIVISION; DRUG DESIGN; EVALUATION STUDIES; HUMANS; INHIBITORY CONCENTRATION 50; JURKAT CELLS; PERHEXILINE; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR CELLS, CULTURED;

EID: 2942536387     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.05.011     Document Type: Article

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14. The convergent synthesis of library of compounds started from commercially available starting materials such as substituted benzophenones, (L)-proline methyl ester and the appropriate phenylacetic acids. The routine synthetic steps such as reduction of benzophenone with sodium borohydride afforded benzhydrols. The coupling of a variety of aryl acetic acid derivatives with proline methyl ester using either dicyclohexylcarbodiimide or (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate yielded proline amides, or piperidine amides subsequent double reduction of amide and ester functionalities furnished amino-alcohols. Final synthesis of ethers from benzhydrols and N-substituted prolinols or piperidinols was achieved with p-toluene sulfonic acid condensation, using a Dean-Stark
15. The standard reductions employed on the benzophenone would in no way induce a stereochemical preference on the forming benzhydrol. Therefore, these compounds were synthesized as the racemate and were subsequently submitted for biological assaying as the two possible diasteriomers
16. All piperidine isomers were purchased as the racemic mixture and no further chiral resolutions or chiral separations were employed to increase the enantiomeric mixture
17. 2: C, 74.38; H, 6.94; N, 3.21. Found: C, 74.64; H, 6.88; N, 3.24
18. The piperidine analogs, in each case, were submitted as a mixture of the four possible diasteriomers