title: Synthesis and characterization of tritylthioethanamine derivatives with potent KSP inhibitory activity.
abstract: Assembly of a bipolar mitotic spindle requires the action of class 5 kinesins, and inhibition or depletion of this motor results in mitotic arrest and apoptosis. S-Trityl-l-cysteine is an allosteric inhibitor of vertebrate Kinesin Spindle Protein (KSP) that has generated considerable interest due to its anti-cancer properties, however, poor pharmacological properties have limited the use of this compound. We have modified the triphenylmethyl and cysteine groups, guided by biochemical and cell-based assays, to yield new cysteinol and cysteamine derivatives with increased inhibitory activity, greater efficacy in model systems, and significantly enhanced potency against the NCI60 tumor panel. These results reveal a promising new class of conformationally-flexible small molecules as allosteric KSP inhibitors for use as research tools, with activities that provide impetus for further development as anti-tumor agents.
authors.affiliation: Department of Biology, New Mexico State University, Las Cruces, NM 88003, USA.
authors.forename: Delany
authors.initials: D
authors.lastname: Rodriguez
authors.forename: Chinnasamy
authors.initials: C
authors.lastname: Ramesh
authors.forename: Lauren H
authors.initials: LH
authors.lastname: Henson
authors.forename: Lori
authors.initials: L
authors.lastname: Wilmeth
authors.forename: Bj K
authors.initials: BK
authors.lastname: Bryant
authors.forename: Samuel
authors.initials: S
authors.lastname: Kadavakollu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hirsch
authors.forename: Johnelle
authors.initials: J
authors.lastname: Montoya
authors.forename: Porsha R
authors.initials: PR
authors.lastname: Howell
authors.forename: Jon M
authors.initials: JM
authors.lastname: George
authors.forename: David
authors.initials: D
authors.lastname: Alexander
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Johnson
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Arterburn
authors.forename: Charles B
authors.initials: CB
authors.lastname: Shuster
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004625:Embryo, Nonmammalian / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D012617:Sea Urchins / Q000187:drug effects / Q000196:embryology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014320:Triphenylmethyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C470243:KIF11 protein, human; D014320:Triphenylmethyl Compounds; D003543:Cysteamine; D016547:Kinesins