title: Synthesis and biological activities of (R)- and (S)-N-(4-Methoxyphenyl)-N,2,6-trimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-aminium chloride as potent cytotoxic antitubulin agents.
abstract: (R,S)-1 is a potent antimitotic compound. (R)-1·HCl and (S)-1·HCl were synthesized from (R)- and (S)-3-methyladipic acid. Both enantiomers were potent inhibitors of cell proliferation and caused cellular microtubule loss and mitotic arrest. They inhibited purified tubulin assembly and the binding of [(3)H]colchicine to tubulin, with (S)-1 being about twice as potent. Cytotoxicity against 60 tumor cell lines, however, indicated that the (S)-isomer was 10- to 88-fold more potent than the (R)-isomer.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA. gangjee@duq.edu
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Cara
authors.initials: C
authors.lastname: Westbrook
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D050256:Antimitotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000814:Aniline Compounds; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D003603:Cytotoxins; C562049:N-(4-methoxyphenyl)-N,2,6-trimethyl-6,7-dihydro-5H-cyclopenta(d)pyrimidin-4-aminium; D011743:Pyrimidines; D050257:Tubulin Modulators