Synthesis and Biological Activities of (R)- and (S)-N-(4-methoxy-phenyl)-N26-trimethyl-67-dihydro-5H-cyclopentadpyrimidin-4-aminium Chloride as Potent Cytotoxic Antitubulin Agents

摘要

(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 [³H]colchicine to tubulin, with (S)->1, being about twice as potent. Cytotoxicity against a panel of 60 tumor cell lines, however, indicated that the (S)-isomer was 10- to 88-fold more potent than the (R)-isomer.