SynthesisandBioevaluationsofTetrahydroisoquinolinesasNovelKinesinSpindleProtein(KSP)Inhi.docVIP

Design, Synthesis and Bio-evaluations of Tetrahydroisoquinolines as Novel Kinesin Spindle Protein (KSP) Inhibitors Cheng Jiang 1, Qidong You *1, Lei Yang 2, Mengling Chen 3, Fei Liu 1, Wutong Wu 2, Jiwang Chern 3 1 Department of Medicinal Chemistry, 2 School of Life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China 3 School of Pharmacy, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, Taiwan Abstract Based on the pharmacophore we have mapped and the binding structure of monastrol with the target protein, a series of tetrahydroisoquinolines have been identified as novel kinesin spindle protein (KSP) inhibitors. Human KSP protein was cloned, expressed and purified; KSP inhibitory activities of the designed compounds were tested. All the designed compounds displayed more potent inhibitory activities in the KSP ATPase assays and about half of them showed better in vitro cytotoxicities against HepG2 cell line, the first reported small molecule KSP inhibitor monastrol was used as a control compound. Introduction Kinesin spindle protein (KSP), also known as Hs Eg5, is a member of the kinesin superfamily of molecular motors that utilize the energy generated from the hydrolysis of ATP to transport vesicles, organelles, and microtubules [1]. The protein is also required for centrosome separation during prophase or prometaphase [2]. Inhibition of KSP prevents the formation of normal bipolar spindle, which leads to mitotic arrest with a characteristic monoastral phenotype and subsequently to apoptosis in transformed cells, without disturbing mocrotubules [3, 4]. Thus KSP inhibition represents a novel and specific mechanism to target the mitotic spindle that may be devoid of the neuropathy-associated, mechanism-based side effects common to the taxanes and other natural products that target microtubules. In recent years, several classes of KSP inhibitors have been reported [5-23]. And based on