| The abnormal expression of Polo-like kinase (Plks) is related to the occurrence and developments of tumor, and it has been identified Plks is over-expressed in a variety of tumor cell lines. Plks is a member of serine-threonine kinase which is only expressed in dividing cells to promote cell prolifration, and it reaches the peak at M phase of cell cycle. On the base of the important role in cell prolifration and the conserved structures, Plks has been a key target for the treatment of tumor. In addition, numorous Plks inhibitors’structures and antineoplastic activity were identified. ON01910, which inhibits tumor cell proliferation in nanamole ranges is reseached in a phase Ⅲ clinical trial as a siginicant Plks inhibitor. The profile of its paharmacokinetics is characterized by high protein binding, fast elimination, short half-life and the elimiation is focused on liver at low doses. Furthermore, the tissue distribution studies exhibited that most drugs accumulated in liver, followed by kidney. The common adverse effects were slight hematotoxicity and liver damage while myelotoxicity, neuropathy and cardiotoxicity were scared.In consideration of the general strategies to study me-too drugs and the SAR studies, the local structures of ON01910were modified to change its acid-base property, lipid-aqueous partition coefficient, metabolic transformation and action time. At the same time, resolution and chial synthesis were adopted to get different isomers. On another aspect, hydroximic acid group was introduced. It was expected to act as a pro-drug with better ADME behavior and form chelation with metalloprotease to inhibit tumor in several signaling pathway, such as HDAC, APN, MMP and so on.4-Methoxy-3-nitrotuluene was used as starting material, which was modified with several steps inclding bromination with NBS, SN2reaction with TGA, oxidization with30%H2O2, reduction with sodium hydrosulfite, and finally substituted by BAM to get L6. The methyl ester group was hydrolyzed to carboxyl (L7) or modified by NH2OK to intoduce hydroxyl oxime acid group (L8). In addition, L7formed salts with some base, such as aminoethanol, lysine, argine, choline, Ca(OH)2, Mg(OH)2, KOH and NaOH (L9～L16). And several analogs with sulfinyl were synthesized. The structures of those compounds were identified by ESI-MS and1H-NMR.In addition to the studies on ON01910analogs, four α-lipoic acid derivatives were synthetized according to the combinatin principles. And two of them (Ⅰ2,Ⅰ3) are equipped with optical activity and another one (Ⅱ) is condensed by a-lipoic acid and TPZ. They are expected to achieve better anti-cancer activiy and provide a new method for the design of anti-cancer drugs.These target compounds’antineoplastic activity were assayed preliminarily. First, L8, L21, Ⅰ1and Ⅱ inhibited HDAC moderately as measured by fluorescence analysis. And the results of MTT assay identifed the significant activity to inhibit the prolifration of tumor cells. Especially, IC50S of L7-8and L21-22were under1μmol·L-1in these three tested cell lines. The nude mouse NOD/SCID model burdened with PLC liver cancer was used to evaluate the activity of L12and this resulted with satisfactoried data, which has theoretical significance and practical significance for the studies on anticancer compounds. |
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