Design,Synthesis And Biological Activity Of Multifunctional Antitumor Platinum Complexes

Malignant tumor is a challenging issue to the whole world,which has always threatened human life and health.Up to now,a lot of researches have been carried out in the field of malignant tumor therapy.In the field of chemotherapy（drug therapy）,five chemotherapeutic drugs（HDAC inhibitors）targeting histone deacetylases（HDACs）have been approved.All the inhibitors show good antitumor effects in clinic,while the clinical application of broad-spectrum HDAC inhibitors is limited by the adverse effects of nausea,vomiting and bone marrow suppression.Therefore,the development of selective HDAC inhibitors has become a hot research topic.In addition,in chemotherapy field,platinum-based antitumor drugs also play an important role.There are currently seven platinum chemotherapy drugs approved in clinic.Although platinum-based drugs have a wide range of clinical applications in cancer treatment,their severe side effects and lack of tumor selectivity greatly limit the therapeutic effect.Therefore,it has become another hot topic to break through the structure-activity relationship（SAR）of classical platinum drugs and develop novel multifunctional platinum anticancer drugs.Based on the classical structure-activity relationship between HDAC inhibitors and platinum drugs,two series of novel multifunctional platinum antitumor complexes have been designed and prepared by choosing and designing functional active ligands rationally.（1）In the first part,three bifunctional platinum complexes as selective HDAC6inhibitors have been designed and synthesized,including compounds Ⅰ-1,Ⅰ-2 and Ⅰ-3,to address the poor selectivity of broad-spectrum HDAC inhibitors.Homology modeling showed that the catalytic activity channel of HDAC6 was larger and shallower than that of HDAC1.Based on the dsp²hybridized properties of platinum and the excellent antitumor properties of platinum drugs,this series of compounds have been designed with broad-spectrum HDAC inhibitor volinota（SAHA）as a template,in which the"cap"part of SAHA derivatives containing pyridine moiety was introduced by the platinum complexes with tridentate ligands includes diethylenetriamine,2,6-diammethylpyridine,bis（2-pyridyl methyl）amine in order to increase the specific recognition and location of the compounds for HDAC6.The results showed that the target compounds showed high HDAC inhibiting activity and HDAC6 selective inhibition.The HDAC6 inhibitory activity of compound Ⅰ-3 was comparable to that of positive SAHA,and the selectivity factors of SF6/1 and SF6/8 were 40.30 and 64.00,respectively,which were much higher than that of SF6/1 and SF6/8 of SAHA（2.17 and28.50,respectively）.The results showed that compound Ⅰ-3 significantly increased the selective inhibition activities of HDAC6（relative to HDAC1 and HDAC8）,which were19-fold and 2-fold higher than those of SAHA.In addition,the IC₅₀value of compound Ⅰ-3 against U937 cell line was 9.24μM in vitro,which was comparable to those of SAHA and cisplatin.The results above indicated that the designed bifunctional HDAC6inhibitor conjugated with platinum complex had high HDAC6 selective inhibitory activity and antitumor effect,which proved that the design of this series of compounds is reasonable and effective.（2）In the second part,two multifunctional platinum（Ⅳ）compounds Ⅱ-1 and Ⅱ-2have been prepared by introducing the HDAC inhibitor 4-phenylbutyl acid（4-PBA）in the axial groups of platinum（Ⅳ）complexes,of which especially the multifunctional platinum（Ⅳ）complex Ⅱ-2 possessed two different axial groups contained HDAC inhibition（4-phenylbutyric acid）and tumor targeting group biotin so as to overcome the limitations of clinically used platinum drugs.In vitro cytotoxicity studies showed that compound Ⅱ-2 exhibited comparable or superior cytotoxicity to that of cisplatin against tested tumor cell lines,whereas its toxicity towards human normal liver cells LO2 was significantly reduced,suggesting that compound Ⅱ-2 has potential tumor selectivity.Molecular docking studies showed that compound Ⅱ-2 could effectively interact with the over-expressed biotin-specific receptors on the cancer cell surface,resulting in enhanced cellular accumulation.A series of biological evaluations demonstrated that compound Ⅱ-2 induced DNA damage and inhibited HDAC to exert cytotoxic activity through mitochondrial apoptosis pathway.