The Discovery Of Benzoxaboroles As Novel Anticancer Agents And Study Of Target Proteins

Benzoxaboroles are a class of boron containning compounds with particular physicochemical properties.These versatile compounds play critical roles in various fields,such as organic synthesis,supramolecular chemistry,molecular recognition,and medicinal chemistry.Recent years,there are several successful cases of benzoxaboroles are approved as clinical drugs,and more derivatives are approved for clinical trals.Therefore,the development of benzoxaboroles as novel drugs has a promising prospect.To date,benzoxaboroles have been widely applied as antifungal,antiviral,antibacterial,anti-inflammatory,and antiparasitic agents.However,the application of them in anticancer field was rarely reported.In order to develop novel anticancer agents and extend the range of application of benzoxaboroles,we screened our compounds library in vitro.Fortunately,several benzoxaboroles showed good activities to inhibit the growth of a panel of cancer cell lines.Therefore,we further modified these active compounds to develop more potent compounds and our attention was focused on 7-benzoxaborole-chalcone hybrids,6-benzoxaborole-chalcone hybrids,and 7-substituted propanamide substituted benzoxaboroles,which were shown in chapters 2,3,and 4.In addition,we synthesized two photoaffinity probes derived from6-benzoxaborole-chalcone hybrid(ZCL432),and we then successfully identified 6-benzoxaborole-chalcone hybrid's intracellular targets.To 7-benzoxaborole-chalcone hybrids,33 compounds were synthesized and evaluated.SARs research revealed that the motif of chalcone was essential for activity and the oxaborole ring contributed to about 3 fold increase of potency.Among these compounds,3,4-dichloro substituted compound 54 was the most potent compound.It showed selectively potency to inhibit SKOV3 cell line with IC₅₀ value of 2.92?M and a relative low toxicity to human normal cell lines.And the inhibitory activity of compound 54 was also confirmed in SKOV3 mice xenograft model.To 6-substituted benzoxaborole-chalcone hybrids,40 compounds were evaluated.Among these analogues,compound 4 was the most potent compound to inhibit SKOV3,MDA-MB231,and HCT116 with IC₅₀ values of 1.39,1.59,and 2.79?M,respectively.However,it also showed relatively strong toxicity on human normal cell lines MCF-10A and WI-38 with IC₅₀ values of 11.75 and 7.63?M,respectively.However,compounds 75 and 102 selectively inhibited SKOV3 cell line with IC₅₀values of 4.24 and 1.65?M,respectively,and showed low toxicity to normal cell lines(IC₅₀>100?M).In addition,in order to explore the intracellular targets of benzoxaboroles,we synthesized two photoaffinity probes 126 and 142 derived from 6-benzoxaborole-chalcone hybrid(ZCL432).With the two probes,we successfully identified 53 potential targets of ZCL432.Tubulin,Exportin,Importin,Na+/K+-transporting ATPase,Heat shock protein,Elongation factor,Clathrin,Coatomer,ATP-citrate synthase and Transportin-1 were the top ten abundant potential target proteins.7-Propanamide substituted benzoxaborole 6 showed excellent inhibitory activities to SKOV3,MDA-MB231,and HCT116 cell lines with IC₅₀values of 0.20,0.23,and 0.35?M,respectively.We then further designed,synthesized,and evaluated 62 analogues.SARs research revealed that terminal aromatic ring,amide,flexible linker,and oxaborole ring were indispensable for anticancer potency.Further study confirmed that the replacement of terminal phenyl ring to substituted biphenyls could help to improve activities.3'-Methoxyl and 4'-acetyl substituted compounds 252 and 264 were the two most potent compounds with IC₅₀values of 32.9 and 20.9 n M to inhibit SKOV3,respectively.And their activities were also confirmed in SKOV3 mice xenograft model.In a word,our work successfully extended the application of benzoxaboroles into anticancer field.Several derivatives showed excellent inhibitory activities both in vitro and in vivo.In addition,our exploration on intracellular targets of benzoxaboroles might be a good start for further research of benzoxaboroles'mechanisam research.