Design,synthesis And Pharmacological Activity Research Of Tumor-targeted Prodrug Hydroxychloroquine

Malignant tumors seriously endanger human health and survival,and are one of the leading causes of death.In China,malignant tumors have become the leading cause of death for urban and rural residents.For a long time,people mainly rely on surgery,and at the same time use radiotherapy and chemotherapy to intervene in tumors.Chemotherapy,as one of the three conventional treatment methods of tumor,has become an indispensable means of tumor treatment.At present,most chemotherapy drugs have poor selectivity,the widespread distribution of drugs in the whole body and the multidrug resistance of most tumor cells,which greatly reduces the therapeutic effect of drugs and affects the effect of drug treatment.Therefore,designing anticancer drugs that can target tumor sites is one of the research hotspots and development trends in the field of anti-tumor at home and abroad.Among them,targeted treatment for the metabolic characteristics of tumor cells has become one of the new strategies of tumor therapy.The vector or ligand used in this targeted strategy is a small molecule in the metabolic pathway of tumor cells,which has the characteristics of small molecular weight,stable physical and chemical properties,strong targeting and small toxic side effects.Tumor cells from arterial blood intake of natural fatty acids as biochemical precursors and energy sources,natural polyunsaturated fatty acids as a carrier,can effectively target anti-tumor drugs to carry tumor cells,improve the efficiency of drug killing tumor cells,while reducing the accumulation of chemotherapy drugs in non-target tissues,reduces the effect of chemotherapy drugs on normal cells.Therefore,natural polyunsaturated fatty acids as a carrier,?especially alpha linolenic acid,both as carriers and anti-tumor activity?,and anti-tumor active drugs prepared into precursor drugs,in the tumor targeting research has a broad prospect.Hydroxychloroquine is a4-aminoquine derivative,a traditional antimalarial drug used to control malaria clinical symptoms and inhibitory prevention of malaria.The recent studies showed that hydroxychloroquine has a good inhibitory effect on a variety of malignant tumors.However,there are many shortcomings in the physical and chemical properties of hydroxychloroquine,the characteristics of distribution in the body,the way of use of drugs,etc.The invivo characteristics and physical and chemical properties of hydroxychloroquine need to be improved,so in view of the chemical structure of hydroxychloroquine,there is the possibility of ester,through structural modification can improve its physical and chemical properties,and thus improve the activity and in vivo characteristics.In this study,the natural polyunsaturated fatty acid alpha linolenic acid was used as a carrier,through the covalent connection with hydroxychloroquine to form a double-acting anti-tumor activity of the two-acting target forward drug,and its anti-tumor activity,mechanism and metabolic were studied in this study.It was found that hydroxychloroquine linolen?AHQ?had a good inhibitory effect on tumor proliferation in both in vivo and in vitro.In vitro,AHQ can induce G₁ cell cycle arrest in human colon cancer cells and it also can induce tumor cells apoptosis.In addition,AHQ has better in vivo pharmacokinetic characteristics,the absolute bioavailability of AHQ is about 30%in SD rats.After the AHQ is injected with the experimental aninmals of different genus,it has a wide distribution in SD rats,and it has the same distribution as hydroxychloroquine,which indicating that AHQ can convert to hydroxychloroquine well.And the conversion rate of AHQ to hydroxychloroquine is50%.And it has a wide distribution in rats and can be well converted to hydroxychloroquine in different tissues.The absolute bioavailability of AHQ in Beagle dogs is about 40%,and the conversion rate of AHQ to hydroxychloroquine is about87%.In summary,the new tumor targeted prodrug AHQ improves hydroxychloroquine's original physical and chemical properties and distribution characteristics,and provides new ways for hydroxychloroquine in tumor treatment,and it also provides new ideas and strategies for the development of anti-tumor drugs.