Synthesis Of Anticancer Chlorine Nida Ming, Quality And Crystal Research

Lonidamine(LND),a thermo-sensitive anti-cancer drug,has been approved for the treatment of lung,breast,prostate and brain cancer in some countries.The anti-cancer mechanism of lonidamine may involve the interference with the energy metabolism of neoplastic cells by disruption of the mitochondrial membrane and inhibition of hexokinase. Because of the close relation between the therapeutic effects and its crystal form,it is necessary to study the crystal structure of lonidamine.Lonidamine was synthesized from isatin,through ring-opening,diazotization, reduction and cyclization to yield 1H-indazole-3-carboxylic acid,followed by reacting with 2,4-dichlorobenzyl chloride to give the target product.The study of quality was performed on the basis of synthesis,and the quality standard was established.Three crystal structure forms of lonidamine:formⅠ,formⅡand formⅢhave been disclosed,confirmed and characterized by XRD,DSC and IR.What's more,single crystal X-ray crystallography was used to characterize the crystal structure and unit parameters of formⅡand formⅢ.The solubility in vitro and bioavailabity of different crystalline forms of lonidamine have been studied,the results showed that the bioavailability of three crystalline forms of lonidamine were equal,and the solubility of them was better than that of amorphous forms of lonidamine.The results of this research provide some basis for production of lonidamine.