Synthesis And Antitumor Activity Of Some Steroidal Nitrogen - Containing Compounds And Their Relationship With Structure - Activity

In recent years, the applications of steroidal drugs in the medical field were expanded, with the deepening of the research on steroid chemistry, scientists have found that introducing some nitrogen functional groups into the nucleus of steroid, or leading a N atoms into the rings of steroid, or modifying the structure of steroid, it would make the steroidal compounds have unique biological activity even exceeding the parent compound. Therefore, using different chemical reaction and different method of functional transformed, some steroidal compounds of similar structure with Orostanal, steroidal oximes and steroidal hydrazones compounds were synthesized in this paper, and at the same time the anti-tumor activity of some compounds were tested.Using natural cholesterol, stigmasterol as starting materials, by different chemical reaction and different method of functional transformed, leading different nitrogen functional groups into the rings of steroid, thirty-eight steroids with different structures were synthesized, including fifteen nitrogen-contained steroidal compounds, and twelve steroidal compounds with [6-5-6-6] structure. The structures of products were characterized by IR, 1H NMR, 13C NMR and Mass Spectra and the antiproliferative activity of compounds synthesized was investigated in vitro.First, nine 6-substitued steriodal oximes were prepared by PCC oxidation, NaBH4 reduction, Jones oxidation, selective oximation using cholesterol, stigmasterol, and sitosterol as starting materials. All of these compounds were tested by a preliminary screening of antiproliferative activity in vitro, it found that all of those compounds have a distinct cytotoxicity against MGC 7901 (human ventriculi carcinoma cell line), hela (human cervical carcinoma cell line), SMMC 7404 (human liver carcinoma cell line). Their IC50 are being tested.Secondly, using stigmasterol as a starting material, by protection of hydroxy, ozonization and condensation reaction, twelve steroidal compounds with nitrogen functional groups were synthesized. The results of screening of antiproliferative activity in vitro showed that compound 18 displayed a good cytotoxic activity against liver cancer cell (SMMC 7404) and gastric cancer cell (MGC 7901). The cytotoxicity of other similar compounds are being investigated.In addition, according to reports of the literatures, Orostanal which was separated from natural compound has significant biological activities. Therefore, using cholesterol as a starting material, by the ozonization, cyclization and functional trasformation of 6- formoxyl, seventeen steroidal compounds with a [6-5-6-6] structure were synthesized, including sixteen new compounds. Meantime, the antiproliferative activity of these compounds was tested in vitro. The results showed that all those comounds displayed a good cytotoxicity against SMMC 7404 and MGC 7901. For example, the compound 37 revealed IC50 of 8.6 and 8.4μmol/L against 7404 and 7901 cancer cells respectively.We have prepared a series of nitrogen-contained steroidal compounds and steroidal compounds with a [6-5-6-6] structure by modifying the structure of steroidal B-rings and side-chain. The results of antiproliferative test showed that the steroids with the [6-5-6-6] structure similar to Orostanal displayed a good cytotoxic activity against liver cancer cell (SMMC 7404) and gastric cancer cell (MGC 7901). Therefore, the further structural modifications and anti-tumor activity study in vivo would be in progress. Our findings provide new evidence showing the relationship between the chemical structure and biological function. The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs for cancer.