Study On Synthesis And Antitumor Activities Of Derivatives Of Podophyllotoxin

The study of designing, synthesis, antitumor activity in vitro and structure- activity relaiidiiship of two new kinds of derivatives of podophyllotoxin is reported in this paper. 1. Designing and synthesis of 4-f3-carbon substituted-epipodophyllotoxin derivatives According to the present known structure-activity relationship of podophyllotoxin and its derivatives, the C4 position in C ring of podophyllotoxin is a very important location to be modified. In our previous research, we have synthesized many 4-13-0, S, N or Se substituted-4?demethylepipodophyllotoxin analogues. But there are very little studies n 4-13-carbon substituted derivatives of epipodophyllotoxin. On the basis of the iteratures, and synthesized three series of 4-13-carbon substituted-4-deoxy-4 demethylepipodophyllotoxin analogues, and we have also examined their antitumor activity in vitro. We have designed d synthesized two key compounds: 4-43-cyano-4-deoxy-4? demethylepipodophyl otoxin(127) and 4-j3-carboxyl-4-deoxy-4?-demethylepipodo- phyllotoxin(128). The further synthesis of derivatives of the two compounds gave the three series of analogues of podophyllotoxin: 4-13-alkylaminocarbonyl-4-deoxy-4? demethylepipodophyllotoxin(I), 4-f3-alkoxylcarbonyl-4-deoxy-4?-demethylepipodo- phyllotoxin(II) and 4-13-alkylthiocarbonyl-4-deoxy-4?-demethylepipodophyllotoxin (III). When yi esized the key compound of 4-13-cyano-4-deoxy-4?demethylepi- podophyllotoxin, we used the dry dusty potassium cyanide as the nucleophilic agent, and got the target compound in the presence of BF3 Et20 at ?5 0C in low yield (<10%). In further research, we found that trimethylsilyl cyanide, a versatile silicon agent, gave us a satisfying result with high yield and 100% stereospecificity (J 7.34Hz). In a mixed solvent of acetic acid, hydrochloric acid and water, 4-f3-cyano-4- deoxy-4?demethylepipodophyllotoxin can be easily hydrolyzed to the 4- 3-carboxyl- 4-deoxy-4?-de-methylepi-podophyllotoxin. While synthesizing the derivatives I, II and III from 4- -carboxyl-4-deoxy-4? demethylepipodophyllotoxin, we got good results by using thionyl chloride to form the intermediate of acyl chloride, followed by reaction with various appropriate amine, alcohol/phenol and thioalcohol/thiophenol without separation of the acyl chloride. We have synthesized 82 new compounds of I, II and III totally, all of them have been characterized by melting point, optical rotation, MS and -NMR. 2. Designing and synthesis of acetals/ketals of 4- -amino-(2,3-dihydroxy1)- propyl-4-deoxy-4emethylepipodophyllotoxin Much attention has given to the modification of etoposide, since it was used in clinic. By simplifying and simulating the structure of etoposide, we have designed and synthesized acetals/ketals of 4- -O-(2,3 -dihydroxypropyl)-4?-demethylepipodo- phyllotoxin, and their chiral analogues which have R or S configuration at 2?position in the side chain. These compounds exhibited excellent activity against L1210 and KB cell lines in vitro. According to the principle of Bioisosterism, we designed and synthesized acetals/ketals of 4-13-amino-{2,3-dihydroxypropyl)-4-deoxy-4?-demethyl- epipodophyllotoxin(IV), and their chiral analogues(V and VI) in order to find out the effect of the configuration of the C-2?position in the side chain...