The Design Of Anti-tumor Effect Of New Podophyllotoxin Derivatives, Synthesis And Activity Evaluation

Podophyllotoxin is an antitumor lignan isolated from American P. peltatum Linnaceus. and Indian or Tibetan P. emodi Wall. Podophyllotoxin was used for the treatment of virus infections such as herpes simplex, condyloma acuminatum, and other venereal and perianal warts. Etoposide (VP-16) and teniposide (VM-26) are semi-synthetic anticancer drugs derived from podophyllotoxin, and are clinically useful for the treatment of a variety of cancers, including small cell cancer, testicular carcinoma, lymphoma, and Kaposi's sarcoma. However, the therapeutic application of these drugs is severely hampered by drawbacks of poor water solubility, low oral bioavailability, myelosuppression, and drug resistance. Therefore, extensive synthetic efforts have been devoted to structural modification of podophyllotoxin in order to find novel derivatives with better antitumor spectra and lower side-effects.To improve the pharmaceutical profile and increase water-solubility of podophyllotoxin derivatives, four series of novel derivatives with different C4 linkages have been designed, synthesized and evaluated against tumor cell lines herein. Series A and B are 4β-carbon substituted-4-deoxy-epipodophyllotoxin derivatives, while series C and D are 4β-nitrogen substituted-4-deoxy-epipodophyllotoxin derivatives. Totally,39 podophyllotoxin derivatives have been synthesized, including 26 novel structures. All of them have been characterized by and MS-ESI. The 25 target compounds have been tested against both sensitive and drug-resistant tumor cell lines with SRB assay. Preliminary results have indicated that some of the target compounds are comparable or even superior GL-331 in antitumor activities.