Design, Synthesis, And Anti-Cancer Or Anti-HIV-1 Studies Of Novel Podophyllotoxin Derivatives

Podophyllotoxin as well as its congeners and derivatives exhibit pronounced biological activity mainly as strong antineoplastic drugs and as antiviral agents, which is a good source of the arylteralin-type lignan. The podophyllotoxin derivatives etoposide(VP-16), teniposide(VM-26) and Etopophos (etoposide phosphate), which are optimized from podophyllotoxin as lead compound, are thus successfully utilized in treatment of a variety of cancers, including small-cell lung cancer, testicular carcinoma, lymphoma, and Kaposi's sarcoma. In addition, podophyllotoxin was used as antiviral agent in treatment of herpes simplex type I and condyloma acuminatum caused by human papilloma virus and others venereal and perianal warts. To obtain better the therapeutic agents with high activities and less toxic to natural cell, three kinds of derivatives of podophyllotoxin were designed, synthesized and evaluated for their biological activities in this thesis.1. Based on antimetabolite 5-fluorourcial is one of the major anticancer agents used clinically, as well as amino acids with better biological activity and good water-solubility in the human body, 27 Compounds were synthesized though associated 4'-demethylepipodophyllotoxin and 5-FU with natural I-amino acid as linker. As the results, most target compounds showed more effective superior or comparable cytotoxicities than VP-16 and 5-FU, against human leukemic(HL-60, K562) and huaman lung carcinoma(A-549) in vitro. At the same time, they are stability in huaman plasma, mouse plasma and phosphate buffer solution, and they interacted weakly with calf thymus DNA.2. To explore the range of biological activities of the podophyllotoxin compound class, another series of podophyllotoxin derivatives were designed and synthesized, which were conjugates of stavudine (d4T) and structural modifications at the methylenedioxy A-ring of podophyllotoxin with natural I-amino acid as linker. The results of their anti-HIV-1 activity showed that these derivatives were less toxicity 100 times to natural cell than podophyllotoxin, but they also showed weaker anti-HIV-1activities than podophyllotoxin.3. To further investigate the structure anti-HIV activity relationship of podophyllotoxin derivatives, the third series of podophyllotoxin analogues were designed and synthesized, which were combinations of stavudine and different structural 4-amido-podophyllotoxin and 5-FU-acetic acid ester of A-ring modified podophyllotoxin derivatives. Compound 14d showed good anti-HIV-1 activity with TI value of 466.91. The SAR revealed that the derivatives of podophyllotoxin with the A-ring opened and methylated, the 4'-position demethylated and 4-N or C substituted are encouraging and warrant further structural modification to both decrease cytotoxicity and increase antiviral inhibitory activity.