Design,Synthesis And Antitumor Evaluation Of 4β-Disulfide And Muitisulfide Podophyllo- Toxin Derivatives

The aryltetralin-type lignan podophyllotoxin (PTOX) possesses many biological activities such as antioxidative activity, antitrypanosomal activity, and anti-melanocortin-4 receptor (MC4R) activity, especially for their antineoplastic and antiviral properties. Based on podophyllotoxin, medicinal chemists had successfully designed and developed two well-known clinical anti-cancer drugs:etoposide and teniposide, which are clinically used in combination with other drugs for the treatment of a variety of malignancies including breast cancer, testicular cancer, non small-cell lung cancer, lymphoma and childhood leukemia. However, there are some issues still remained when using these two medicines, such as poor water-solubility, high toxicity and acquired cross drag-resistance.On the other side, there are a variety of natural products bearing disulflde or multisulfide bonds were found to display potent antitumor activities. For example, calicheamicins, a disufide-containing antineoplastic drug, can produce highly reactive electrophile(s) or cytotoxic species that may cause DNA strand scission and induce cell apoptosis to generate antitumor effect via the cleavage of disulfide or multisulfide bonds. Thereby, the importance of disulfide or multisulfide groups in the areas of chemistry, biology, and pharmacology has been well recognized.Therefore, we firstly selected podophyllotoxin as leading compound to construct a series of podophyllotoxin derivates via introduction of disulfide or multisulfide onto its 4p position. Meanwhile, the isssues including water solubility and drug-resistance were seriously taken into consideratin in the design of target compounds. Accordingly, 39 novel derivates (SS, DS, TS series) were designed and synthesized. The structures were confirmed by 1H NMR,13C NMR and MS. Then, In vitro cytotoxicities assay showed that most compounds exhibited potent antiproliferation activities against KB cell lines and KB/VCR (multi-resistent KB cell lines), while moderate/weak aintiproliferative activities against A549 cell lines. To be of interest, aintiproliferative activities of disulfide-containing podophyllotoxin derivates (DS series) against KB cell lines and KB/VCR were even better than that of etoposdie. The most potent compound DS-13 showed potent aintiproliferative activities against KB, KB/VCR and A549 (IC50 values:0.55 μM,0.94 μM and 16.08 μM, respectively), suporior to that of etoposide(IC5o values:5.88 μM,28.46 μM and 4.68 μM, respectively). DS-13 was used for in vitro evaluation of human plasma stability, and the result revealed that DS-13 has a satisfied stability. Further pharmacodynamics study of DS-13 in S180 tumor-bearing mice showed that the inhibitory rate was 11.1% in vivo, lower than that of etoposide. We speculated that it might be relative with the insensitivity of selected tumor cell lines.