Synthesis and in vitro anti-cancer evaluation of novel podophyllotoxin derivatives

Podophyllotoxin is the main component of podophyllum resin, a naturally occurring antimitotic cyclolignan which shows strong anticancer activity against various cancer cell lines. Due to its complicated side effects such as nausea, vomiting and damage of normal tissues, attempts to use podophyllotoxin in the treatment of human neoplasia have been mostly unsuccessful. In the 1950s, a search was initiated to identify a more effective podophyllotoxin derivative, that eventually resulted in the development of a new class of anti-neoplastic agents. The most important of these compounds are etoposide, teniposide, and etoposide phosphate, which are semisynthetic derivatives of 4- epipodophyllotoxin. They have several limitations, such as poor water solubility, development of drug resistance, metabolic inactivation. Recently novel 4-aza-2,3-didehydropodophyllotoxins have been reported by a number of researchers, which displayed cytotoxicity comparable to that of podophyllotoxin. In the present study we report the synthesis and biological evaluation of novel Podophyllotoxin derivatives as anticancer agents. benzene-1,2-diamine and tetronic acid were stirred in ethanol in the presence of catalytic amount of acetic acid to afford 4-((2-aminophenyl)amino)furan- 2(5H)-one, then substituted benzaldehydes dissolved in chloroform and combined in the presence of catalytic amount of acetic acid under microwave irradiation to obtain the target compounds, then chloroacetyl derivatives were prepared using chloroacetyl chloride. The compounds were characterized by nuclear magnetic resonance, infrared and mass spectrometry.The cytotoxic activity of the synthesized compounds is under evaluation against MCF-7, PC3, cancer cells employing the MTT assay. Some of our compounds showed significant toxicity in MCF-7 cancer cells after initial assessment. DNA fragmentation occurs due to cell-cycle arrest in the G2/M phase. To investigate whether compounds exhibiting high cytotoxic activity induce apoptosis of cells, the effects of this compounds to induce apoptosis are also under evaluation by apoptosis assay

کلیدواژه ها:

Breast Cancer ، Cancer Diagnosis ، Cancer Treatment and Management ، Drugs and Cancer ، Chemotherapy