The Structural Modification Of Bufalin And Its Structure-Cytotoixcity Relationships Study

Cardiac glycosides are a diverse family of naturally derived compounds that bind to and inhibit Na+/K+-ATPase. Members of this family have been in clinical use for many years for treatment of heart failure and atrial arrhythmia. More recently, considerable in vitro, in vivo and epidemiological data support novel roles for such drugs for the treatment of cancer. Most notably, it is now established that cardiac glycosides can induce apoptosis and inhibit the growth of cancer cell lines at concentrations close to those found in the plasma of patients with cardiac conditions. Furthermore, on the basis of the increased susceptibility of cancer cells to cardiac glycosides, the potential use of cardiac glycosides as anticancer agents might be associated with fewer side effects than traditional cytotoxic therapies. Bufadienolides are a type of natural cardiac steroids with potent antitumor activities, originally isolated from the Traditional Chinese Medicine Chan’Su. Bufalin is one of major components of Chan’Su, and its content in the crude drug could be as high as1-5%of the dry weight. It also is one of the most potent bufadienolides against cancer cells, such as PC3, DU145, U937, HL60and HeLa cell lines, with IC50values of10-9to10-8mol/L. Furthermore, bufalin can inhibit the growth of human HepG2cell-transplanted tumor in nude mice and prolong the survival of host significantly. Its cytotoxic activities are mediated by induction of cell apoptosis, cell differentiation and cell autophagy. From the1990s, a lot of bufalin analogues have been prepared by isolation, and chemical, biological transformation and evaluated for testing their in vitro and in vivo cytotoxicities. The essential structural requirements of bufalin for increasing cytotoxicities have been indentified:a steroidal C/D cis ring junctures with a C14β-hydroxyl group and a C17β-2-pyrone ring. Unfortunately, these efforts have provided few new more active bufalin derivatives. Therefore, new ideas and approaches are needed to extend investigations of the use of these bufadienolides as anticancer agents.In this paper, we summarized the SARs of cardiac glycosides from literatures in brief. Identified SARs have pointed out the importance of the3-substituted groups. Then, we have designed and synthesized more than30bufalin derivatives with different groups, including ether derivatives and ester derivatives, at C-3position based on bufalin as lead compound, and found compound3(IC50values on HeLa and A549cell lines were0.76nM and0.34nM, respectively) displayed a significant cytotoxic potency compared to the parent compound bufalin (IC50values on HeLa and A549cell lines were26.3nM and14.2nM, respectively) by evaluating their cytotoxic activities against two human tumor cell lines (A549and Hela cells) in vitro. The structure-cytotoxicity relationships (SARs) of these two new series were described.