Diphyllin Analogues: Design, Synthesis And Biological Evaluation

In this paper, analogues based on natural compounds diphyllin have been synthesized to discover new antitumor candidate agents.Lignans and in particular arylnaphthalene lignans have attracted more and more attention from researchers working in the field of oncology. Diphyllin is a typical 1-arylnaphthalene lignan isolated from the plants of Justicia procumbens L. (Acanthaceae), which was found possesing a wide spectrum of biological and pharmacological activities, including anticancer, antimicrobial, and antiviral. We conclude the structure-activity relationships based on the literatures before: 1) The different cytotoxicity between diphyllin and other justicidins indicated that theγ-lactone ring carbonylαto C-2 instead of C-3 is essential to potent cytotoxicity. 2) Protection at C-4 of diphyllin resulted in enhanced cytotoxic activity. 3) O-glycosylation with more than one sugar unit at C-4 led to less cytotoxic activity. 4) The methoxyl at C-6 and C-7 are essential to the activity.So we have designed, synthesized four types analogues (26 compounds) including ethers, esters, heterocycles and glycosides. The cytotoxic activities of some fifteen compounds were determined by the MTT or SRB assays, using the MCF-7, A549, and K562 cell lines. Three compounds (57, 61 and 71) showed moderate cytotoxic activities. 57 and 61 with octyl and cyclohexyl in C-4 position exhibited better activities than the natural products diphyllin and justicidin A against MCF-7 and K562 cell lines. The results implicated larger hydrophobic groups at C-4 position of diphyllin may lead to higher cytotoxic activities. On the other side, modification on ring C in diphyllin (compound 71) may also lead to a new kind of cytotoxitic agents. Further investigations are actively being pursued in this laboratory and will be reported in due course.