Design And Synthesis Of Novel Deguelin Derivatives And Research On Their Antitumor Activities

Objective:Deguelin is a compound of rotenone, a natural compound was separated from a vine or Lour tamarin Meng beans(legumes). Recent studies have found Deguelin inhibit a variety of tumor cells and the molecular targets were very extensive, including cell proliferation signal(cyclin D1, pRb), apoptotic signal(NF-κB, IκBα, Bcl-2, Bcl-xl, survivin, PI3K-Akt, AMPK-mTOR), protein and nucleic acid nuclear pore protein signaling(Nup88, Nup98, Nup214), steroid receptors SRC-3 and DNA topoisomerase. However, in rats, when Deguelin dose was greater than the effective concentration, produced the heart, lungs and nervous system damage, and also caused Parkinson’s disease, so that a huge obstacle for the practical application of Deguelin. Deguelin against these undesirable side effects, we designed and synthesized of six Deguelin derivatives and developed two novel targeted Deguelin derivatives based on Deguelin structural and tested for their anti-tumor activity. Methods:(1) Synthesizing and transforming of Deguelin structure, structural characterization;(2) In vitro evaluation antitumor activity of Deguelin and Deguelin derivatives;(3) Developing two new targeted and imaging Deguelin derivatives, structural characterization and in vitro evaluating anti-tumor activity of two Deguelin derivatives. Results:(1) Six Deguelin derivatives(3a ~ 3c, 4, 5, 6) were tested By CCK-8 method, the results show that the six Deguelin derivatives for A549, H1299, Caco-2, Hela cells have a good inhibition. Compared to the parent Deguelin, 4 and 5 of these four inhibitory effect of tumor cells were better than Deguelin, which means Deguelin’s active sites may be located in keto carbonyl position. In addition, 3a ~ 3c inhibitory effect on H1299 cell was better than Deguelin,but not on the other three cells inhibitory effect, which may be due to 3a ~ 3c of H1299 cells for A549, Caco-2, Hela cytostatic mechanism of apoptosis of tumor cells is not the same, leading to different results. IC50 value of four kinds of tumor cells show that the inhibitory effect of 6 was not better than parent Deguelin, it means Deguelin oxime modification did not improve efficacy.(2) When the concentration of 10 uM and 1uM targeting and imaging Deguelin derivatives 8 and 9 inhibitory activity were better than 3a and 3c on A549 cell, the difference was significant.