Synthesis And Anti-tumor Activities Of Novel Cleistanthin A Analogues

ObjectiveIn this study, the lignan and glycosyl of Cleistanthin A, was modified to improve the inhibitory activities of Cleistanthin A against vacuolar H+-ATPase(V-ATPase) and water solubility. A series of analogues of Cleistanthin A were acquired and their antiproliferative activity in cancer cells was assessed.Methods1) Chemistry: A ring or D ring in lignan of Cleistanthin A was modified through chemical synthesis, various of aromatic aldehydes were used as basic materials to synthesis lignan analogues by a five-step reaction including Adol and Diels-Alder reaction, and their overall yields were 38.5-43.5%. Then, eight diphyllin glycosides analogues were synthesized from lignan analogues and 2-O-acetyl-3,4-di-O-methyl-α-xylopyranosyl bromide using the reaction of phase transfer catalysis(PTC). Various heterocyclic bases, such as morpholine, and piperidine, were connected to C-2” hydroxyl group of glycosides of Cleistanthin A by means of different length of fatty acid chains as the connecting arm and 14 diphyllin glycoside derivatives were achieved.2) Antitumor activities: A549, HCT-116, Hep G2, and Hela cells were exposed to 22 Cleistanthin A analogues. IC50 values were calculated to determine the anti-proliferative activities of these compounds by MTT assay.3) Octanol-water partition coefficient assay: Ultraviolet–visible spectroscopy(UV-Vis) was used to measure the large absorption wavelength of 22 Cleistanthin A analogues in water-saturated solution and n-octyl alcohol solution, showing the absorption value in aqueous phase and oil phase. Then, the octanol-water partition coefficient log P was calculated through the formula logP=log(Co/Cw).Results1) Twenty two analogues of Cleistanthin A were synthesized, and their chemical structures were confirmed by 1H NMR, 13 C NMR and HRMS.2) The IC50 values of 22 Cleistanthin A analogues were obtained by MTT assay. Structure-activity relationship analysis showed that the anti-proliferative activities of compound through modifying substituent of A ring or D ring in lignan were decreased compared to Cleistanthin A, while adding 3-hydroxy to D ring increased its activities. The compound showed strong inhibitory activites through adding various chain of heterocyclic base to hydroxyl of C-2” in the part of glycosyl-Cleistanthin A. Their activities were gradually deceased along with the increased length of C-chain of glycosyl. When terminal base was morpholine or methyl piperazine, their activities wound be better than other base. The results also showed that the inhibitory activities of these 22 compounds against HCT-116 cells were stronger than other three cancer cell lines, and this indicated the selectivity to cancer cells.3) Higher logP value indicates good fat solubity, inversely, the water solubity. When the log P value was less than 5, oral bioavailability of the compound became better, providing important evidence for pharmacodynamics. All the log P values of these 22 Cleistanthin A analogues were distributed between 2 and 6, suggesting the better oral bioavailability.ConclusionsTwenty two Cleistanthin A analogues were synthesized. The majority displayed good pharmacodynamics and strong anti-proliferative activities. The inhibitory activity of compound 9e was better than natural diphyllin glycosides Cleistanthin A; Twenty-two Cleistanthin A analogues also showed good selectivity to cancer cells.