Discovery,Methodological Study,structural Modificationand Antitumor Activity Research Of A Novel Celastrol Derivative XS0696

Celastrol,a principal bioactive ingredient of Celastraceae plants used in traditional Chinese medicine,has been reported to be able to regulate numerous cellular pathways.And it has been demonstrated to be a potent inhibitor of proliferation of different cancer cells,such as breast and prostate as well as leukemia,hampering their invasion and metastasis.Various celastrol derivatives have been synthesized because it suffers some limitations of druglike properties,such as poor water stability,low bioavailability,high toxicity,and narrow therapeutic window.But the reported modifications are always limited on C-2,C-3 of ring A,C-6 of ring B and C-20 of ring E,while alternation on other sites haven’t been developed.Therefore,this project aims to obtain celastrol analogs with novel structure and intellectual property rights.First,we synthesized a new celastrol derivative XS0696.The work related to this compound include:1)Confirm XS0696’s structure by employing various strategies such as nuclear magnetic resonance,high resolution mass spectrometry,and single crystal X-ray diffraction.2)Developed a synthetic method of novel oxidized celastrol:celastrol was dissolved in 1,4-Dioxane,accompanied with the treatment of SeO2 and concentrated sulfuric acid.The reaction was stirred at room temperature and normal pressure for 4 hours,resulting in a product with a yield of more than 90%.3)We proposed the mechanism of the reaction.The celastrol was first rearranged to obtain the intermediate XS0455 under the catalytic acidic,then SeO2 triggered and facilitated the further oxidation,ring C cleavage,the rotation of ring D/E and recoupling into a ring.And finally the ring A/B/C possess "a piece of straight" conformation,which breaking out of the traditional pentacyclic triterpene skeleton.Moreover,we synthesized a total of 21 derivatives of XS0696:including esterified,amidation of the C-20 carboxylic acid,etherificated one or two hydroxyl groups on ring A,as well as developed a new modification site on the ring C.Then we screened the derivatives’ inhibition effects on tumor cell proliferation activity.It was found that compound XS0571 had the effect of inhibiting cell growth in five tumor cell lines such as MDA-MB-231,Hela,and A375.Further mechanistic studies showed that it may promote tumor cell apoptosis and/or inhibit tumor cell invasion and metastasis by affecting the Akt/mTOR/P70S6K pathway,thereby achieving tumor suppressive activity.