Optimization Of Antipyretic Activity Of 1,2,3-triazolopiperazine Hsp90 Inhibitors And Their Antitumor Activity (I) Synthesis Of Chloramphenicol-derived Oxazolidinones And Their Asymmetric Induction In Aldol Reactions (II )

Hsp90 is a molecular chaperone widely spread in eukaryotic cell and it facilitates proper folding of client proteins and prevents them from degradating via the ubiquitin-proteasome pathway under stress conditions. Because multiple oncogenic proteins belong to Hsp90 client protein, hsp90 has emerged as a potent cancer target which can simutaneously disrupt multiple oncogenic pathways.This paper is based on the previous study of our research group and choose the scaffold of tetrahydro-[1,2,3]-triazolopyrazin as ATPase inhibitor in the N-terminal of Hsp90 to further investigate the effect of the substistutes of the phenoxyl on pharmacological activity. The main point are shown as follows:1. Two strategies have been introduced for the choosing of two-substituted phenols, one is to select market-available phenols; second is to use the empirical design method which is to rearange the kinds and the positions of substitutes showing good activity to investigate the synergistic effect of them.2. Mainly two methods were used to introduce sulfhydryl group which is reported rarely in literatures. One is to introduce it by the synthesis of benzoheterocycle; second is through Newmann-Kwart rearrangement reaction. We follow pevious route to synthetise parent structure and connect with above-mentioned two-substituted phenols. Finally 87 target compounds were obtained.3. Preliminary structure-activity relationship was proposed based on the pharmacological activity determination of this library of compounds. When the substitutes are electron withdrawing groups, such as CN、F、Cl、 NO2, either at meta-or para-position, compounds carrying these substitutes in this series generally exhibited high activities. This is the opposite case for the molecules carrying substitutes like -OCH3、-SCH3、SOCH3、SO2CH3. At the cellular level, multiple compounds were found anti-tumor active with the IC50s between 1-10 μM, part were with the IC50s between 0.1-1μM.The two componds 34-4 and 34-18 can reach 10-8 M level for the inhibition of melanoma cell line. At the molecular level, the inhibitory activity of this series of compounds can competed with AUY922, all with the IC50s in 10-8M level.Oxazolidinone chiral auxiliaries are widely used in asymmetric synthesis, such as asymmetric alkylation、asymmertic Diels-Alder and aymmertic aldol reations. This kind of auxiliary is usually prepared from the compound containing 1,2-amino alcohol functionality. In this paper, we synthesize the oxazolidinone derivative from Chloramphenicol in 5 steps and then investigate its asymmertric induction in aldol reaction. The main ponts are shown as follows:1. The total yield of oxazolidinone derivative from Chloramphenicol in 5 steps is 34%. In the first four steps, the yields are really high, however the last Mitsunobu reaction can only be 46%. The reason may be the nitro group on benzene is reduced under this condition.2. For the optimization of aldol reaction conditions, we choose n-Bu2BOTf and TiCl4 as Lewis acid,and three different bases, such as Et3N、DIPEA and TMEDA. At the same time, the amount of Lewis acid and base is also investigated. Finally the opitimizing condition is TiCl4(2.0 equiv.)/TMEDA(3.6 equiv.).3. Aldol reactions between enolates bearing this auxiliary and varied aldehydes in the presence of TiC14/TMEDA were found to proceed in high yield (>80%) and diastereoselectivity (dr≥ 19:1) to give Evans-syn-aldol adducts.4. The structure of enolate donors has no effect on the aldol reaction. It’s worth mentioning that the compound containing branched chain on β position 15c (R=i-Pr) can also proceed well, which is thought as poor substrate in aldol reaction.