Qiong Xiao

Concise total synthesis of largazole

The concise total synthesis of largazole was accomplished. The key step included the use of the Nagao thiazolidinethione auxiliary for the diastereoselective acetate aldol reaction and it acts as an acylating agent for the peptide formation.

Highly Efficient and Versatile Synthesis of Lactams and N-Heterocycles via Al(OTf)3-Catalyzed Cascade Cyclization and Ionic Hydrogenation Reactions

The discovery and development of an efficient and versatile method for the synthesis of N-substituted lactams is described. Pyrrolindinones, piperidones, and structurally related heterocycles were formed by Al(OTf)3-catalyzed cascade cyclization and ionic hydrogenation reactions of corresponding nitrogen substituted ketoamides in good yields.

Development of a selective S1P1 receptor agonist, Syl930, as a potential therapeutic agent for autoimmune encephalitis

Sphingosine-1-phosphate receptor subtype 1 (S1P1) is essential for lymphocyte egress from secondary lymphoid organs and is a validated drug target for the treatment of autoimmune disorders. However, during the preclinical and clinical trials of S1P1 modulators, the undesired activation of S1P3, a subtype of sphingosine 1-phosphate (S1P) receptors family, by S1P1 modulators often results in bradycardia in patients. Thus, we designed and synthesized a new series of selective S1P1 agonists. One of them, Syl930 (the prodrug), is preference to activate S1P1 but not S1P3. In this study, we further investigated the therapeutic potential of Syl930 on an experimental autoimmune encephalomyelitis (EAE) model in Lewis rats. We found that Syl930 can activate and internalize S1P1 receptors and effectively decreased the periphery blood lymphocytes (PBL) in SD rats, and subsequently rendered PBL insensitive to egress signal from secondary lymphoid organs (SLO). Intriguingly, the treatment of Syl930 did not bring any side effect on heart rate of the tested rats. Furthermore, the suppressed PBL caused by Syl930 was able to recover within 3 days after the last dose of treatment, which is correlated to the relatively short elimination half-life of Syl930. In the rat EAE model, therapeutic treatment with Syl930 significantly inhibited the progression of EAE and EAE-associated histological changes in brain and spinal cord of Lewis rats. These results illustrate that, as a selective S1P1 agonist, Syl930 exhibits a profound and rapidly reversible suppression of lymphocyte trafficking and it has the potential to serve as a therapeutic agent for autoimmune encephalitis.

Total synthesis of (+)-conagenin

A new approach for the synthesis of the (+)-conagenin has been achieved based on Evans asymmetry syn-aldol reaction and the self-regeneration of stereocenters strategy.

Design, synthesis and docking-based 3D-QSAR study of novel 2-substituted 2-aminopropane-1,3-diols as potent and selective agonists of sphingosine-1-phosphate 1 (S1P1) receptor

Spingosine-1-phosphate receptor 1 (S1P1) has been actively pursued as an important therapeutic target in immune regulation. A series of 2-substituted 2-aminopropane-1,3-diols were designed and synthesized as selective S1P1 agonists. Most of the compounds with a biphenyl ether scaffold showed moderate to excellent S1P1/S1P3 selectivity. Compound 40c is identified as a potent S1P1 agonist with 350-fold S1P1/S1P3 selectivity. 39c, the alcohol form of 40c exerted good lymphopenia activity in vivo but with weak influence on heart rate. To investigate the SARs of 2-substituted 2-aminopropane-1,3-diols in more details, COMFA (q2 = 0.547, r2 = 0.986) and COMSIA (q2 = 0.544, r2 = 0.943) models were established based on molecular docking alignment, which were validated with high reliability in predicting activities of agonists. The 3D-QSAR models will be helpful in the design of novel, potent and selective S1P1 agonists.

Total synthesis of (−)-talaumidin and (−)-galbelgin

( − )-Talaumidin (1) and ( − )-galbelgin (2) have been synthesized via 4-pentenoic acid as a starting material with the overall yield of about 17.8 and 16.9%, respectively. The key steps include Evans asymmetry anti-aldol reaction, TBS protection, hydroboration, oxidation, Friedel–Crafts arylation, etc.

Synthesis of dihydrobenzoheterocycles through Al(OTf)3-mediated cascade cyclization and ionic hydrogenation.

A facile and versatile synthesis of dihydrobenzoheterocycles via Al(OTf)3-mediated cascade cyclization and ionic hydrogenation has been developed. The reaction is applicable to a wide range of substrates with various functional groups to afford the corresponding products in good yields.

Assembly of substituted phenanthridines via a cascade palladium-catalyzed coupling reaction, deprotection and intramolecular cyclization

The discovery and development of a general method for the one-pot synthesis of substituted phenanthridines is presented. In the presence of Pd(PPh3)4, accessible precursors undergo a Suzuki cross-coupling reaction with 2-(Boc-amino)benzeneboronic acid pinacol ester and then spontaneously undergo deprotection and intramolecular condensation to form the corresponding phenanthridines in one step. This reaction has a wide range of substrates with various functional groups, and the corresponding products have been obtained in good yields.

Resolution and chiral recognition of muscone as well as actions on neural system.

In this letter, (R)-muscone and (S)-muscone were prepared by optical resolution of dl-muscone using N,N′-dibenzyl-l-tartaramide or N,N′-dibenzyl-d-tartaramide, according to the method reported by Kunihiko Takabe. But we separated the diastereomers using EtOH instead of MeOH in the recrystallization step to get the goal product with higher optical purity and yield. The regulatory effect of muscone and its enantiomer on the neural system showed that they could prolong mouse hypoxia tolerance and dose-dependently enhance mouse spinal cord stimulation induced by strychnine nitrate. (R)-muscone and (S)-muscone had a synergistic action on shortening sleep time induced by sodium pentobarbital in mice.

Synthesis, identification, and biological activity of metabolites of two novel selective S1P1 agonists.

SYL927 and SYL930 are selective S1P1 agonists under preclinical development. However, during their pharmacokinetic studies we detected two metabolites in rat blood that were tentatively identified as monohydroxylated metabolites of SYL927 and SYL930 based on LC-MS/MS data. In this study, we designed and synthesized possible monohydroxylated products 6a-e and used them as references to confirm the structures of the two metabolites detected by LC-MS/MS. We also evaluated the in vitro and in vivo biological activities of these two metabolites.