目前实验室研究方向主要有原子经济有机合成方法学开发，天然产物高效或仿生全合成，利用化学生物学新策略探索小分子与靶点的相互作用鉴定药物新靶点与重要的生物学机理，以及基于新靶点的小分子药物开发。实验室开发了新颖的烷基锆广谱偶联合成方法学，首次发现了烷基锆试剂的光化学与新型自由基偶联反应途径；首次完成硼元素导向的烷基锆选择性远程迁移控制并应用到高对映选择性手性硼试剂的合成中。基于自然界丰富的天然原材料如呋喃，吲哚，单糖以及天然氨基酸等，通过分子骨架重排或者去平面化策略成功构建了以sp3杂化原子为主的三维立体“优势药效骨架”并应用到高生物活性的天然产物的全合成和仿生合成中；基于高通量筛选鉴定苗头化合物，结合构效关系和计算机辅助药物设计进行系统的药物化学开发了几类尚未满足临床需求的原创新药备选分子,如抑制乙肝病毒感染的胆酸二聚体，调节生物钟和睡眠的虫草素衍生物以及癌症治疗相关的激酶抑制剂和诱导蛋白降解或者介导蛋白蛋白相互作用的分子胶水等。

Novel Synthetic Methodology(合成方法学):

The use of small molecules to probe systematic and disease-associated biological phenomena is an important aspect of our research. Motivated by the urgent applications of small molecules in therapeutics and biomedical research, we are devoted to design innovate strategy that assembly a wide variety of challenging complex molecules in a highly efficient manner for biomedical evaluation and novel function exploration.

Saturation of carbon or heteroatoms, especially sp³-hybridized and stereogenic atoms in pharmacophore allows the preparation of architecturally more complex molecules for the exploration of more diverse chemical space. While biological activity of small molecule and clinical success are highly correlated with greater complexity of the molecule, the increasing sp3 character of carbon may improve the complexity and therefore increase the opportunity to adjust molecular shape by out-of-plane 3-D interaction of receptor/ligand that are not accessible for a flat aromatic ring, and thus improve potency and selectivity.  In our lab, we mainly focus on the synthetic logic and strategy for the activation, functionalization, and formation of sp3-carbon-carbone or sp3-carbon-heteroatom single bond. We, for the first time, developed the visible-light-induced single nickel-catalyzed C(SP³)–C(SP³), C(SP³)–C(SP²), and C(SP³)–C(SP) cross-coupling of alkylzirconocenes, which are easily prepared from unactivated alkenes either via steric-releasing “chain-walking” or Boron-directed “chain-walking”. High functional group tolerance and pharmacophore derivatization under mild conditions enable this method to be of practical significance. Furthermore, we have developed a highly enantioselective cross-coupling to build C(SP³)–C(SP³) single bond with chiral center asymmetrically. The mechanism studies supported a novel radical cross-coupling process and the synthetic potential of organozirconium will be extended within the lab.

Total Synthesis of Natural product:

While biological activity of small molecule and clinical success are highly correlated with greater complexity of the molecule, the increasing sp3 character of carbon may improve the complexity and therefore increase the opportunity to adjust molecular shape by out-of-plane 3-D interaction of receptor/ligand that are not accessible for a flat aromatic ring, and thus improve potency and selectivity. These criteria have also been applied to molecular complexity of natural product-like drug candidates by reducing the aromatic character of a molecule, which might further improve physical characteristics not only for better efficacy, but also for better bioavailability.

Inspired by the rapid and efficient construction of molecular complexity from simple precursors in natural living systems, our lab is mainly focused on the logic of the total synthesis of sp3-atoms enriched natural product from biomass-derivatives or naturally abundant feedstocks. The utility of these renewable green building blocks has been demonstrated by the total synthesis of a variety of natural products through sp2 to sp3 carbon skeleton transfer strategy and environmentally friendly cascade process, which involves the formation of several chemical bonds and stereogenic centers simultaneously with excellent stereoselectivity. We developed a cascade reaction of chemoselective furan oxidation in combination with the controllable indole nucleophilic cyclization, which provides a rapid means for constructing a diverse set of structurally unrelated indole alkaloids and their unnatural analogues. Furan derivatives-based Aza-Achmatowicz rearrangement enabled the asymmetric total synthesis of (-)-alstofolinine A. Another sp2 to sp3 carbon skeleton transfer via indole hydrogenation strategy has been successfully effectuated and the resulting hydrogenated indole synthons has been applied into the total synthesis of architecturally complex natural products, such as lycorane-type alkaloids, strychnos and akuammicine alkaloids. Besides the total synthesis, the mode of action study is highly investigated in the lab to reveal the role that natural products have and will continue to play in mapping important biochemical networks and identification of novel therapeutic targets.

Medicinal Chemistry:

The use of small molecules to probe systematic and disease-associated biological phenomena is an important aspect of our pursuits for exciting discoveries of biomaterials, chemical biology as well as pharmaceutical agents to solve serious health problem in living system. Motivated by the urgent and valuable applications of small molecules in therapeutics and biomedical research, we are devoted to synthesizing small molecules in novel ways and examining their biological properties among a wide variety of biological areas conducted at NIBS.  The outcomes of this biological evaluation and the performance in biological screening are the main guidance for further synthesis design. After a range of chemicals is screened against a particular drug target or disease model, and the qualified “hits” chemicals are concentrated and analyzed. Hit to lead development will be conducted to extend out the chemical library through “activity-oriented synthesis”. Lead optimization will be enforced with subtle and profound modifications to satisfy a variety of pharmaceutical rules before they become clinical candidates, including but not limited to solubility, oral bioavailability, cell membrane permeability and many other known druggability features. In close collaboration with several biology labs at NIBS, we have developed one small molecule that regulates circadian clock for 12 hours and identified the molecular target. We also discovered two novel types of molecular glue, one is promoting CDK12-DDB1 interaction to trigger Cyclin K degradation, another one inducing the phosphodiesterase 3A-schlafen 12 interaction to trigger the cancer cell apoptosis. We also identified the molecular target of an indole alkaloid, Nauclefine, and elucidated its mechanism of action in phosphodiesterase 3A-schlafen 12 dependent apoptosis. A highly potent and unique dimeric bile acid type of NTCP inhibitor for HBV infection and four novel kinase inhibitors towards BTK, LCK, IKKε and PDK2 have been developed. 

High-Throughput Screening

HTS is a drug-discovery process widely used in the pharmaceutical companies and biomedical research institutes. Using robotics, data processing and control software, liquid handling devices and sensitive detectors, HTS conduct extremely scalable assay to test the biological or biochemical activity of a large number of small molecules for discovering active agents for receptors, enzymes, ion-channels or other pharmacological targets in the molecular and cellular level of biomolecular pathway. Typically, HTS assays are performed in microtiter plates with a 96 or 384 well format. HTS is one of main facilities in our lab to provide comprehensive services including the use of HTS technology, compounds in various libraries, a database of results from screens and lead optimization. On a collaborative basis, HTS has the capability to support cellular and biochemical assays using absorbance, fluorescent kinetics, fluorescence resonance energy transfer, AlphaScreen, bioluminescence and cellular fluorescence imaging. In addition, HTS has expertise in adapting those biological and biochemical bench-top assays into high-throughput screening settings.  Our HTS libraries are designed for diversity around not only well-established pharmacophore, but also very strict molecular property profiles that were balanced between diversity, physicochemical favorability, intrinsic complexity, and synthetic tractability. Encouraged by the fact that a significant number of marketed drugs are derived from natural products, we are also interested in expanding natural chemical products in compound libraries and developing effective strategy to diversify the core backbone structure of natural products. We will design and explore biomimetric synthetic pathways to build up the molecule efficiently. Easily modified structure and high selective strategy will be preferred. The organocascade type assembling of complex structure will eventually result in the discovery of novel bio-valuable molecules to diversify the library. Biomedical and clinical property profiles will be highly considered for the library design and construction process.