Chinese Academy of Medical Sciences & Peking Union Medical College

RESEARCH

Department of Synthetic Medicinal Chemistry

The Department of Synthetic Medicinal Chemistry is a key department for research and development of new drugs in IMM. The research interests are mainly focused on discovery and development of innovative therapeutic agents against cancer, cardiovascular and cerebrovascular diseases, diabetes, psychiatric and neurologic diseases, autoimmune diseases, and infectious diseases. The department consists of 70 scientists, including 16 professors and 19 associate professors. The discipline of medicinal chemistry has been recognized by the Ministry of Education as a key discipline in national medical universities. The department currently has 15 Ph.D. supervisors and 16 M.Sc. supervisors, and has established a postdoctoral program.

In the past six decades, under the guidance and encouragement of many distinguished scientists such as professor Huang Liang and professor Liang Xiaotian, many disciplines related to drug research and development were well established and evolved into an integrated platform in the department. In the process of drug research and development, abundant innovation experience and potent innovation capabilities were developed, and a multidisciplinary scientific research team was established. Presently, many drugs such as Bicyclol tablet, Butylphthalide soft capsules (NBP), Meisoindigotin, Imrecoxib,etc ., have been launched into market. Moreover, some drug candidates including Potassium Butylphthlide, Chlorobenzopiperidone Hydrochloride, Nicousamide, Levo-clausenamide, Buagafuran, Phenlarmide, Pyrifazimine, Procymod, Etomod and Immdiphen are in clinical trials, and there are also numerous patented new chemical entities under preclinical evaluation.

Main research interests:

1) Target-based drug design, optimization and druggability evaluation: using computer-aided drug design and artificial intelligence technology to discover and optimize small-molecule lead compounds; preclinical candidate selection for further development based on comprehensive druggability evaluation.

2) Total synthesis, structural modification and development of bioactive natural products: optimization of complex natural products for the discovery of innovative drugs that originate from natural sources.

3) Chemical biology: design and synthesis of structurally diverse chemical entities (natural products or synthetic molecules) to probe into the biological function and pathological role of novel biological targets, and explore and elucidate the nature of interactions and binding modes between the protein and small molecules.

Principal Investigators

Phase II Clinical Study of Buagafuron: an Anti-anxiety Drug with a Novel Mechanism of Action (Prof. Dalin Yin’s Group)Buagarofuran, derived from natural product from Aquilaria sinensis (Lour.) Gilg, is an anti-anxiety drug developed by Yin’s group. Recently, in a 6-week, multicenter, randomized, double-blind, placebo-controlled clinical study evaluating the efficacy of buagafuran 30–120mg twice daily compared with placebo, buagafuran shows good effect in the treatment of generalized anxiety disorder (GAD). But there was no significant difference between the middle and high dose groups. Meanwhile, the curative effect lasted at least six weeks without the tolerance phenomenon.
Furthermore, adverse events and adverse reactions were relatively few, and most of them were mild, with no need for treatment. There were no severe adverse events including death relevant to the drug.
In conclusion, buagafuran can show an efficient effect for GAD with statistical significance indicating that it has great potential to be a drug on the market. Currently, the phase III clinical trials are being carried out.Read More
Design, Synthesis and Biological Evaluation of Exiguamine A Analogues as IDO1 Inhibitors (Prof. Zhanzhu Liu’s Group)A series of exiguamine A analogues were designed and synthesized via 15 steps. Most analogues exhibited potent IDO1 inhibitory activities with IC50 values at the level of 10-7-10-8 M. The most potent compound showed IDO1 inhibitory activities with an IC50 value of 65.3 nM, which was comparable with the positive control epacadostat (IC50 = 46 nM). Moreover, this compound showed higher selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO) and no cytotoxicity at its effective concentration, rending it justifiable for further optimization and evaluation. The results were published on European Journal of Medicinal Chemistry (Eur. J. Med. Chem., 2021, 223, 113631-113645).Read More
Novel Anti-Drug Resistant TB Drug OTB-658 Has Been Approved for Clinical Trial by NMPA (Prof. Haihong Huang’s Group)Tuberculosis (TB) remains a serious public health challenge, and the research and development of new anti-TB drugs is an essential component of the global strategy to eradicate TB. OTB-658, a conformationally constrained oxazolidinone with improved anti-TB activity and safety profile was developed through a focused lead optimization effort. The discovery and druggability evaluation of OTB-658 were published on the Journal of Medicinal Chemistry (J. Med. Chem. 2020, 63, 17, 9316–933) in July 2020.Read More
Total Synthesis of the Proposed Structure of Characellide B (Prof. Ping Xie’s Group)In 2019, Characellides B were isolated from the marine sponge Characella pachastrelloides. Studies show that it possesses potent anti-inflammatory activity. We attempted and achieved the total synthesis of the proposed structure of characellide B. The key steps include a base-catalyzed α-stereoselective glycosylation, the stereoselective intramolecular reductive etherification of δ-trialkylsilyloxy substituted ketone, and an asymmetric aza-Cope rearrangement reaction. However, comparison of the data of the synthetic characellide B with those of the natural characellide B indicated some possible errors in the original structural assignment. Furthermore, we synthesized the other four stereoisomers, focusing on the D-Asp-D-allo-Thr fragment to determine the actual structure of Characellide B. Nevertheless, the data of the stereoisomers were not consistent with that of the natural product. This work was published on Organic Letters (Org. Lett., 2021, 23, 3680-3684).Read More
Discovery of N-Arylsulfonyl-Indole-2-Carboxamide Derivatives as Potent, Selective, and Orally Bioavailable Fructose-1,6-Bisphosphatase Inhibitors (Prof. Bailing Xu’s Group)Liver fructose-1,6-bisphosphatase (FBPase) is a key enzyme in the gluconeogenesis pathway. Novel N-arylsulfonyl-indole-2-carboxamide derivatives have been disclosed as FBPase inhibitors, possessing a unique binding mode revealed by the X-ray co-crystal structure. Cpd118 produced significant enzymatic activity and glucose-lowering effects on both type 2 diabetic KKAy mice and ZDF rats. This work demonstrated that highly potent FBPase inhibitors with good oral bioavailability could be achieved. The results were published on Journal of Medicinal Chemistry in 2020 (J. Med. Chem. 2020, 63, 10307-10329).Read More
Discovery and Development of Small Molecule PD-1/PD-L1 Inhibitors (Prof. Zhiqiang Feng’s Group)Although immune checkpoint inhibitor PD-1 / PD-L1 mAbs have shown excellent and relatively long-lasting efficacy in a variety of malignant tumors, there are inherent defects of mAbs, such as immunogenicity, instability, poor membrane permeability. Small molecule inhibitors of PD-1 / PD-L1 signaling pathway, which may make up for its deficiency, are more ideal choices. Recently published articles: our team has done a lot of research on the discovery of PD-1 / PD-L1 small molecule inhibitors, and some of the work has been published on European Journal of Medicinal Chemistry (Eur. J. Med. Chem. 2021, 217, 113377) and Bioorganic Chemistry (Bioorg. Chem. 2021, 114, 105034). The patent of the PD-1/PD-L1 small molecule inhibitor discovered by the research group has been authorized by the United States, Russia and other countries. The PD-1 / PD-L1 small molecule inhibitor developed by the research group for tumor immunotherapy has entered clinical research.Read More
Construction of the Tricycle[4.3.1.03,7]decane Core of Palhinine Family Alkaloids (Prof. Shu Xu’s Group)Palhinine family alkaloids are the most structurally complex type of Lycopodium alkaloids. A concise synthesis of the tricyclo[4.3.1.03,7]decane caged core of palhinine alkaloids was developed with SmI2-mediated cyclization and photo-induced radical addition−fragmentation as key steps. Compared with the reported racemic routes which are all based on Diels−Alder-type key reactions, our strategy would be more readily accessible to the asymmetric total syntheses of the palhinine alkaloids (Org. Lett. 2019, 21, 5567–5569).Read More
Rapid Differentiation Between Bacterial Infections and Cancer Using a Near-Infrared Fluorogenic Probe (Prof. Hai-Yu Hu’s Group)The reliable differentiation between bacterial infections and other pathologies is crucial for both diagnostics and therapeutic approaches. To accommodate such needs, we reported the development of an activatable near-infrared fluorescent probe that could be applied in the ultrafast, ultrasensitive and specific detection of nitroreductase (NTR) activity in bacterial pathogens both in vitro and in vivo. Most remarkably, this probe was capable of noninvasively identifying bacterial infection sites without showing any significantly increased signal of tumour sites in the same animal within 30 min.Read More
Design, Synthesis, and Biological Evaluation of a Novel Photocaged PI3K Inhibitor toward Precise Cancer Treatment (Prof. Heng Xu’s Group)Aberrant activation of PI3K/AKT/mTOR signaling pathway plays a vital role in cancer, which therefore has been intensively targeted for cancer therapeutics. Based on our previously disclosed methylquinazoline PI3K inhibitor scaffold, a novel photocaged PI3K inhibitor was discovered. Upon UV irradiation, the photocaged inhibitor demonstrated remarkably enhanced antiproliferative activities against multiple cancer cell lines and significant efficacy in the patient derived tumor organoid model. Furthermore, the photocaged inhibitor also showed favorable anticancer activity in the in vivo zebrafish xenocraft model. Taken together, the photocaged PI3K inhibitor could represent a promising avenue for novel therapeutics toward precise cancer treatment. This work has been published in Journal of Medicinal Chemistry (J. Med. Chem., 2021, 64, 7331-7340).Read More
Caspase‑1 Specific Light-Up Probe with Aggregation-Induced Emission Characteristics for Inhibitor Screening of Coumarin-Originated Natural Products (Prof. Chongjing Zhang’s Group)Zhang’s group chose the fluorophore of tetraphenylethylene−thiophene (TPETH) with aggregation-induced emission characteristics and a large Stokes shift of about 200 nm to develop a molecular probe, C1−P3. The probe has little background signal in aqueous media and exerts a fluorescent turn-on effect in the presence of caspase-1. Moreover, when evaluating the inhibition potency of coumarin-originated natural products, the new probe could generate a true and objective result but not for the commercial probe (Ac-YVAD-AMC), which is evidenced by HPLC analysis. The quick light-up response and accurate screening results make C1−P3 very useful in fundamental study and inhibitior screening toward caspase-1. (ACS Appl. Mater. Interfaces. 2018, 10, 12173−12180.)Read More
Design, Synthesis, and Biological Evaluation of Amidobenzimidazole Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists (Prof. Xiaojian Wang’s Group)A series of amidobenzimidazole STING agonists was described with high potency for the STING receptor. The structure−activity relationship was studied. The lead compounds were measured by a competition binding assay. A deep study of the effect on STING signaling pathway demonstrated that 16g, 24b, and 24e significantly increased the protein levels and mRNA levels of IFN-β, CXCL10, and IL-6. 24b as a representative compound effectively triggered the phosphorylation of STING, TBK1, and IRF3 in both human peripheral blood mononuclear and THP-1 cells. In addition, compound 24b demonstrated impressive antitumor efficacy in mice with established syngeneic colon tumors by intravenous administration. This work has been published in Journal of Medicinal Chemistry (J. Med. Chem. 2020, 63, 260-282).Read More
Determining Essential Requirements for Fluorophore Selection in Various Fluorescent Applications Taking Advantage of Diverse Structure Fluorescence Information of Chromone Derivatives (Prof. Huaqing Cui’s Group)As the key element of fluorescence technique, the selection of different fluorophores affects the detection performance, such as, sensitivity, accuracy and selectivity. Our research found that different fluorescence techniques preferred to use different photophysical properties of fluorophores. The study was published as an inner cover paper in Journal of Medicinal Chemistry (J. Med. Chem. 2021, 64, 1001-1017)Read More
A rapid and sensitive method for chiroptical sensing of α-amino acids via click-like labeling with o-phthalaldehyde and p-toluenethiol (Prof. Li Li’s Group)Li’s group and Professor Chen Gong’s group developed a highly practical method for comprehensive chiroptical sensing of free -amino acids with streamlined operation and high sensitivity via dual CD/UV measurements. The assay takes advantage of an efficient and selective three-component labeling reaction of primary amines with o-phthalaldehyde and p-toluenethiol reagents to derivatize the NH2 group of analytes into an isoindole. The covalent labeling generates sensitive UV and CD readouts, both of which show an excellent linear relationship with the concentration of analytes. The high reactivity and the novel optical reporting mechanism allow fast and accurate measurement without background interference. The sensing assay also works well for other chiral amine compounds. This work has been published on Chemical Science (Chem. Sci., 2021, 12, 2504-2508).Read More
Binding of the SARS-CoV-2 Spike Protein to Glycans (Prof. Zhongping Tan's Group)Infection normally starts with the attachment of the virus to cell-surface glycans like heparan sulfate (HS) and sialic acid-containing glycolipids/glycoproteins. The Tan group with the collaboration of the Cui group examined and compared the binding of the subunits and spike proteins of SARS-CoV-2, SARS-CoV and MERS-CoV to these glycans. Their results revealed that these spike proteins and subunits can bind to HS in a sulfation-dependent manner, the length of HS is not a critical factor for the binding, and no binding with sialic acid residues was detected. Overall, this work suggests that HS binding may be a general mechanism for the attachment of these coronaviruses to host cells, and supports the potential importance of HS in infection and in the development of antiviral agents against these viruses. A research article describing this study was published online in the journal of Science Bulletin on January 19,2021. (Sci. Bulletin, 2021, 66, 1205-1214)Read More