Showing papers by "Chang-Lun Shao published in 2023"

Highly efficient and scalable total syntheses and stereochemical assignment of potent anti-inflammatory pesimquinolones I and J

Abstract: A highly efficient and scalable total synthesis of pesimquinolone I (1) was accomplished in 5 steps with 3 chromatographic purifications.

Targeted isolation of antitubercular cycloheptapeptides and an unusual pyrroloindoline-containing new analog, asperpyrroindotide A, using LC–MS/MS-based molecular networking

Abstract: Further insights on the secondary metabolites of a soft coral-derived fungus Aspergillus versicolor under the guidance of MS/MS-based molecular networking led to the isolation of seven known cycloheptapeptides, namely, asperversiamides A-C (1-3) and asperheptatides A-D (4-7) and an unusual pyrroloindoline-containing new cycloheptapeptide, asperpyrroindotide A (8). The structure of 8 was elucidated by comprehensive spectroscopic data analysis, and its absolute configuration was determined by advanced Marfey's method. The semisynthetic transformation of 1 into 8 was successfully achieved and the reaction conditions were optimized. Additionally, a series of new derivatives (10-19) of asperversiamide A (1) was semi-synthesized and their anti-tubercular activities were evaluated against Mycobacterium tuberculosis H37Ra. The preliminary structure-activity relationships revealed that the serine hydroxy groups and the tryptophan residue are important to the activity.The online version contains supplementary material available at 10.1007/s42995-022-00157-8.

Analogues of natural products yaequinolones as potential inflammatory inhibitors: Design, synthesis and biological evaluation.

Abstract: Inflammation is connected with a variety of diseases and there is still a need to develop more effective and safer anti-inflammatory drugs. Herein, we synthesized, resolved, and characterized eight enantiopure isomers of yaequinolone J1 (1), yaequinolone J2 (2), 4'-desmethoxyyaequinolone J1 (3), and 4'-desmethoxyyaequinolone J2 (4). The key synthetic steps were extended and 34 racemic analogues modified at the 4-aryl, the N-position, and the pyran ring were designed and synthesized. All the synthesized compounds were evaluated for their anti-inflammatory activities in RAW 264.7 cells of which 13 compounds showed significant inhibition of nitric oxide (NO) production at a concentration of 0.1 μM, which was more potent than that of indomethacin. Furthermore, compounds (-)-3, (-)-4, 5h, and 6g reduced the production of IL-6 in LPS-stimulated RAW 264.7 cells at a concentration of 50 nM. A preliminary SAR indicated that 3'-Br (5h), 4'-NO2 (6g) on 4-phenyl and 3-bromobenzyl (7f) on the N-position were the most effective substituents. This is the first report of the anti-inflammatory yaequinolone alkaloids and the present study provided evidence for exploiting this series of highly efficacious derivatives for new anti-inflammatory agents.

Discovery of a natural small-molecule AMP-activated kinase activator that alleviates nonalcoholic steatohepatitis

Abstract: Non-alcoholic steatohepatitis (NASH) is a primary cause of cirrhosis and hepatocellular carcinoma. Unfortunately, there is no approved drug treatment for NASH. AMP-activated kinase (AMPK) is an important metabolic sensor and whole-body regulator. It has been proposed that AMPK activators could be used for treating metabolic diseases such as obesity, type 2 diabetes and NASH. In this study, we screened a marine natural compound library by monitoring AMPK activity and found a potent AMPK activator, candidusin A (CHNQD-0803). Further studies showed that CHNQD-0803 directly binds recombinant AMPK with a KD value of 4.728 × 10-8 M and activates AMPK at both molecular and intracellular levels. We then investigated the roles and mechanisms of CHNQD-0803 in PA-induced fat deposition, LPS-stimulated inflammation, TGF-β-induced fibrosis cell models and the MCD-induced mouse model of NASH. The results showed that CHNQD-0803 inhibited the expression of adipogenesis genes and reduced fat deposition, negatively regulated the NF-κB-TNFα inflammatory axis to suppress inflammation, and ameliorated liver injury and fibrosis. These data indicate that CHNQD-0803 as an AMPK activator is a novel potential therapeutic candidate for NASH treatment.The online version contains supplementary material available at 10.1007/s42995-023-00168-z.

Inhibition of influenza A virus replication by a marine derived quinolone alkaloid targeting virus nucleoprotein

Abstract: Owing to the emergence of drug resistance and high morbidity and mortality, the need for novel anti‐influenza A virus (IAV) drugs with divergent targets is highly sought after. Herein, a novel quinolone alkaloid (QLA) derived from marine fungus was discovered with broad‐spectrum anti‐IAV activities with low toxicity. Distinct from current anti‐IAV drugs, QLA may block virus replication and viral RNA (vRNA) export from the nucleus by targeting virus nucleoprotein (NP). QLA can block the binding of chromosome region maintenance 1 to nuclear export signal 3 of NP to inhibit the nuclear export of NP and vRNP. QLA may also affect vRNP assembly by interfering with the binding of NP to RNA rather than NP oligomerization. Arg305 and Phe488‐Gly490 may be required for the interaction between QLA and NP, and the binding pocket around these amino acids may be a promising target for anti‐IAV drugs. Importantly, oral administration of QLA can protect the mice against IAV‐induced death and weight loss, superior to the effects of the clinical drug oseltamivir. In summary, the marine derived compound QLA has the potential to be developed into a novel anti‐IAV agent targeting virus NP protein in the future.