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第十二届海洋药物学术年会

作者： SUN Tian-wen WANG Shi-xiao ZHAO Jian-chun DING Zhong-peng CHENG He-juan LIU Xiao-chun LIU Li CAI Bing GUAN Hua-shi LI Wen-bao School of Medicine and Pharmacy Ocean University of China marine Biomedical Research Institute of Qingdao

Plinabulin is a synthesized diketopiperazine type tubulin inhibitor discovered based on the structure-activity relationship（SAR）study of Phenylahistin,which was isolated from *** was observed that Plinabulin binds between alpha and beta tubulin subunit which is close to colchicine-binding site of *** study indicated that it has good efficacy,pharmacokinetics and safety properties,current it is in phaseⅢclinical ***,we are working on optimization of its synthesis *** ethyl isocyanoacetate and three methyl acetic anhydride as starting materials,the imidazole aldehyde was obtained through four steps;and then the target molecule was accomplished through two steps of condensation reaction,the total synthesis yield is 12%.The double bond Z,E isomers can be produced in the second condensation reaction,and the Z isomer,which has anti-tumor activity,can be obtained by avoiding *** screening indicated that Plinabulin has strong inhibition the growth of A431 human skin cancer cell,the inhibition rate was91.8%in 12.5 nm concentration *** intracellular fluorescence intensity of the microtubule protein enhanced,and the cell morphology altered were observed with using Alexa488 *** order to obtain a new generation of anti-tumor drugs with better biological activity and to overcome the existing drug resistance,our group has designed and synthesized a series of novel derivatives based on the structure of ***-001,a new marine anti-tumor drug candidate having good druggability,was selected to preclinical study through activity screening,preliminary pharmacokinetics and safety studies.

关键词： Plinabulin Tubulin inhibitor marine drug Anti-tumor drug candidate

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Recent Advances of Bioactive marine Natural Products in drug Discovery

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Journal of Ocean University of China 2024年第5期23卷 1297-1318页

作者： ZHANG Qun LV Liuxia WANG Wenhui WEI Meiyan GU Yucheng SHAO Changlun Key Laboratory of marine drugs Ministry of Education of ChinaSchool of Medicine and PharmacyOcean University of ChinaQingdao 266100China Laboratory for marine drugs and Bioproducts Qingdao Marine Science and Technology CenterQingdao 266237China Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education College of Chemistry and Chemical EngineeringHainan Normal UniversityHaikou 571158China Syngenta Jealott’s Hill International Research Centre BracknellBerkshire RG426EYUK

marine natural products(MNPs)are valuable resources for drug *** date,17 drugs from marine sources are in clinical use,and 33 pharmaceutical compounds are in clinical *** the success of drug development from the marine resources is higher than the industry *** is a feasible strategy to conduct the discovery of druglead compounds based on marine chemical ecology by fully exploiting the pharmacological potential of marine chemical defense *** the search for bioactive MNPs,our group has constructed a biological resources library including more than 1500 strains of *** on the strategy of Blue drug Library,we have discovered a series of novel MNPs with abundant biological *** efficient and scalable total synthesis of(+)-aniduquinolone A(44)and pesimquinolone I(48)have been completed,which will facilitate access to sufficient quantities of candidates for in vivo pharmacological and toxicological *** a nucleoprotein(NP)inhibitor,QLA(75)possesses significant anti-influenza A virus(IAV)activities both in vitro and in ***-00803(76)is a potent and selective AMP-activated kinase(AMPK)activator that can effectively inhibit metabolic disorders and metabolic dysfunction-associated steatohepatitis(MASH)***,we identified two new candidate molecules with potent anti-hepatocellular carcinoma ***,as a natural guanine-nucleotide exchange factors for ADP-ribosylation factor GTPases(Arf-GEFs)inhibitor prodrug,CHNQD-01255(78)is qualified to be developed as a targeted candidate anticancer drug,which may be promising to apply for cancer ***,it is evident that MNPs play an important role in drug development.

关键词： marine medicinal organisms natural products marine drug discovery and optimization drug development

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

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marine Life Science & Technology 2023年第2期5卷 196-210页

作者： Jin Chen Li Xu Xue-Qing Zhang Xue Liu Zi-Xuan Zhang Qiu-Mei Zhu Jian-Yu Liu Muhammad Omer Iqbal Ning Ding Chang-Lun Shao Mei-Yan Wei Yu-Chao Gu Key Laboratory of marine drugs the Ministry of EducationSchool of Medicine and PharmacyOcean University of ChinaQingdao 266003China Laboratory for marine drugs and Bioproducts Laoshan LaboratoryQingdao 266237China College of Food Science and Engineering Ocean University of ChinaQingdao 266003China Key Laboratory of Glycoscience and Glycotechnology of Shandong Province Qingdao 266003China The Massachusetts General Hospital Cancer Center Harvard Medical SchoolBostonMA 02114USA

Non-alcoholic steatohepatitis(NASH)is a primary cause of cirrhosis and hepatocellular ***,there is no approved drug treatment for ***-activated kinase(AMPK)is an important metabolic sensor and whole-body *** has been proposed that AMPK activators could be used for treating metabolic diseases such as obesity,type 2 diabetes and *** 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 K_(D) value of 4.728×10^(-8) M and activates AMPK at both molecular and intracellular *** then investigated the roles and mechanisms of CHNQD-0803 in PA-induced fat deposition,LPS-stimulated infammation,TGF-β-induced fbrosis cell models and the MCD-induced mouse model of *** results showed that CHNQD-0803 inhibited the expression of adipogenesis genes and reduced fat deposition,negatively regulated the NF-κB-TNFαinfammatory axis to suppress infammation,and ameliorated liver injury and *** data indicate that CHNQD-0803 as an AMPK activator is a novel potential therapeutic candidate for NASH treatment.

关键词： NASH AMPK Infammation Lipid metabolism Fibrosis marine drug

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A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3232-3250页

作者： Ping Yu Tanwei Gu Yueyang Rao Weimin Liang Xi Zhang Huanguo Jiang Jindi Lu Jianglian She Jianmin Guo Wei Yang Yonghong Liu Yingfeng Tu Lan Tang Xuefeng Zhou Guangdong Provincial Key Laboratory of New drug Screening Guangdong-Hong Kong-Macao Joint Laboratory for New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China CAS Key Laboratory of Tropical marine Bio-Resources and Ecology Guangdong Key Laboratory of Marine Materia MedicaSouth China Sea Institute of OceanologyChinese Academy of SciencesGuangzhou 510301China NMPA Key Laboratory for Research and Evaluation of drug Metabolism School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Guangdong Lewwin Pharmaceutical Research Institute Co. Ltd.Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and ResearchGuangdong Engineering Research Center for Innovative Drug Evaluation and ResearchGuangzhou 510990China

Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its *** study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)***,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS *** to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed *** developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 *** encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,*** main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated *** summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.

关键词： Acute kidney injury Piericidin glycoside Peroxiredoxin 1 Nanodrug Kim-1 targeted ADME marine drug druggability

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