{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T05:27:16Z","timestamp":1765949236700,"version":"3.48.0"},"reference-count":49,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82460846"],"award-info":[{"award-number":["82460846"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Key Research and Development Program of Hainan Province","award":["No. ZDYF2022SHFZ037"],"award-info":[{"award-number":["No. ZDYF2022SHFZ037"]}]},{"name":"the Hainan provincial Nature Science Foundation of China","award":["221MS040"],"award-info":[{"award-number":["221MS040"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cassytha filiformis is a folkloric herbal medicine used to treat type 2 diabetes mellitus (T2DM). In this study, an oxidized aporphine alkaloid, designated as Filiforidine (3,10,11-trimethoxy-1,2-methylenedioxy-7-oxoaporphine), was isolated from C. filiformis, and its structure was elucidated through comprehensive spectroscopic analysis. Owing to its novel structure and significant glucose consumption activity, the total synthesis of Filiforidine was achieved for the first time. The key steps featured an electrophilic addition reaction, involving the reduction of a nitro group to an amino group with lithium tetrahydroaluminum, and a copper bromide-catalyzed oxidative aromatization reaction as well as a photocyclization reaction. Several experimental steps were optimized. Furthermore, a complex post-treatment method was developed, which reduced the column chromatography separation steps. Specifically, 2-(4-methoxybenzo[d][1,3]dioxol -5-yl) ethan-1-amine is salted with dilute hydrochloric acid. Cytotoxicity assay and glucose oxidase assay showed that Filiforidine had significant glucose consumption-promoting effects on HL-7702 cells at 0.625 \u03bcM, 1.25 \u03bcM, and 2.5 \u03bcM but without cytotoxicity. Therefore, Filiforidine might be a promising drug candidate for the treatment of diabetes.<\/jats:p>","DOI":"10.3390\/molecules30244763","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T15:27:20Z","timestamp":1765553240000},"page":"4763","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Isolation, Total Synthesis and Anti-Diabetic Activity of Filiforidine from Cassytha filiformis"],"prefix":"10.3390","volume":"30","author":[{"given":"Caiyun","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China"},{"name":"School of Pharmaceutical Science, Hainan Medical University, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Hainan Medical University, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Hainan Medical University, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuexia","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Hainan Medical University, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zibao","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Hainan Medical University, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Hainan Medical University, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niangen","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Hainan Medical University, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaopo","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Hainan Medical University, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanhui","family":"Fu","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7785","DOI":"10.1038\/s41598-019-44076-8","article-title":"ATAC-seq reveals alterations in open chromatin in pancreatic islets from subjects with type 2 diabetes","volume":"9","author":"Bysani","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e70003","DOI":"10.1002\/cph4.70003","article-title":"Type 2 diabetes mellitus: A comprehensive review of pathophysiology, comorbidities, and emerging therapies","volume":"15","author":"Singh","year":"2025","journal-title":"Compr. Physiol."},{"key":"ref_3","unstructured":"I.D.F. (2025). Diabetes Atlas, I.D.F.. [11th ed.]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/s41586-018-0088-0","article-title":"Pancreas regeneration","volume":"557","author":"Zhou","year":"2018","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2147\/JEP.S226113","article-title":"A recent achievement in the discovery and development of novel targets for the treatment of type-2 diabetes mellitus","volume":"12","author":"Belete","year":"2020","journal-title":"J. Exp. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jare.2024.06.027","article-title":"Anti-diabetic effect of dicaffeoylquinic acids is associated with the modulation of gut microbiota and bile acid metabolism","volume":"72","author":"Huang","year":"2025","journal-title":"J. Adv. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"140965","DOI":"10.1016\/j.foodchem.2024.140965","article-title":"Rapid and accurate detection of cinnamon oil adulteration in perilla leaf oil using atmospheric solids analysis probe-mass spectrometry","volume":"462","author":"Wu","year":"2025","journal-title":"Food Chem."},{"key":"ref_8","first-page":"7298","article-title":"Polysaccharide from Momordica charantia L. Alleviates Type 2 Diabetes Mellitus in Mice by Activating the IRS1\/PI3K\/Akt and AMPK Signaling Pathways and Regulating the Gut Microbiota","volume":"73","author":"Zhang","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural products as aources of new drugs over the nearly four decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_10","first-page":"725","article-title":"Research progress of total alkaloids of Mulberry Twig in the treatment of diabetes mellitus","volume":"35","author":"Shen","year":"2021","journal-title":"Chin. J. Pharmacol. Toxicol."},{"key":"ref_11","first-page":"380","article-title":"Evaluation of antioxidant activity of Cassytha filiformis","volume":"2","author":"Mythili","year":"2011","journal-title":"Int. J. Appl. Biol. Pharm. Technol."},{"key":"ref_12","first-page":"59","article-title":"Effect of alkaloids from Cassytha filiformis on mice hepatocellular carcinoma","volume":"28","author":"Cheng","year":"2011","journal-title":"Fujian Norm. Univ."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1055\/s-2004-818967","article-title":"Alkaloids from Cassytha filiformis and related aporphines: Antitrypanosomal activity, cytotoxicity, and interaction with DNA and topoisomerases","volume":"70","author":"Hoet","year":"2004","journal-title":"Planta Med."},{"key":"ref_14","first-page":"6","article-title":"Preliminary evaluation of the antihyperglycaemic properties of medicinal plants in Nsukka Area, Enugu State, Nigeria","volume":"5","author":"Ezeigbo","year":"2010","journal-title":"Int. J. Curr. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1021\/np970348g","article-title":"Chemical constituents from Cassytha filiformis II","volume":"61","author":"Chang","year":"1998","journal-title":"J. Nat. Prod."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, C.Y., Lin, Y.R., Xie, L.C., Wang, Y.R., Xie, Z.R., Dong, L., and Fu, Y.H. (2025). Three new aporphine alkaloids with glucose consumption increase activity from Cassytha filiformis. Molecules, 30.","DOI":"10.3390\/molecules30234544"},{"key":"ref_17","first-page":"704","article-title":"Research progress in anti-diabetic activities of aporphine alkaloids","volume":"41","author":"Liu","year":"2017","journal-title":"Prog. Pharm. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"155986","DOI":"10.1016\/j.phymed.2024.155986","article-title":"Effects of the oxoaporphine alkaloid hernandonine on dengue virus. Evidence for its mechanisms of action","volume":"134","author":"Liao","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"104883","DOI":"10.1016\/j.fitote.2021.104883","article-title":"New compounds from the stems of Fissistigma oldhamii var. longistipitatum and their cytotoxic activities","volume":"151","author":"Chen","year":"2021","journal-title":"Fitoterapia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3701","DOI":"10.1016\/S0040-4020(01)90654-4","article-title":"Approaches to the synthesis of 7-hydroxyaporphines: Stereoselective synthesis of (\u00b1)-10,11-dimethoxy-7-oxoaporphine, (\u00b1)-7-hydroxyaporphine and (\u00b1)-7-hydroxynoraporphine","volume":"30","author":"Granchelli","year":"1974","journal-title":"Tetrahedron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1055\/s-1986-31796","article-title":"A high-yield method for the methylenation ofo-dihydroxyaromatic compounds: Synthesis of methylenedioxycoumarins","volume":"1986","author":"Castillo","year":"1986","journal-title":"Synthesis"},{"key":"ref_22","unstructured":"Al-Awar, R., Isaac, M., Chau, A.M., Mamai, I., Watson, G., Poda, P., Subramanian, B., Wilson, D., Uehling, M., and Prakesch, B. (2019). Preparation of Substituted Pyrrolopyrimidinylacetamides as Inhibitors of the BCL6 BTB Domain Protein-Protein Interaction and Uses Thereof. (WIPO Patent 2019153080A1)."},{"key":"ref_23","unstructured":"Kirkpatrick, L.D., Indarte, M., and Ihle, N.T. (2015). Methods and Compositions for Inhibiting CNKSR1. (U.S.Patent Application US20150307482A1)."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1007\/s12010-020-03442-3","article-title":"Immobilized arabidopsis thaliana hydroxynitrile lyase-catalyzed retro-henry reaction in the synthesis of (S)-\u03b2-nitroalcohols","volume":"193","author":"Rao","year":"2021","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Liu, M., Gui, D., Deng, P., and Zhou, H. (2019). Asymmetric Henry Reaction of 2-Acylpyridine N-Oxides Catalyzed by a Ni-Aminophenol Sulfonamide Complex: An Unexpected Mononuclear Catalyst. Molecules, 24.","DOI":"10.3390\/molecules24081471"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1021\/acs.joc.4c02491","article-title":"Squaramide-catalyzed asymmetric mannich\/hemiketalization retro-henry cascade reaction of o-hydroxy-alpha-aminosulfones with alpha-nitroketones","volume":"90","author":"Zhu","year":"2025","journal-title":"J. Org. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2868","DOI":"10.1002\/asia.201800799","article-title":"Copper (II) and sodium (I) complexes based on 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo [3.3.1] nonane-5-oxide: Synthesis, characterization, and catalytic activity","volume":"13","author":"Mahmoud","year":"2018","journal-title":"Chem. Asian J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1002\/chem.201203254","article-title":"Template syntheses of copper (II) complexes from arylhydrazones of malononitrile and their catalytic activity towards alcohol oxidations and the nitroaldol reaction: Hydrogen bond-assisted ligand liberation and E\/Z isomerisation","volume":"19","author":"Kopylovich","year":"2013","journal-title":"Chemistry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13912","DOI":"10.1021\/acs.inorgchem.8b02434","article-title":"Bottom-up assembly of a highly efficient metal-organic framework for cooperative catalysis","volume":"57","author":"Li","year":"2018","journal-title":"Inorg. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6137","DOI":"10.1016\/j.bmc.2017.02.005","article-title":"Synthesis and biological evaluation of a D-ring-contracted analogue of lamellarin D","volume":"25","author":"Colligs","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1002\/cmdc.201300261","article-title":"Tetrahydroisoquinolinone-based steroidomimetic and chimeric microtubule disruptors","volume":"9","author":"Leese","year":"2014","journal-title":"Chem. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"115627","DOI":"10.1016\/j.ejmech.2023.115627","article-title":"Antimicrobial activiity of natural and semi-synthetic carbazole alkaloids","volume":"259","author":"Ding","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6962","DOI":"10.1016\/j.bmcl.2012.08.123","article-title":"Antibacterial activity of substituted dibenzo[a,g]quinolizin-7-ium derivatives","volume":"22","author":"Parhi","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1021\/jm00161a029","article-title":"Synthesis and renal vasodilator activity of some dopamine agonist 1-aryl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diols: Halogen and methyl analogs of fenoldopam","volume":"29","author":"Weinstock","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1002\/cmdc.201800318","article-title":"Discovery of aporphine analogues as potential antiplatelet and antioxidant agents: Design, synthesis, structure-activity relationships, biological evaluations, and in silico molecular docking studies","volume":"13","author":"Sharma","year":"2018","journal-title":"Chem. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1021\/jo01317a021","article-title":"Subsessiline: Structure revision and synthesis","volume":"44","author":"Skiles","year":"1979","journal-title":"J. Org. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"28997","DOI":"10.1039\/C8RA05338C","article-title":"Novel total syntheses of oxoaporphine alkaloids enabled by mild Cu-catalyzed tandem oxidation\/aromatization of 1-Bn-DHIQs","volume":"8","author":"Zheng","year":"2018","journal-title":"RSC Adv."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4974","DOI":"10.1021\/jo400645g","article-title":"Direct conversion of 1-(2-bromobenzoyl)isoquinolines to dibenzo[de,g]quinolin-7-ones via reductive photocyclization","volume":"78","author":"Chuang","year":"2013","journal-title":"J. Org. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5435","DOI":"10.3390\/jcm11185435","article-title":"Comparison of glucose-lowering drugs as second-line treatment for type 2 diabetes: A systematic review and meta-analysis","volume":"11","author":"Gu","year":"2022","journal-title":"J. Clin. Med."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Nasykhova, Y.A., Tonyan, Z.N., Mikhailova, A.A., Danilova, M.M., and Glotov, A.S. (2020). Pharmacogenetics of type 2 diabetes progress and prospects. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186842"},{"key":"ref_41","first-page":"596","article-title":"Side effects and practices to improve management of type 2 diabetes mellitus from the viewpoint of patient experience and health care management. A narrative review","volume":"66","year":"2019","journal-title":"Endocrinol. Diabetes Nutr. (Engl. Ed.)"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"110975","DOI":"10.1016\/j.biopha.2020.110975","article-title":"Anti-inflammatory phytochemicals for the treatment of diabetes and its complications: Lessons learned and future promise","volume":"133","author":"Kong","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"487","DOI":"10.2174\/1573399813666170519103230","article-title":"Alternative therapies for diabetes: A comparison of western and Traditional Chinese Medicine (TCM) approaches","volume":"14","author":"Xiao","year":"2018","journal-title":"Curr. Diabetes Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S0254-6272(16)30074-7","article-title":"Review of systematic reviews and Meta-analyses investigating Traditional Chinese Medicine treatment for type 2 diabetes mellitus","volume":"36","author":"Liu","year":"2016","journal-title":"J. Tradit. Chin. Med."},{"key":"ref_45","unstructured":"Dai, H., and Mei, W. (2008). Pharmacology of Li Nationality, Science and Technology Press of China."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1055\/a-0948-9072","article-title":"In Vitro modulation of glibenclamide transport by P-glycoprotein inhibitory antidiabetic african plant extracts","volume":"85","author":"Ezuruike","year":"2019","journal-title":"Planta Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3481","DOI":"10.3390\/ijms15033481","article-title":"Purification and characterization of aporphine alkaloids from leaves of Nelumbo nucifera Gaertn and their effects on glucose consumption in 3T3-L1 adipocytes","volume":"15","author":"Ma","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1055\/s-2006-947199","article-title":"Antihyperglycemic effect of aporphines and their derivatives in normal and diabetic rats","volume":"72","author":"Chi","year":"2006","journal-title":"Planta Med."},{"key":"ref_49","first-page":"111","article-title":"Chrysanthemi Indici FlosAnti-diabetic effects of linarin from via AMPK activation","volume":"42","author":"Ma","year":"2019","journal-title":"Chin. Herb. Med."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/24\/4763\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T05:22:51Z","timestamp":1765948971000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/24\/4763"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,12]]},"references-count":49,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["molecules30244763"],"URL":"https:\/\/doi.org\/10.3390\/molecules30244763","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2025,12,12]]}}}