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Furanonyl amino acid derivatives as hemostatic drugs: design, synthesis and hemostasis performance

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Abstract

Using 3,4-dihalo-2(5H)-furanones and easily available hemostatic drugs, such as tranexamic acid (TA), 4-aminomethylbenzoic acid (ABA), aminocaproic acid (AA) as starting materials, serial multi-functional molecules 2(5H)-furanonyl amino acids are designed by the combination of different pharmacophores, and successfully synthesized by a transition metal-free Michael addition–elimination reaction. The reaction is carried out under mild conditions with ethanol-dichloromethane as solvent and only stirring at room temperature for 24 h, and the yield can be up to 91%. All products are well characterized by infrared spectroscopy (IR), nuclear magnetic resonance (NMR), high-resolution mass spectra (HRMS). Ten typical target compounds among them are selected out for the experiments of hemostasis performance by the evaluation of in vitro clot formation model and liver hemorrhage model. The test results show that, their hemostasis effect is better than the original drugs. Especially the target compound G, a TA derivative from 5-borneoloxy-3,4-dibromo-2(5H)-furanone, has the best hemostasis effect among all the tested compounds. These obtained target molecules are expected to be used as multi-functional hemostatic drugs.

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References

  • Bae J, Cho E, Park JS, Won TH, Seo SY, Oh DC, Oh KB, Shin J (2020) Isocadiolides A–H: polybrominated aromatics from a synoicum sp. ascidian. J Nat Prod 83:429–437

    Article  CAS  PubMed  Google Scholar 

  • Betti M, Genesio E, Panico A, Coccone SS, Wiedenau P (2013) Process development and scale-up for the preparation of the 1-methyl-quinazoline-2,4-dione Wnt inhibitor SEN461. Org Process Res Dev 17:1042–1051

    Article  CAS  Google Scholar 

  • Byczek-Wyrostek A, Kitel R, Rumak K, Skonieczna M, Kasprzycka A, Walczak K (2018) Simple 2(5H)-furanone derivatives with selective cytotoxicity towards non-small cell lung cancer cell line A549 e synthesis, structure-activity relationship and biological evaluation. Eur J Med Chem 150:687–697

    Article  CAS  PubMed  Google Scholar 

  • Cao L, Luo SH, Wu HQ, Chen LQ, Jiang K, Hao ZF, Wang ZY (2017) Copper(I)-catalyzed alkyl- and arylsulfenylation of 3,4-dihalo-2(5H)-furanones (X = Br, Cl) with sulfoxides under mild conditions. Adv Synth Catal 359:2961–2971

    Article  CAS  Google Scholar 

  • Cao L, Li JX, Wu HQ, Jiang K, Hao ZF, Luo SH, Wang ZY (2018) Metal-free sulfonylation of 3,4-dihalo-2(5H)-furanones (X = Cl, Br) with sodium sulfinates under air atmosphere in aqueous media via a radical pathway. ACS Sustain Chem Eng 6:4147–4153

    Article  CAS  Google Scholar 

  • CCDC 2072782 (2021) (for the new compound 6b) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif

  • Cervi G, Magnaghi P, Asa D, Avanzi N, Badari A, Borghi D, Caruso M, Cirla A, Cozzi L, Felder E, Galvani A, Gasparri F, Lomolino A, Magnuson S, Malgesini B, Motto I, Pasi M, Rizzi S, Salom B, Sorrentino G, Troiani S, Valsasina B, O’Brien T, Isacchi A, Donati D, D’Alessio R (2014) Discovery of 2-(cyclohexylmethylamino) pyrimidines as a new class of reversible valosine containing protein inhibitors. J Med Chem 57:10443–10454

    Article  CAS  PubMed  Google Scholar 

  • Cook R, Lyon-Maris J, Martin R (2020) Nihr signals tranexamic acid is safe to use following mild-to-moderate traumatic brain injury. Br Med J 368:m514

    Article  Google Scholar 

  • Costanzo MJ, Almond HR, Hecker LR, Schott MR, Yabut SC, Zhang HC, Andrade-Gordon P, Corcoran TW, Giardino EC, Yabut SC, Lewis JM, de Garavilla L, Haertlein BJ, Maryanoff BE (2005) In-depth study of tripeptide-based alpha-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S-1’subsite and its implications to structure-based drug design. J Med Chem 48:1984–2008

    Article  CAS  PubMed  Google Scholar 

  • Cui QY, Wu TQ, Chen HF, Qin LM, Yu ZQ, Shen HS, Wang ZY (2015) Effective treatment with para-aminomethylbenzoic acid for chronic disseminated intravascular coagulation associated with aortic dissection. Blood Coagul Fibrin 26:334–336

    Article  CAS  Google Scholar 

  • Fedorchuk TP, Khusnutdinova AN, Evdokimova E, Flick R, Yakunin AF (2020) One-pot biocatalytic transformation of adipic acid to 6-aminocaproic acid and 1,6-hexamethylenediamine using carboxylic acid reductases and transaminases. J Am Chem Soc 142:1038–1048

    Article  CAS  PubMed  Google Scholar 

  • Hai Y, Chen MB, Huang A, Tang Y (2020) Biosynthesis of mycotoxin fusaric acid and application of a PLP-dependent enzyme for chemoenzymatic synthesis of substituted l-pipecolic acids. J Am Chem Soc 142:19668–19677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanna CC, Kriegesmann J, Dowman LJ, Becker CFW, Payne RJ (2022) Chemical synthesis and semisynthesis of lipidated proteins. Angew Chem Int Ed 61:e202111266

    Article  CAS  Google Scholar 

  • He Y, Liu DR (2011) A sequential strand-displacement strategy enables efficient six-step DNA-templated synthesis. J Am Chem Soc 133:9972–9975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hom RK, Gailunas AF, Mamo S, Fang LY, Tung JS, Walker DE, Davis D, Thorsett ED, Jewett NE, Moon JB, John V (2004) Design and synthesis of hydroxyethylene-based peptidomimetic inhibitors of human beta-secretase. J Med Chem 47:158–164

    Article  CAS  PubMed  Google Scholar 

  • Husain A, Khan SA, Iram F, Iqbal MA, Asif M (2020) Insights into the chemistry and therapeutic potential of furanones: a versatile pharmacophore. Eur J Med Chem 171:66–92

    Article  CAS  Google Scholar 

  • Jeong HG, Cha BG, Kong DW, Kim D, Yang W, Ki SK, Kim SI, Han J, Kim CK, Kim J, Lee SH (2019) Ceria nanoparticles fabricated with 6-aminohexanoic acid that overcome systemic inflammatory response syndrome. Adv Healthc Mater 8:1801548

    Article  CAS  Google Scholar 

  • Katoh T, Suga H (2022) In vitro selection of foldamer-like macrocyclic peptides containing 2-aminobenzoic acid and 3-aminothiophene-2-carboxylic acid. J Am Chem Soc 144:2069–2072

    Article  CAS  PubMed  Google Scholar 

  • Lin JY, Luo SH, Chen SH, Yang LT, Xiao Y, Huang ZH, Wang ZY (2020) Efficient synthesis, characterization, and application of biobased scab-bionic hemostatic polymers. Polym J 52:615–627

    Article  CAS  Google Scholar 

  • Liou YC, Su YH, Ku KC, Edukondalu A, Lin CK, Ke YS, Karanam P, Lee CJ, Lin WW (2020) Organophosphane-promoted synthesis of functionalized α, β-unsaturated alkenes and furanones via direct β-acylation. Org Lett 21:8339–8343

    Article  CAS  Google Scholar 

  • Liu DD, Wang JS, Liu WQ, Zhang FL, Zhou YR (2020) Synthesis of polycyclic spiro pyrrolidone derivatives via DBU-catalyzed diastereoselective vinylogous aldol-Michael cascade reaction. ChemCatChem 12:3212–3215

    Article  CAS  Google Scholar 

  • Liu WL, Yu ZM, Winssinger N (2021) Total syntheses of paraconic acids and 1,10-seco-guaianolides via a barbier allylation/translactonization cascade of 3-(bromomethyl)-2(5H)-furanone. Org Lett 23:969–973

    Article  CAS  PubMed  Google Scholar 

  • Lokhande G, Carrow JK, Thakur T, Xavier JR, Parani M, Bayless KJ, Gaharwar AK (2018) Nanoengineered injectable hydrogels for wound healing application. Acta Biomater 70:35–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo SH, Yang K, Lin JY, Gao JJ, Wu XY, Wang ZY (2019) Synthesis of amino acid derivatives of 5-alkoxy-3,4-dihalo-2(5H)-furanones and their preliminary bioactivity investigation as linkers. Org Biomol Chem 17:5138–5147

    Article  CAS  PubMed  Google Scholar 

  • Macías-Acosta MP, Valerdi-Contreras L, Bustos-Angel ED, García-Reyes RA, Alvarez-Zavala M, González-Ávila M (2022) Involvement of the fecal amino acid profle in a clinical and anthropometric study of Mexican patients with insulin resistance and type 2 diabetes mellitus. Amino Acids 54:47–55

    Article  PubMed  CAS  Google Scholar 

  • Mo YQ, Wang ZY, Mei WJ, Fu JH, Tan YH, Luo SH (2012) Reaction of 5-alkoxy-3,4-dihalo-2(5H)-furanones with secondary amines: expected versus unanticipated products and their preliminary bioactivity investigations. Monatsh Chem 143:443–453

    Article  CAS  Google Scholar 

  • Obara R, Kamiya M, Tanaka Y, Abe A, Kojima R, Kawaguchi T, Sugawara M, Takahashi A, Noda T, Urano Y (2020) γ-Glutamyltranspeptidase (GGT)-activatable fluorescence probe for durable tumor imaging. Angew Chem Int Ed 60:2125–2129

    Article  CAS  Google Scholar 

  • Palanki MSS, Bhat A, Lappe RW, Liu B, Oates B, Rizzo J, Stankovic N, Bradshaw C (2012) Development of novel linkers to conjugate pharmacophores to a carrier antibody. Bioorg Med Chem Lett 22:4249–4253

    Article  CAS  PubMed  Google Scholar 

  • Pang S, Wang X, Wang P, Ji Y (2021) Biomimetic amino acid functionalized phenazine flow batteries with long lifetime at near-neutral pH. Angew Chem Int Ed 60:4953–4963

    Article  CAS  Google Scholar 

  • Peng P, Xiong JF, Mo GZ, Zheng JL, Chen RH, Chen XY, Wang ZY (2014) A concise synthesis of benzimidazoles via the microwave-assisted one-pot batch reaction of amino acids up to a 10-g scale. Amino Acids 46:2427–2433

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez-Lopez P, Barrenengoa AE, Pascual-Saez S, Cabo ML (2019) Efficacy of synthetic furanones on listeria monocytogenes biofilm formation. Foods 8:647

    Article  PubMed Central  CAS  Google Scholar 

  • Sattler JH, Fuchs M, Mutti FG, Grischek B, Engel P, Pfeffer J, Woodley JM, Kroutil W (2014) Introducing an in situ capping strategy in systems biocatalysis to access 6-aminohexanoic acid. Angew Chem Int Ed 53:14153–14157

    Article  CAS  Google Scholar 

  • Shi J, Tang XD, Wu YC, Li HN, Song LJ, Wang ZY (2015) Palladium-catalyzed desulfitative arylation of 5-alkoxy-3,4-dibromo-2(5H)-furanone with sodium arylsulfinates. Eur J Org Chem 2015:1193–1197

    Article  CAS  Google Scholar 

  • Slomski A (2019) Tranexamic acid improves outcomes in TBI. JAMA-Jam Med Assoc 322:2375–2375

    Google Scholar 

  • Troyano FJA, Merkens K, Anwar K, Gomez-Suarez DA (2021) Radical-based synthesis and modification of amino acids. Angew Chem Int Ed 60:1098–1115

    Article  CAS  Google Scholar 

  • Wang BW, Liu Y, Hao ZF, Hou JQ, Li JY, Li ST, Pan SH, Zeng MH, Wang ZY (2018) Recent progress in C–C bond construction based on 2(5H)-furanone. Chin J Org Chem 38:1872–1884

    Article  CAS  Google Scholar 

  • Wei MX, Zhang J, Ma FL, Li M, Yu JY, Luo W, Li XQ (2018) Synthesis and biological activities of dithiocarbamates containing 2(5H)-furanone-piperazine. Eur J Med Chem 155:165–170

    Article  CAS  PubMed  Google Scholar 

  • Wu LY, Lu K, Packiarajan M, Jubian V, Chandrasena G, Wolinsky TC, Walker MW (2012) Indolyl and dihydroindolyl N-glycinamides as potent and in vivo active NPY5 antagonists. Bioorg Med Chem Lett 22:2167–2171

    Article  CAS  PubMed  Google Scholar 

  • Wu YC, Luo SH, Mei WJ, Cao L, Wu HQ, Wang ZY (2017) Synthesis and biological evaluation of 4-biphenylamino-3-halo-2(5H)-furanones as potential anticancer agents. Eur J Med Chem 139:84–94

    Article  CAS  PubMed  Google Scholar 

  • Wu HQ, Luo SH, Cao L, Shi HN, Wang BW, Wang ZY (2018a) DABCO-mediated C-O bond formation from Csp2-halogen bond-containing compounds and alkyl alcohols. Asian J Org Chem 7:2479–2483

    Article  CAS  Google Scholar 

  • Wu YC, Cao L, Mei WJ, Wu HQ, Luo SH, Zhan HY, Wang ZY (2018b) Bis-2(5H)-furanone derivatives as new anticancer agents: Design, synthesis, biological evaluation, and mechanism studies. Chem Biol Drug Des 92:1232–1240

    Article  CAS  PubMed  Google Scholar 

  • Wu HQ, Yang K, Chen XY, Mani A, Wang N, Chen SH, Wang ZY (2019a) 3,4-Dihalo-2(5H)-furanone initiated ring-opening reaction of DABCO in the absence of metal catalyst and additive and its application in one-pot multicomponent reaction. Green Chem 21:3782–3788

    Article  CAS  Google Scholar 

  • Wu HQ, Yang K, Luo SH, Wu XY, Wang N, Chen SH, Wang ZY (2019b) C4-selective synthesis of vinyl thiocyanates and selenocyanates through 3,4-dihalo-2(5H)-furanones. Eur J Org Chem 2019:4572–4580

    Article  CAS  Google Scholar 

  • Wu AL, Guo YX, Li XB, Xue HM, Fei JB, Li JB (2020) Co-assembled supramolecular gel of dipeptide and pyridine derivatives with controlled chirality. Angew Chem Int Ed 60:2099–2103

    Article  CAS  Google Scholar 

  • Yang K, Yang JQ, Luo SH, Mei WJ, Lin JY, Zhan JQ, Wang ZY (2021) Synthesis of N-2(5H)-furanonyl sulfonyl hydrazone derivatives and their biological evaluation in vitro and in vivo activity against MCF-7 breast cancer cells. Bioorg Chem 107:104518

    Article  CAS  PubMed  Google Scholar 

  • Yang K, Chen ZX, Zhou YJ, Chen Q, Yu SW, Luo SH, Wang ZY (2022) Simple inorganic base promoted polycyclic construction using mucohalic acid as C3 synthon: Synthesis and AIE probe application of benzo[4,5]imidazo[1,2-a]pyridines. Org Chem Front 9:1127–1136

    Article  CAS  Google Scholar 

  • Yasui M, Yamada A, Tsukano C, Hamza A, Papai I, Takemoto Y (2020) Enantioselective acetalization by dynamic kinetic resolution for the synthesis of gamma-alkoxybutenolides by thiourea/quaternary ammonium salt catalysts: application to strigolactones. Angew Chem Int Ed 59:13479–13483

    Article  CAS  Google Scholar 

  • Zhang ZY, Kuang GZ, Zong S, Liu S, Xiao HH, Chen XS, Zhou DF, Huang YB (2018) Sandwich-like fibers/sponge composite combining chemotherapy and hemostasis for efficient postoperative prevention of tumor recurrence and metastasis. Adv Mater 30:1803217

    Article  CAS  Google Scholar 

  • Zhou HX, Gao Y, Liu YC, Wu YT, Fang Y, Wang BJ, Xu BX (2022) Targeted fluorescent imaging of a novel FITC-labelled PSMA ligand in prostate cancer. Amino Acids 54:147–155

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to the Guangdong Provincial Natural Science Foundation (No. 2021A1515012342), National Natural Science Foundation of China (No. 20772035) and the Open Fund of the Key Laboratory of Functional Molecular Engineering of Guangdong Province in SCUT (No. 2017kf01), the Natural Science Project of Guangdong Food and Drug Vocational College (Nos. 2018ZR001, 2014YZ007), Scientific Research Fund of Jiangxi Provincial Education Department (No. GJJ201504) and Scientific Research Project of Gannan Medical University (No. YB201903) for financial support.

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  1. Neng Wang and Jian-Yun Lin have contributed equally to this work.

Authors and Affiliations

  1. School of Chemistry, Key Laboratory of Theoretical Chemistry of Environment, Ministry of Education, South China Normal University, Guangzhou, 510006, People’s Republic of China

    Neng Wang, Jian-Yun Lin, Shi-He Luo, Yong-Jun Zhou, Kai Yang, Guo-Xian Yang & Zhao-Yang Wang

  2. Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, 381 Wushan Road, Guangzhou, 510640, People’s Republic of China

    Shi-He Luo & Zhao-Yang Wang

  3. College of Pharmacy, Gannan Medical University, Ganzhou, 341000, People’s Republic of China

    Kai Yang

  4. Guangdong Food and Drug Vocational College, Guangzhou, 510520, People’s Republic of China

    Ren-Hong Chen

  5. School of Chemistry, Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine, South China Normal University, Guangzhou, 510006, People’s Republic of China

    Neng Wang, Jian-Yun Lin, Shi-He Luo, Yong-Jun Zhou, Kai Yang, Guo-Xian Yang & Zhao-Yang Wang

  6. School of Chemistry, GDMPA Key Laboratory for Process Control and Quality Evaluation of Chiral Pharmaceuticals, South China Normal University, Guangzhou, 510006, People’s Republic of China

    Neng Wang, Jian-Yun Lin, Shi-He Luo, Yong-Jun Zhou, Kai Yang, Guo-Xian Yang & Zhao-Yang Wang

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  1. Neng Wang
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Correspondence to Shi-He Luo, Kai Yang, Ren-Hong Chen or Zhao-Yang Wang.

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All animal procedures complied with the Animal Management Rule of the Ministry of Health, People’s Republic of China (Document No. 55, 2001), and the experiments with the animals were carried out according to the protocols approved by the Ethic Committee of Gannan Medical University. This study does not contain any studies with human participants performed by any of the authors.

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Crystal data; steps of in vitro blood hemostasis test; characterization data for all products, and so on, can be found in Supporting Information (PDF) (PDF 2705 KB)

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Wang, N., Lin, JY., Luo, SH. et al. Furanonyl amino acid derivatives as hemostatic drugs: design, synthesis and hemostasis performance. Amino Acids 54, 989–999 (2022). https://doi.org/10.1007/s00726-022-03155-3

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