PDF herunterladen
Planta Med 2023; 89(07): 700-708
DOI: 10.1055/a-2009-0732
Biological and Pharmacological Activity
Original Papers

Oxidation Products from the Neolignan Licarin A by Biomimetic Reactions and Assessment of in vivo Acute Toxicity

Juliana Neves de Paula e Souza
1   Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
,
Rodrigo Moreira da Silva
1   Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
,
Simone Silveira Fortes
2   Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
,
Anderson Rodrigo Moraes de Oliveira
2   Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
,
Leandro S. Ferreira 
1   Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
3   Departamento de Farmácia, Universidade Federal do Rio Grande do Norte (UFRN), Natal, RN, Brazil
,
Ricardo Vessecchi
2   Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
,
Norberto Peporine Lopes 
1   Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
,
Denise Brentan Silva 
1   Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
4   Laboratório de Produtos Naturais e Espectrometria de Massas (LAPNEM), Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição (FACFAN), Universidade Federal de Mato Grosso do Sul, Campo Grande, MS, Brazil
› Institutsangaben
› Weitere Informationen
Auch verfügbar auf
    Lizenzen und Reprints

Abstract

Licarin A, a dihydrobenzofuranic neolignan presents in several medicinal plants and seeds of nutmeg, exhibits strong activity against protozoans responsible for Chagas disease and leishmaniasis. From biomimetic reactions by metalloporphyrin and Jacobsen catalysts, seven products were determined: four isomeric products yielded by epoxidation from licarin A, besides a new product yielded by a vicinal diol, a benzylic aldehyde, and an unsaturated aldehyde in the structure of the licarin A. The incubation with rat and human liver microsomes partially reproduced the biomimetic reactions by the production of the same epoxidized product of m/z 343 [M + H]+. In vivo acute toxicity assays of licarin A suggested liver toxicity based on biomarker enzymatic changes. However, microscopic analysis of tissues sections did not show any tissue damage as indicative of toxicity after 14 days of exposure. New metabolic pathways of the licarin A were identified after in vitro biomimetic oxidation reaction and in vitro metabolism by rat or human liver microsomes.

Key words

Myristica fragrans - Myristicaceae - in vitro metabolism - biomimetic reactions - metalloporphyrins - Jacobsen catalysts - acute toxicity

Supporting Information

    Electronic supplementary information is available for this publication. All the MS, MS/MS, and NMR data from the oxidation products, as well as the biochemical parameters, were determined from acute toxicological essays.

  • Ergänzendes Material


Publikationsverlauf

Eingereicht: 27. Juli 2022

Angenommen: 18. Dezember 2022

Artikel online veröffentlicht:
08. März 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Alvarenga DJ, Matias LMF, Oliveira LM, Leão LPMO, Hawkes JA, Raimundo BVB, Castro LFD, Campos MMA, Siqueira FS, Santos T, Carvalho DT. Exploring how structural changes to new licarin A derivatives effects their bioactive properties against rapid growing mycobacteria and biofilm formation. Microb Pathog 2020; 144: 104203
    CrossrefPubMedGoogle Scholar
  • 2 Ma CJ, Sung SH, Kim YC. Neuroprotective Lignans from the bark of the Machilus thunbergii . Planta Med 2004; 70: 78-80
    PubMedGoogle Scholar
  • 3 Paiva MRB, Vasconcelos-Santos DV, Coelho MM, Machado RR, Lopes NP, Silva-Cunha A, Fialho SL. Licarin A as a Novel Drug for Inflammatory Eye Diseases. J Ocul Pharmacol Ther 2021; 37: 290-300
    CrossrefPubMedGoogle Scholar
  • 4 Murakami Y, Shoji M, Hirata A, Tanaka S, Yokoe I, Fujisawa S. Dehydrodiisoeugenol, an isoeugenol dimer, inhibits lipopolysaccharide-stimulated nuclear factor kappa B activation and cyclooxygenase-2 expression in macrophages. Arch Biochem Biophys 2005; 434: 326-332
    CrossrefPubMedGoogle Scholar
  • 5 Maheswari U, Ghosh K, Sadras SR. Licarin A induces cell death by activation of autophagy and apoptosis in non-small cell lung cancer cells. Apoptosis 2018; 23: 210-225
    CrossrefPubMedGoogle Scholar
  • 6 Néris PLN, Caldas JPA, Rogrigues YKS, Amorim FM, Patrícia LN, Leite JA, Mascarenhas SR, Barbosa-Filho JM, Rodrigues LC, Oliveira MR. Neolignan Licarin A presents effect against Leishmania (Leishmania) major associated with immunomodulation in vitro . Exp Parasitol 2013; 35: 307-313
    CrossrefPubMedGoogle Scholar
  • 7 Pereira AC, Magalhães LG, Gonçalves UO, Luz PP, Moraes ACG, Rodrigues V, Guedes PMM, Silva Filho AA, Cunha WR, Bastos JK, Nanayakkara NPD, Silva MLA. Schistosomicidal and trypanocidal structure–activity relationships for (±)-licarin A and its (−)- and (+)-enantiomers. Phytochemistry 2011; 72: 1424-1430
    CrossrefPubMedGoogle Scholar
  • 8 Yadav J, Hassani ME, Sodhi J, Lauschke VM, Hartman JM, Russell LE. Recent developments in vitro and in vivo models for improved translation of preclinical pharmacokinetics and pharmacodynamics data. Drug Metab Rev 2021; 53: 207-233
    CrossrefPubMedGoogle Scholar
  • 9 Fernandes EFA, Oliveira ARM, Barros VP, Guaratini T, Lopes NP. Biomimetic metabolism of kaurenoic acid validated by microsomal reactions. Rev Bras Farmacog 2020; 30: 551-558
    CrossrefPubMedGoogle Scholar
  • 10 Bernadou J, Meunier B. Biomimetic chemical catalysts in the oxidative activation of drugs. Adv Synth Catal 2004; 346: 171-184
    CrossrefPubMedGoogle Scholar
  • 11 Yan X, Lu N, Gu Y, Li C, Zhang T, Liu H, Zhang Z, Zhai S. Catalytic activity of biomimetic model of cytochrome P450 in oxidation of dopamine. Talanta 2018; 179: 401-408
    CrossrefPubMedGoogle Scholar
  • 12 Nieheus M, Barros VP, Emery SF, Dias-Baruffi M, Assis DM, Lopes PN. Biomimetic in vitro oxidation of lapachol: A model to predict and analyse the in vivo phase I metabolism of bioactive compounds. Eur J Med Chem 2012; 54: 804-812
    CrossrefPubMedGoogle Scholar
  • 13 Lee SU, Shim KS, Ryu SY, Min YK, Kim SH. Machilin A isolated from Myristica fragrans stimulates osteoblast differentiation. Planta Med 2009; 75: 152-157
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 14 Barbosa-Filho MJ, Da-Cunha LVE, Silva SM. Complete assignment of the 1H and 13C spectra of some lignoids from Lauraceae. Magn Reson Chem 1998; 36: 929-935
    CrossrefPubMedGoogle Scholar
  • 15 Moser A, Range K, York DM. Accurate proton affinity and gas-phase basicity values for molecules important in biocatalysis. J Phys Chem B 2010; 114: 13911-13921
    CrossrefPubMedGoogle Scholar
  • 16 Amad MH, Cech NB, Jackson GS, Enke CG. Importance of gas-phase proton affinities in determining the electrospray ionization response for analytes and solvents. J Mass Spectrom 2000; 35: 784-789
    CrossrefPubMedGoogle Scholar
  • 17 Bolzon LB, Bindeiro AKS, Souza LMO, Zanatta LD, Paula R, Cerqueira BC, Santos JS. rhodamine B oxidation promoted by P450- bioinspired Jacobsen catalysts/cellulose systems. RSC Adv 2021; 11: 33823-33834
    CrossrefPubMedGoogle Scholar
  • 18 Han HJ, Hong JS, Lee YE, Lee HJ, Kim JH, Kwak H. Conversion of epoxides into trans-diols or trans-diol mono-ethers by iron (III) porphyrin complex. Bull Korean Chem Soc 2005; 26: 1434-1436
    CrossrefPubMedGoogle Scholar
  • 19 Yoo KS, Han HJ, Lee JS, Ryu YJ, Kim WS, Jin WS, Kim Y, Nam W. Conversion of olefins into trans-diols or trans-diol mono-ethers by using iron porphyrin(III) complex and H2O2 . Inorg Chem Commun 2003; 6: 1148-1151
    CrossrefPubMedGoogle Scholar
  • 20 Li F, Yang WX. Simultaneous determination of diastereomers (+)-licarin A and isolicarin A from Myristica fragrans in rat plasma by HPLC and its application to their pharmacokinetics. Planta Med 2008; 74: 880-884
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 21 Cardozo KHM, Vessecchi R, Carvalho VM, Pinto E, Gates PJ, Colepicolo P, Galembeck SE, Lopes NP. A theorical and mass spetrometry sutdy of the fragmentation of mycosporine – like amino acids. Int J Mass Spectrom 2008; 273: 11-19
    CrossrefPubMedGoogle Scholar
  • 22 Lv QQ, Yang XN, Yan DM, Liang WQ, Liu HN, Yang XW, Li F. Metabolomic profiling of dehydrodiisoeugenol using xenobiotic metabolomics. J Pharmaceut Biomed 2017; 145: 725-733
    CrossrefPubMedGoogle Scholar
  • 23 Fasinu P, Bouic PJ, Rosenkranz B. Liver-based in vitro technologies for drug biotranformation studies – a review. Curr Drug Metab 2012; 13: 215-224
    CrossrefPubMedGoogle Scholar
  • 24 Shaab EH, Crotti AEM, Iamamoto Y, Kato MJ, Lotufo LVC, Lopes NP. Biomimetic oxidation of piperine and piplartine catalyzed by iron (III) and manganese (III) porphyrins. Biol Pharm Bull 2010; 5: 912-916
    CrossrefPubMedGoogle Scholar
  • 25 Marques LMM, Silva-Junior EA, Gouvea DR, Vessecchi R, Pupo MT, Lopes NP, Kato MJ, Oliveira ARM. In vitro metabolism of the alkaloid piplartine by rat liver microsomes. J Pharm Biomed Anal 2014; 95: 113-120
    CrossrefPubMedGoogle Scholar
  • 26 Ferreira LS, Callejon DR, Engemann A, Cramber B, Humpf HU, Barros VP, Assis MD, Silva DB, Albuquerque S, Okano LT, Kato MJ, Lopes NP. In vitro metabolismo of grandisin, a lignan with anti-chagasic activity. Planta Med 2012; 78: 1939-1941
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 27 Messiano GB, Santos RAS, Ferreira LDS, Simões RA, Jabor VAP, Kato MJ, Lopes NP, Pupo MT, Oliveira ARM. In vitro metabolism study of the promissing anticâncer agent the lignan (−)-grandisin. J Pharm Biomed Anal 2013; 72: 240-244
    CrossrefPubMedGoogle Scholar
  • 28 Barth T, Habenschus MD, Moreira FL, Ferreira LDS, Lopes NP, Oliveira ARM. In vitro metabolismo of the lignan (−)-grandisin, an anticancer drug candidate, by human liver microsomes. Drug Test Anal 2015; 7: 780-786
    CrossrefPubMedGoogle Scholar
  • 29 Rocha BA, Oliveira ARM, Pazin M, Dorta DJ, Rodrigues APN, Berretta AA, Peti APF, Moraes LAB, Lopes NP, Pospisil S, Gates PJ, Assis MD. Jacobsen catalyst as a cytochrome P450 biomimetic model for the metabolismo of monensin A. Biomed Res Int 2014; 2014: 152102
    CrossrefPubMedGoogle Scholar
  • 30 Mauro M, Silva RM, Campos ML, Bauermeister A, Lopes NP, Moraes NV. In vitro metabolism of copalic and kaurenoic acid in rat and human liver microsomes. Quim Nova 2021; 6: 700-708
    PubMedGoogle Scholar
  • 31 Simões MMQ, Paula RD, Neves MGPMS, Cavaleiro JAS. Metalloporphyrins in the biomimetic oxidative valorization of natural and other organic substrates. J Porphyr Phthalocyanines 2009; 13: 589-596
    CrossrefPubMedGoogle Scholar
  • 32 Lehmann-Werman R, Magenheim J, Moss J, Neiman D, Abraham O, Piyanzin S, Zemmour H, Fox I, Dor T, Grompe M, Landesberg G, Loza BL, Shaked A, Olthoff K, Glaser B, Shemer R, Dor Y. Monitoring liver damage using hepatocyte-specific methylation markers in cell-free circulating DNA. JCI Insight 2018; 3: e120687
    CrossrefPubMedGoogle Scholar
  • 33 Ozardalı I, Bitiren M, Karakılcık AZ, Zerin M, Aksoy N, Musa D. Effects of selenium on histopathological and enzymatic changes in experimental liver injury of rats. Exp Toxicol Pathol 2004; 56: 59-64
    CrossrefPubMedGoogle Scholar
  • 34 Lucas HJ, Kennedy ER, Formo MW, Baungratem HE. Organic Synthesis Collective. New York: John Willey & Sons; 1955; 3: 483
    PubMedGoogle Scholar
  • 35 Leopold B. Aromatic keto and hydroxyl-polyethers as lignin models III. Acta Chem Scand 1950; 4: 1523-1537
    CrossrefPubMedGoogle Scholar
  • 36 Becke AD. A new mixing of hartree-fock and local density-functional theories. J Chem Phys 1993; 98: 1372
    CrossrefPubMedGoogle Scholar
  • 37 Lee CT, Yang W, Parr RG. Development of the colle-salvetti correlation-energy formula into a functional of the electron-density. Phys Rev B Condens Matter 1988; 37: 785-789
    CrossrefPubMedGoogle Scholar
  • 38 Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery jr. JA, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA. Gaussian 03, Revision D. 01. Wallingford CT: Gaussian Inc.; 2004
    Google Scholar
  • 39 Organisation for Economic Co-operation and Development (OECD). Test N°423 – Acute Oral Toxicity – Acute Toxic Class Method, OECD Guidelines for the Testing of Chemicals, Section 4. Paris: OECD Publishing; 2002
    Google Scholar