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

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

Publication History

Received: 27 July 2022

Accepted: 18 December 2022

Article published online:
08 March 2023

• 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
• 2 Ma CJ, Sung SH, Kim YC. Neuroprotective Lignans from the bark of the Machilus thunbergii . Planta Med 2004; 70: 78-80
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 10 Bernadou J, Meunier B. Biomimetic chemical catalysts in the oxidative activation of drugs. Adv Synth Catal 2004; 346: 171-184
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 34 Lucas HJ, Kennedy ER, Formo MW, Baungratem HE. Organic Synthesis Collective. New York: John Willey & Sons; 1955; 3: 483
• 35 Leopold B. Aromatic keto and hydroxyl-polyethers as lignin models III. Acta Chem Scand 1950; 4: 1523-1537
• 36 Becke AD. A new mixing of hartree-fock and local density-functional theories. J Chem Phys 1993; 98: 1372
• 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
• 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
• 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