Download PDF
Planta Med 2022; 88(13): 1163-1174
DOI: 10.1055/a-1708-2081
Biological and Pharmacological Activity
Original Papers

In Vitro Cytotoxic and Leishmanicidal Activity of Isolated and Semisynthetic ent-Pimaranes from Aldama arenaria

Adriana da Silva Santos de Oliveira 
1   Postgraduate Program in Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, University of Campinas (UNICAMP), Campinas/SP, Brazil
2   Division of Organic and Pharmaceutical Chemistry of the Pluridisciplinary Research Center for Chemical, Biological, and Agricultural Research (CPQBA) of the University of Campinas (UNICAMP), Paulínia/SP, Brazil
,
Gabrielly Galdino Conrado 
1   Postgraduate Program in Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, University of Campinas (UNICAMP), Campinas/SP, Brazil
2   Division of Organic and Pharmaceutical Chemistry of the Pluridisciplinary Research Center for Chemical, Biological, and Agricultural Research (CPQBA) of the University of Campinas (UNICAMP), Paulínia/SP, Brazil
,
Nathalia Grazzia
3   Department of Animal Biology – Parasitology, Institute of Biology, University of Campinas (UNICAMP), Campinas/SP, Brazil
,
Danilo Ciccone Miguel
3   Department of Animal Biology – Parasitology, Institute of Biology, University of Campinas (UNICAMP), Campinas/SP, Brazil
,
Gilberto Carlos Franchi Júnior
4   Integrated Center for Childhood Oncohematological Research, University of Campinas, Campinas/SP, Brazil
,
Vera Lúcia Garcia
1   Postgraduate Program in Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, University of Campinas (UNICAMP), Campinas/SP, Brazil
2   Division of Organic and Pharmaceutical Chemistry of the Pluridisciplinary Research Center for Chemical, Biological, and Agricultural Research (CPQBA) of the University of Campinas (UNICAMP), Paulínia/SP, Brazil
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Two pimaranes ent-pimara-8(14),15-dien-19-oic acid (1) and ent-8(14),15-pimaradien-3β-ol (2), isolated from Aldama arenaria, and six semi-synthetic derivatives methyl ester of the ent-pimara-8(14),15-dien-19-oic acid (3), ent-pimara-8(14),15-dien-19-ol (4), acetate of ent-pimara-8(14),15-dien-19-ol (5), ent-pimara-8(14),15-dien-19-ol succinic acid (6), acetate of ent-8(14),15-pimaradien-3β-ol (7), ent-8(14),15-pimaradien-3β-ol succinic acid (8) were evaluated in vitro for their cytotoxic activities to childhood leukemia cell lines and leishmanicidal activity against the parasite Leishmania amazonensis. Among these compounds, 1 to 6 presented moderate cytotoxic activity, with compound 4 being the most active (GI50 of 2.6 µM for the HL60 line) and the derivatives 7 and 8 being inactive. Against the parasite Leishmania amazonensis, the most promising derivative was the acetate of ent-pimara-8(14),15-dien-19-ol (5), with EC50 of 20.1 µM, selectivity index of 14.5, and significant reduction in the parasite load. Pimarane analogues 1, ent-pimara-8(14),15-dien-19-oic acid, and 2, ent-8(14),15-pimaradien-3β-ol, presented different activities, corroborating the application of such molecules as prototypes for the design of other derivatives that have greater cytotoxic or leishmanicidal potential.

Key words

leishmanicidal activity - cytotoxic activity - Leishmania amazonensis - pimaranes - Aldama arenaria (syn. Viguiera arenaria) - Asteraceae

Supporting Information

    1H and 13C NMR spectra were obtained on a Bruker 400 operating at 400 and 100 MHz, respectively, using CDCl3 as solvent and TMS as reference. Data from Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS) analyses of compounds 1 – 8, and dose-response curves from the biological tests can be request as supplementary information.

  • Supporting Information


Publication History

Received: 23 August 2021

Accepted after revision: 28 November 2021

Accepted Manuscript online:
28 November 2021

Article published online:
10 February 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Magenta MAG. Viguiera Kunth (Asteraceae, Heliantheae) na América do Sul e sistemática das espécies do Brasil [PhD thesis]. São Paulo: University of São Paulo; 2006
    PubMedGoogle Scholar
  • 2 Schilling EE, Panero JL. A revised classification of subtribe Helianthinae (Asteraceae: Heliantheae) II. Derived lineages. Bot J Linn Soc 2011; 167: 311-331
    CrossrefPubMedGoogle Scholar
  • 3 Ambrosio SR, Schorr K, Da Costa FB. Terpenoids of Viguiera arenaria (Asteraceae). Biochem Syst Ecol 2004; 32: 221-224
    CrossrefPubMedGoogle Scholar
  • 4 Oliveira TS, Bombo AB, Oliveira ASS, Garcia VL, Appezzato-da-Glória B. Seasonal variation of the essential oil from two Brazilian native Aldama La Llave (Asteraceae) species. An Acad Bras Cienc 2016; 88: 1899-1907
    CrossrefPubMedGoogle Scholar
  • 5 Reveglia P, Cimmino A, Masi M, Nocera P, Berova N, Ellestad G, Evidente A. Pimarane diterpenes: Natural source, stereochemical configuration, and biological activity. Chirality 2018; 30: 1115-1134
    CrossrefPubMedGoogle Scholar
  • 6 Ambrosio SR, Tirapelli CR, Bonaventura D, De Oliveira AM, Da Costa FB. Pimarane diterpene from Viguiera arenaria (Asteraceae) inhibit rat carotid contraction. Fitoterapia 2002; 73: 484-489
    CrossrefPubMedGoogle Scholar
  • 7 Ambrosio SR, Tirapelli CR, Da Costa FB, Oliveira AM. Kaurane and pimarane-type diterpenes from the Viguiera species inhibit vascular smooth muscle contractility. Life Sci 2006; 79: 925-933
    CrossrefPubMedGoogle Scholar
  • 8 Ambrosio SR, Arakawa NS, Esperandim VR, Albuquerque S, Da Costa FB. Trypanocidal activity of pimarane diterpenes from Viguiera arenaria (Asteraceae). Phytother Res 2008; 22: 1423-1425
    CrossrefPubMedGoogle Scholar
  • 9 Tirapelli CR, dos Anjos Neto Filho M, Bonaventura D, Melo MC, Ambrosio SR, de Oliveira AM, Bendhack LM, da Costa FB. Pimaradienoic acid inhibits vascular contraction and induces hypotension in normotensive rats. J Pharm Pharmacol 2008; 60: 453-459
    CrossrefPubMedGoogle Scholar
  • 10 Porto TS, Rangel R, Furtado NAJC, De Carvalho TC, Martins CHG, Veneziani RCS, Da Costa FB, Vinholis AHC, Cunha WR, Heleno VCG, Ambrosio SR. Pimarane-type diterpenes: Antimicrobial activity against oral pathogens. Molecules 2009; 14: 191-199
    CrossrefPubMedGoogle Scholar
  • 11 Porto TS, Furtado NAJC, Heleno VCG, Martins CHG, Da Costa FB, Severiano ME, Silva NA, Veneziani RSC, Ambrosio SR. Antimicrobial ent-pimarane diterpenes from Viguiera arenaria against Gram-positive bacteria. Fitoterapia 2009; 80: 432-436
    CrossrefPubMedGoogle Scholar
  • 12 Porto TS, da Silva Filho AA, Magalhães LG, dos Santos RA, Furtado NAJC, Arakawa NS, Said S, de Oliveira DC, Gregório LE, Rodrigues V, Veneziani RC, Ambrósio SR. Fungal transformation and schistosomicidal effects of pimaradienoic acid. Chem Biodivers 2012; 9: 1465-1474
    CrossrefPubMedGoogle Scholar
  • 13 Oliveira ASS, Imamura PM, Ruiz ALTG, Appezzato-da-Glória B, de Oliveira T, Garcia VL. Antiproliferative activity from Aldama arenaria (Baker) E.E. Schill. & Panero. Bol Latinoam Caribe Plant Med Aromat 2021; 20: 51-60
    CrossrefPubMedGoogle Scholar
  • 14 Brazilian National Cancer Institute – INCA. Accessed August 01, 2020 at: http://www.inca.gov.br
    PubMed
  • 15 Ministério da Saúde, Instituto Nacional de Câncer José Alencar Gomes da Silva (INCA). Livro: Ministério da Saúde. Estimativa 2020: Incidência de câncer no Brasil, Edição Anual. Rio de Janeiro, Brasil: Instituto Nacional de Câncer José Alencar Gomes da Silva; 2019
    Google Scholar
  • 16 Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 2020; 83: 770-803
    CrossrefPubMedGoogle Scholar
  • 17 Lee KH, Xiao Z. Podophyllotoxin and Analogs. In: Cragg GM, Kingston DGI, Newman DJ. eds Anticancer Agents from Natural Products. Boca Raton: Taylor and Francis; 2012: 95-122
    Google Scholar
  • 18 Kingston DGI. Taxol and its Analogs. In: Cragg GM, Kingston DGI, Newman DJ. eds Anticancer Agents from Natural Products. Boca Raton: Taylor and Francis; 2012: 123-175
    Google Scholar
  • 19 Alcântara LM, Ferreira TCS, Gadelha FR, Miguel DC. Challenges in drug discovery targeting TriTryp diseases with an emphasis on leishmaniasis. Int J Parasitol Drugs Drug Resist 2018; 8: 430-439
    CrossrefPubMedGoogle Scholar
  • 20 De Souza ROMA, Pereira VLP, Muzitano MF, Falcão CAB, Rossi-Bergmann B, Filho EBA, Vasconcellos MLAA. High selective leismanicidal activity of 3-hydroxy-2-methylene-3-(4-bromophenyl)propanenitrile and analogous compounds. Eur J Med Chem 2007; 42: 99-102
    CrossrefPubMedGoogle Scholar
  • 21 Benchimol JL, Gualandi FC, Barreto DCS, Pinheiro LA. Leishmaniasis: Historical configuration in Brazil with an emphasis on the visceral disease, from the 1930s to the 1960s. Bol Mus Para Emílio Goeldi Ciênc hum 2019; 14: 611-626
    PubMedGoogle Scholar
  • 22 Kedzierski L, Sakthianandeswaren A, Curtis JM, Andrews PC, Junk PC, Kedzierska K. Leishmaniasis: current treatment and prospects for new drugs and vaccines. Curr Med Chem 2009; 16: 599-614
    CrossrefPubMedGoogle Scholar
  • 23 Severiano ME, Simão MR, Ramos HP, Parreira RLT, Arakawa NS, Said S, Furtado NAJC, Oliveira DCR, Gregório LE, Tirapelli CR, Veneziani RCS, Ambrosio SR. Biotransformation of ent-pimaradienoic acid by cell cultures of Aspergillus niger . Bioorg Med Chem 2013; 21: 5870-5875
    CrossrefPubMedGoogle Scholar
  • 24 Matsuo A, Nakayama M, Hayashi S, Yamasaki K, Kasai R, Tanaka O. (−)-Thermarol, a new ent-pimarane-class diterpene diol from Jungermannia thermarum (Liverwort). Tetrahedron Lett 1976; 28: 2451-2454
    CrossrefPubMedGoogle Scholar
  • 25 Ansell SM, Pegel KH, Taylor DAH. Diterpenes from the timber of 20 Erythroxylum species. Phytochemistry 1993; 32: 953-959
    CrossrefPubMedGoogle Scholar
  • 26 Mihashi S, Yanagisawa I, Tanaka O, Shibata S. Further study on the diterpenes of Aralia spp. Tetrahedron Lett 1969; 21: 1683-1686
    CrossrefPubMedGoogle Scholar
  • 27 Jung HA, Lee EJ, Kim JS, Kang SS, Lee JH, Min BS, Choi JS. Cholinesterase and BACE1 inhibitory diterpenoids from Aralia cordata . Arch Pharm Res 2009; 32: 1399
    CrossrefPubMedGoogle Scholar
  • 28 Adams RP. Identification of Essential oil Components by Gas Chromatography/Mass Spectrometry. 4nd edition. Carol Stream, Illinois: Allured Publishing Corporation USA; 2007: 804
    Google Scholar
  • 29 Meragelman TL, Silva GL, Mongelli E, Roberto RG. Ent-Pimarane type diterpenes from Gnaphalium gaudichaudianum . Phytochemistry 2003; 62: 569-572
    CrossrefPubMedGoogle Scholar
  • 30 Severiano ME, Simão MR, Porto TS, Martins CHG, Veneziani RCS, Furtado NAJC, Arakawa NS, Said S, Oliveira DCR, Cunha WR, Gregorio LE, Ambrosio SR. Anticariogenic properties of ent-pimarane diterpenes obtained by microbial transformation. Molecules 2010; 15: 8553-8566
    CrossrefPubMedGoogle Scholar
  • 31 De Almeida VL, Leitão A, Reina LDCB, Montanari CA, Donnici CL, Lopes MTP. Câncer e agentes antineoplásicos ciclo-celular específicos e ciclo-celular não específicos que interagem com o DNA: Uma introdução. Quim Nova 2005; 28: 118-129
    CrossrefPubMedGoogle Scholar
  • 32 Grimaldi jr. G, David JR, McMahon-Pratt D. Identification and distribution of New World Leishmania species caracterized by serademe analysis using monoclonal antibodies. Am J Trop Med Hyg 1987; 36: 270-287
    CrossrefPubMedGoogle Scholar
  • 33 Mosmann TJ. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assay. Immunol Methods 1983; 65: 55-63
    CrossrefPubMedGoogle Scholar
  • 34 Katsuno K, Burrows JN, Duncan K, van Huijsduijnen RH, Kaneko T, Kita K, Mowbray CE, Schmatz D, Warner P, Slingsby BT. Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat Rev Drug Discov 2015; 14: 751-758
    CrossrefPubMedGoogle Scholar
  • 35 Miguel DC, Yokoyama-Yasunaka JKU, Andreoli WK, Mortara RA, Uliana SRB. Tamoxifen is effective against Leishmania and induces a rapid alkalinization of parasite phorous vacuoles harbouring Leishmania (Leishmania) amazonensis amastigotes. J Antimicrob Chemother 2007; 60: 526-534
    CrossrefPubMedGoogle Scholar