Second-generation pterocarpanquinones: synthesis and antileishmanial activity
Tóm tắt
Despite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery. In this paper, we report the synthesis and antileishmanial activity of the second generation of pterocarpanoquinones. The second generation of pterocarpanquinones 2a-f was prepared through a palladium-catalyzed oxyarylation of dihydronaphtalen and chromens with iodolawsone, easily prepared by iodination of lawsone. The spectrum of antileishmanial activity was evaluated in promastigotes and intracellular amastigotes of L. amazonensis, L. braziliensis, and L. infantum. Toxicity was assessed in peritoneal macrophages and selective index calculated by CC50/IC50. Oxidative stress was measured by intracellular ROS levels and mitochondrial membrane potential in treated cells. In this work, we answered two pertinent questions about the structure of the first-generation pterocarpanquinones: the configuration and positions of rings B (pyran) and C (furan) and the presence of oxygen in the B ring. When rings B and C are exchanged, we noted an improvement of the activity against promastigotes and amastigotes of L. amazonensis and promastigotes of L. infantum. As to the oxygen in ring B of the new generation, we observed that the oxygenated compound 2b is approximately twice as active against L. braziliensis promastigotes than its deoxy derivative 2a. Another modification that improved the activity was the addition of the methylenedioxy group. A variation in the susceptibility among species was evident in the clinically relevant form of the parasite, the intracellular amastigote. L. amazonensis was the species most susceptible to novel derivatives, whilst L. infantum was resistant to most of them. The pterocarpanoquinones (2b and 2c) that possess the oxygen atom in ring B showed induction of increased ROS production. The data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents.
Tài liệu tham khảo
Schmidt TJ, Khalid SA, Romanha AJ, Alves TM, Biavatti MW, Brun R, et al. The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part II. Curr Med Chem. 2012;19(14):2176–228.
Netto CD, da Silva AJM, Salustiano EJS, Bacelar TS, Riça IG, Cavalcante MCM, et al. New pterocarpanquinones: synthesis, antineoplasic activity on cultured human malignant cell lines and TNF-alpha modulation in human PBMC cells. Bioorg Med Chem. 2010;18(4):1610–6.
Buarque CD, Militão GCG, Lima DJB, Costa-Lotufo LV, Pessoa C, de Moraes MO, et al. Pterocarpanquinones, aza-pterocarpanquinone and derivatives: synthesis, antineoplasic activity on human malignant cell lines and antileishmanial activity on Leishmania amazonensis. Bioorg Med Chem. 2011;19(22):6885–91.
Silva AJM, Netto CD, Pacienza-Lima W, Torres-Santos EC, Rossi-Bergmann B, Maurel S, et al. Antitumoral, antileishmanial and antimalarial activity of pentacyclic 1,4-naphthoquinone derivatives. J Braz Chem Soc. 2009;20(1):176–82.
Salustiano EJ, Dumas ML, Silva-Santos GG, Netto CD, Costa PRR, Rumjanek VM. In vitro and in vivo antineoplastic and immunological effects of pterocarpanquinone LQB-118. Investig New Drugs. 2016;34(5):541–51.
Maia RC, Vasconcelos FC, de Sá Bacelar T, Salustiano EJ, da Silva LFR, Pereira DL, et al. LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]: a novel class of agent with high apoptotic effect in chronic myeloid leukemia cells. Investig New Drugs. 2011;29(6):1143–55.
de Faria FCC, Leal MEB, Bernardo PS, Costa PRR, Maia RC. NFκB pathway and microRNA-9 and -21 are involved in sensitivity to the pterocarpanquinone LQB-118 in different CML cell lines. Anti Cancer Agents Med Chem. 2015;15(3):345–52.
Nestal de Moraes G, Castro CP, Salustiano EJ, Dumas ML, Costas F, Lam EW-F, et al. The pterocarpanquinone LQB-118 induces apoptosis in acute myeloid leukemia cells of distinct molecular subtypes and targets FoxO3a and FoxM1 transcription factors. Int J Oncol. 2014;45(5):1949–58.
de Sá Bacelar T, da Silva AJ, Costa PRR, Rumjanek VM. The pterocarpanquinone LQB 118 induces apoptosis in tumor cells through the intrinsic pathway and the endoplasmic reticulum stress pathway. Anti-Cancer Drugs. 2013;24(1):73–83.
Martino T, Magalhães FCJ, Justo GA, Coelho MGP, Netto CD, Costa PRR, et al. The pterocarpanquinone LQB-118 inhibits tumor cell proliferation by downregulation of c-Myc and cyclins D1 and B1 mRNA and upregulation of p21 cell cycle inhibitor expression. Bioorg Med Chem. 2014;22(12):3115–22.
de Souza Reis FR, de Faria FCC, Castro CP, de Souza PS, da Cunha VF, Bello RD, et al. The therapeutical potential of a novel pterocarpanquinone LQB-118 to target inhibitor of apoptosis proteins in acute myeloid leukemia cells. Anti Cancer Agents Med Chem. 2013;13(2):341–51.
Cunha-Júnior EF, Martins TM, Canto-Cavalheiro MM, Marques PR, Portari EA, Coelho MGP, et al. Preclinical studies evaluating subacute toxicity and therapeutic efficacy of LQB-118 in experimental visceral Leishmaniasis. Antimicrob Agents Chemother. 2016;60(6):3794–801.
Costa L, Pinheiro RO, Dutra PML, Santos RF, Cunha-Júnior EF, Torres-Santos EC, et al. Pterocarpanquinone LQB-118 induces apoptosis in Leishmania (Viannia) braziliensis and controls lesions in infected hamsters. PLoS One. 2014;9(10):e109672.
da Cunha-Junior EF, Pacienza-Lima W, Ribeiro GA, Netto CD, Canto-Cavalheiro MM, da Silva AJM, et al. Effectiveness of the local or oral delivery of the novel naphthopterocarpanquinone LQB-118 against cutaneous leishmaniasis. J Antimicrob Chemother. 2011;66(7):1555–9.
Ribeiro GA, Cunha-Júnior EF, Pinheiro RO, da-Silva SAG, Canto-Cavalheiro MM, da AJM S, et al. LQB-118, an orally active pterocarpanquinone, induces selective oxidative stress and apoptosis in Leishmania amazonensis. J Antimicrob Chemother. 2013;68(4):789–99.
[No authors listed]. Global leishmaniasis update, 2006–2015: a turning point in leishmaniasis surveillance. Wkly Epidemiol Rec 2017;92(38):557–565.
Kevric I, Cappel MA, Keeling JH. New world and old world Leishmania infections: a practical review. Dermatol Clin. 2015;33(3):579–93.
GBD 2015 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1603–58.
Zulfiqar B, Shelper TB, Avery VM. Leishmaniasis drug discovery: recent progress and challenges in assay development. Drug Discov Today. 2017;22(10):1516–31.
Barcellos JCF, Borges BHF, Mendes JA, Ceron MC, Buarque CD, Dias AG, et al. Synthesis of 11a-N-Arylsulfonyl-5-carbapterocarpans (Tetrahydro-5H-benzo[a]carbazoles) by Azaarylation of Dihydronaphthalenes with o-Iodo-N-(Arylsulfonyl)anilines in poly(ethylene glycol). Synthesis. 2015;47(19):3013–9.
Buarque CD, Domingos JLO, Netto CD, Costa PRR. Palladium-catalyzed Oxyarylation, Azaarylation and α-Arylation reactions in the synthesis of bioactive isoflavonoid analogues. Curr Org Synth. 2015;12(6):772–94.
Moraes PF, Gaspar FV, Borges RHF, Netto CD, Leão RAC, Nájera C, et al. Ligand-free palladium-catalyzed Oxyarylation of Dihydronaphthalenes and Chromenequinone with o-Iodophenols and 3-Iodolawsone in PEG-400: an efficient synthesis of 5-Carbapterocarpans and Pterocarpanquinones. Synthesis. 2015;47(22):3505–12.
Kulshrestha A, Bhandari V, Mukhopadhyay R, Ramesh V, Sundar S, Maes L, et al. Validation of a simple resazurin-based promastigote assay for the routine monitoring of miltefosine susceptibility in clinical isolates of Leishmania donovani. Parasitol Res. 2013;112(2):825–8.
Menna-Barreto RFS, Goncalves RLS, Costa EM, Silva RSF, Pinto AV, Oliveira MF, et al. The effects on Trypanosoma cruzi of novel synthetic naphthoquinones are mediated by mitochondrial dysfunction. Free Radic Biol Med. 2009;47(5):644–53.
Alexandre TR, Lima ML, Galuppo MK, Mesquita JT, do Nascimento MA, dos Santos AL, et al. Ergosterol isolated from the basidiomycete Pleurotus salmoneostramineus affects Trypanosoma cruzi plasma membrane and mitochondria. J Venom Anim Toxins incl Trop Dis. 2017;23:30. https://doi.org/10.1186/s40409-017-0120-0.
Kiss L, Antus S. A convenient synthesis of pterocarpans. Heterocycl Commun. 2011;6(4):309–14.
Kiss L, Papp G, Joó F, Antus S. Efficient synthesis of pterocarpans by heck-oxyarylation in ionic liquids. Heterocycl Commun. 2011;7(5):417–20.
Sundar S, Singh A. Recent developments and future prospects in the treatment of visceral leishmaniasis. Ther Adv Infect Dis. 2016;3(3–4):98–109.
Hefnawy A, Berg M, Dujardin JC, De Muylder G. Exploiting knowledge on Leishmania drug resistance to support the quest for new drugs. Trends Parasitol. 2017;33(3):162–74.
Aronson N, Herwaldt BL, Libman M, Pearson R, Lopez-Velez R, Weina P, et al. Diagnosis and treatment of Leishmaniasis: clinical practice guidelines by the infectious diseases society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis. 2016;63(12):1539–57.
Katsuno K, Burrows JN, Duncan K. Hooft van Huijsduijnen R, Kaneko T, Kita K, et al. hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat Rev Drug Discov. 2015;14(11):751–8.
Costa EC, Cassamale TB, Carvalho DB, Bosquiroli LSS, Ojeda M, Ximenes TV, et al. Antileishmanial activity and structure-activity relationship of Triazolic compounds derived from the neolignans grandisin, veraguensin, and machilin G. Molecules. 2016;21(6):802. https://doi.org/10.3390/molecules21060802.
Werbovetz KA, Bhattacharjee AK, Brendle JJ, Scovill JP. Analysis of stereoelectronic properties of camptothecin analogues in relation to biological activity. Bioorg Med Chem. 2000;8(7):1741–7.
de Melos JLR, Torres-Santos EC, Faiões VS, Del Cistia CN, Sant’Anna CMR, Rodrigues-Santos CE, et al. Novel 3,4-methylenedioxyde-6-X-benzaldehyde-thiosemicarbazones: synthesis and antileishmanial effects against Leishmania amazonensis. Eur J Med Chem. 2015;103:409–17.
Singh N, Mishra BB, Bajpai S, Singh RK, Tiwari VK. Natural product based leads to fight against leishmaniasis. Bioorg Med Chem. 2014;22(1):18–45.
Rodrigues CA, dos Santos PF, da Costa MOL, Pavani TFA, Xander P, Geraldo MM, et al. 4-Phenyl-1,3-thiazole-2-amines as scaffolds for new antileishmanial agents. J Venom Anim Toxins incl Trop Dis. 2018;24:26. https://doi.org/10.1186/s40409-018-0163-x.
Croft SL, Yardley V, Kendrick H. Drug sensitivity of Leishmania species: some unresolved problems. Trans R Soc Trop Med Hyg. 2002;96(Suppl 1):S127–9.
Pal C, Bandyopadhyay U. Redox-active antiparasitic drugs. Antioxid Redox Signal. 2012;17(4):555–82.