Pterocarpanquinones, aza-pterocarpanquinone and derivatives: synthesis, antineoplasic activity on human malignant cell lines and antileishmanial activity on Leishmania amazonensis

Submitted by Sandra Infurna ([email protected]) on 2018-11-17T18:37:01Z No. of bitstreams: 1 edesio_cunhajunior_etal_IOC_2011.pdf: 491185 bytes, checksum: 27d2f7db924ed5f8b197932f625c8a24 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-11-17T18:51:11Z (GMT) No. of bitstreams: 1 edesio_cunhajunior_etal_IOC_2011.pdf: 491185 bytes, checksum: 27d2f7db924ed5f8b197932f625c8a24 (MD5)Made available in DSpace on 2018-11-17T18:51:11Z (GMT). No. of bitstreams: 1 edesio_cunhajunior_etal_IOC_2011.pdf: 491185 bytes, checksum: 27d2f7db924ed5f8b197932f625c8a24 (MD5) Previous issue date: 2011Pontifícia Universidade Católica do Rio de Janeiro. Departamento de Química. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Núcleo de Pesquisas de Produtos Naturais. Laboratório de Química Bioorgânica. Rio de Janeiro, RJ, Brasil.Universidade Federal de Pernambuco. Departamento de Fisiologia e Farmacologia. Recife, PE, Brasil.Universidade Federal do Ceará. Departamento de Fisiologia e Farmacologia. Fortaleza, CE, Brasil.Universidade Federal do Ceará. Departamento de Fisiologia e Farmacologia. Fortaleza, CE, Brasil.Universidade Federal do Ceará. Departamento de Fisiologia e Farmacologia. Fortaleza, CE, Brasil.Universidade Federal do Ceará. Departamento de Fisiologia e Farmacologia. Fortaleza, CE, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Química. Laboratório de Química Orgânica. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Núcleo de Pesquisas de Produtos Naturais. Laboratório de Química Bioorgânica. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Núcleo de Pesquisas de Produtos Naturais. Laboratório de Química Bioorgânica. Rio de Janeiro, RJ, Brasil.Pterocarpanquinones (1a-e) and the aza-pterocarpanquinone (2) were synthesized through palladium catalyzed oxyarylation and azaarylation of conjugate olefins, and showed antineoplasic effect on leukemic cell lines (K562 and HL-60) as well as colon cancer (HCT-8), gliobastoma (SF-295) and melanoma (MDA-MB435) cell lines. Some derivatives were prepared (3-8) and evaluated, allowing establishing the structural requirements for the antineoplasic activity in each series. Compound 1a showed the best selectivity index in special for leukemic cells while 2 showed to be more bioselective for HCT-8, SF-295 and MDA-MB435 cells. Pterocarpanquinones 1a and 1c-e, as well as 8 were the most active on amastigote form of Leishmania amazonensis in culture. Compounds 1a, 1c and 8 showed the best selectivity index

Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice

Submitted by Sandra Infurna ([email protected]) on 2017-05-04T11:55:40Z No. of bitstreams: 1 edesio_cunhajr_etal_IOC_2017.pdf: 1518221 bytes, checksum: 6be150919adf4e381a7886f6406acc7b (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2017-05-04T12:14:58Z (GMT) No. of bitstreams: 1 edesio_cunhajr_etal_IOC_2017.pdf: 1518221 bytes, checksum: 6be150919adf4e381a7886f6406acc7b (MD5)Made available in DSpace on 2017-05-04T12:14:58Z (GMT). No. of bitstreams: 1 edesio_cunhajr_etal_IOC_2017.pdf: 1518221 bytes, checksum: 6be150919adf4e381a7886f6406acc7b (MD5) Previous issue date: 2017Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Universidade de São Paulo. Instituto de Medicina Tropical. São Paulo, SP, Brasil / Instituto Adolfo Lutz. Centro de Parasitologia e Micologia. São Paulo, SP, Brasil.Instituto Adolfo Lutz. Centro de Parasitologia e Micologia. São Paulo, SP, Brasil.Universidade de São Paulo. Instituto de Medicina Tropical. São Paulo, SP, Brasil.Centro de Investigaciones BioloÂgicas (CSIC). Unidad Asociada Interacciones, Metabolismo y Bioanálisis CSIC-CEU. Madrid, Spain.Universidad CEU San Pablo. Faculty of Pharmacy. Center for Metabolomics and Bioanalysis (CEMBIO. Madrid, Spain.Centro de Investigaciones BioloÂgicas (CSIC). Unidad Asociada Interacciones, Metabolismo y Bioanálisis CSIC-CEU. Madrid, Spain.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Instituto Adolfo Lutz. Centro de Parasitologia e Micologia. São Paulo, SP, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.The leishmanicidal action of tricyclic antidepressants has been studied and evidences have pointed that their action is linked to inhibition of trypanothione reductase, a key enzyme in the redox metabolism of pathogenic trypanosomes. Cyclobenzaprine (CBP) is a tricyclic structurally related to the antidepressant amitriptyline, differing only by the presence of a double bond in the central ring. This paper describes the effect of CBP in experimental visceral leishmaniasis, its inhibitory effect in trypanothione reductase and the potential immunomodulatory activity

Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection

Submitted by Sandra Infurna ([email protected]) on 2017-07-13T16:48:02Z No. of bitstreams: 1 cristiana_silva_etal_IOC_2017.pdf: 757102 bytes, checksum: c6e1b124c629b18cadf5c0a3ada29ee8 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2017-07-13T17:00:16Z (GMT) No. of bitstreams: 1 cristiana_silva_etal_IOC_2017.pdf: 757102 bytes, checksum: c6e1b124c629b18cadf5c0a3ada29ee8 (MD5)Made available in DSpace on 2017-07-13T17:00:16Z (GMT). No. of bitstreams: 1 cristiana_silva_etal_IOC_2017.pdf: 757102 bytes, checksum: c6e1b124c629b18cadf5c0a3ada29ee8 (MD5) Previous issue date: 2017Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanossomatídeos. Rio de Janeiro, RJ. Brasil.Augusta University. Department of Chemistry and Physics. Augusta, USA.Georgia State University. Department of Chemistry. Atlanta, GA, USA.Georgia State University. Department of Chemistry. Atlanta, GA, USA / Mansoura University. Faculty of Pharmacy. Department of Pharmaceutical Organic Chemistry. Mansoura, Egypt.Georgia State University. Department of Chemistry. Atlanta, GA, USA.Augusta University. Department of Chemistry and Physics. Augusta, USA.Georgia State University. Department of Chemistry. Atlanta, GA, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.Abstract: Arylimidamides (AIAs), previously termed as reversed amidines, present a broad spectrum of activity against intracellular microorganisms. In the present study, three novel AIAs were evaluated in a mouse model of Trypanosoma cruzi infection, which is the causative agent of Chagas disease. The bis-AIAs DB1957, DB1959 and DB1890 were chosen based on a previous screening of their scaffolds that revealed a very promising trypanocidal effect at nanomolar range against both the bloodstream trypomastigotes (BTs) and the intracellular forms of the parasite. This study focused on both mesylate salts DB1957 and DB1959 besides the hydrochloride salt DB1890. Our current data validate the high activity of these bis-AIA scaffolds that exhibited EC50 (drug concentration that reduces 50% of the number of the treated parasites) values ranging from 14 to 78 nM and 190 to 1,090 nM against bloodstream and intracellular forms, respectively, also presenting reasonable selectivity indexes and no mutagenicity profile predicted by in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET). Acute toxicity studies using murine models revealed that these AIAs presented only mild toxic effects such as reversible abdominal contractions and ruffled fur. Efficacy assays performed with Swiss mice infected with the Y strain revealed that the administration of DB1957 for 5 consecutive days, with the first dose given at parasitemia onset, reduced the number of BTs at the peak, ranging between 21 and 31% of decrease. DB1957 was able to provide 100% of animal survival, while untreated animals showed 70% of mortality rates. DB1959 and DB1890B did not reduce circulating parasitism but yielded .80% of survival rates

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

Abstract Background 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. Methods 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. Results 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. Conclusions The data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents

<i>In vitro</i> activity of CBP.

<p>(A) Promastigotes of <i>L</i>. <i>infantum</i> were incubated with CBP for 72 h. The growth inhibition was measured using resazurin. (n = 3) (B) Peritoneal macrophages were infected with <i>L</i>. <i>infantum</i> and treated with CBP for 72 h. The slides were stained and the results were expressed as an infection index^# [II = % infected cells × (number of amastigotes/total number of macrophages)]. The inset shows representative photos from the slides. (n = 3).</p

Increase of Nitric Oxide levels in macrophages treated with CBP.

<p>The production of nitric oxide (NO) by macrophages was measured after 24 h incubation with cyclobenzaprine (12 μM). The nitric oxide content was colorimetrically determined by the Griess reaction in the culture supernatants. Lipopolysaccharide (LPS) was used as positive control (1 μg/mL) (C). (n = 3) *p<0.05.</p

Effect of CBP on TryR and ROS production.

<p>(a) <i>TryR assay</i>. Soluble extract of promastigotes of <i>L</i>. <i>infantum</i> using oxidized trypanothione as substrate and clomipramine (50 μM) as positive control (PC) of inhibition. Reading was initiated after adding 100 μM of DTNB at 410nm (n = 3). (b) <i>ROS production</i>. Promastigotes of <i>L</i>. <i>infantum</i> were incubated with CBP and ROS generation was measured with H₂DCFDA reagent. Antimycin A 10 μM was used as positive control (PC). (n = 3) *p<0.05, ** p<0.01 and ***p<0.001.</p