RESUMO
The availability of pure individual betalains in sufficient quantities which permit deeper understanding is still a challenge. This study investigates the high-yielding semisynthesis of betaxanthins using betalamic acid from a natural source (Opuntia dillenii), followed by condensation with Ê-amino acids and further purification. Moreover, the color stability of the four synthesized individual betaxanthins, namely proline (Ê-ProBX), alanine (Ê-AlaBX), leucine (Ê-LeuBX), and phenylalanine (Ê-PheBX) betaxanthins, was investigated at different pHs. Their relative contribution to free radical scavenging was also scrutinized by TEAC and DPPH. Ê-AlaBX and Ê-LeuBx showed a significantly (p < 0.05) higher antioxidant activity, whereas Ê-ProBX was the most resistant to the hydrolysis of betaxanthin and hence the least susceptible to color change. The color stability was strongly influenced by pH, with the color of Ê-ProBX, Ê-LeuBX, and Ê-AlaBX at pH 6 being more stable, probably due to the easier hydrolysis under acid conditions. The semisynthesis and purification allowed us to have available remarkable quantities of pure individual betaxanthins of Opuntia dillenii for the first time, and to establish their color properties and antioxidant capacity. This study could be a step forward in the development of the best natural food colorant formulation, based on the betalain structure, which is of special interest in food technology.
Assuntos
Betacianinas , Betaxantinas , Opuntia , Betacianinas/química , Betaxantinas/química , Opuntia/química , Antioxidantes/química , Antioxidantes/síntese química , Antioxidantes/farmacologia , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/síntese química , CorRESUMO
Type 2 diabetes (T2D) is one of the most common diseases and the 8th leading cause of death worldwide. Individuals with T2D are at risk for several health complications that reduce their life expectancy and quality of life. Although several drugs for treating T2D are currently available, many of them have reported side effects ranging from mild to severe. In this work, we present the synthesis in a gram-scale as well as the in silico and in vitro activity of two semisynthetic glycyrrhetinic acid (GA) derivatives (namely FC-114 and FC-122) against Protein Tyrosine Phosphatase 1B (PTP1B) and α-glucosidase enzymes. Furthermore, the in vitro cytotoxicity assay on Human Foreskin fibroblast and the in vivo acute oral toxicity was also conducted. The anti-diabetic activity was determined in streptozotocin-induced diabetic rats after oral administration with FC-114 or FC-122. Results showed that both GA derivatives have potent PTP1B inhibitory activity being FC-122, a dual PTP1B/α-glucosidase inhibitor that could increase insulin sensitivity and reduce intestinal glucose absorption. Molecular docking, molecular dynamics, and enzymatic kinetics studies revealed the inhibition mechanism of FC-122 against α-glucosidase. Both GA derivatives were safe and showed better anti-diabetic activity in vivo than the reference drug acarbose. Moreover, FC-114 improves insulin levels while decreasing LDL and total cholesterol levels without decreasing HDL cholesterol.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ácido Glicirretínico , Humanos , Animais , Ratos , Diabetes Mellitus Experimental/tratamento farmacológico , Simulação de Acoplamento Molecular , Qualidade de Vida , alfa-Glucosidases , Ácido Glicirretínico/farmacologiaRESUMO
Sesquiterpene lactone (SL) subtypes including hirsutinolide and cadinanolide have a controversial genesis. Metabolites of these classes are either described as natural products or as artifacts produced via the influence of solvents, chromatographic mobile phases, and adsorbents used in phytochemical studies. Based on this divergence, and to better understand the sensibility of these metabolites, different pH conditions were used to prepare semisynthetic SLs and evaluate the anti-inflammatory and antiproliferative activities. Therefore, glaucolide B (1) was treated with various Brønsted-Lowry and Lewis acids and bases-the same approach was applied to some of its derivatives-allowing us to obtain 14 semisynthetic SL derivatives, 10 of which are hereby reported for the first time. Hirsutinolide derivatives 7a (CC50 = 5.0 µM; SI = 2.5) and 7b (CC50 = 11.2 µM; SI = 2.5) and the germacranolide derivative 8a (CC50 = 3.1 µM; SI = 3.0) revealed significant cytotoxic activity and selectivity against human melanoma SK-MEL-28 cells when compared with that against non-tumoral HUVEC cells. Additionally, compounds 7a and 7c.1 showed strongly reduced interleukin-6 (IL-6) and nitrite (NOx) release in pre-treated M1 macrophages J774A.1 when stimulated with lipopolysaccharide. Despite the fact that hirsutinolide and cadinanolide SLs may be produced via plant metabolism, this study shows that acidic and alkaline extraction and solid-phase purification processes can promote their formation.
Assuntos
Antineoplásicos , Sesquiterpenos , Humanos , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Anti-Inflamatórios/farmacologia , Lactonas/farmacologia , Lactonas/químicaRESUMO
Betaxanthins are natural products with high antioxidant and anti-inflammatory properties. Here, we describe the semisynthesis of twenty-one betaxanthins derived from proteinogenic amino acids, including the elusive betaxanthin of l-cysteine and two betaxanthins derived from l-lysine, and rationalize their antioxidant properties in mechanistic terms. The antioxidant capacity and redox potential of these betaxanthins were compared to those of model betaxanthins derived from dopamine, l-DOPA (L-3,4-dihydroxyphenylalanine), and pyrrolidine and structure-property relationships were established by using matched molecular pair analysis and a model developed using a genetic algorithm. Either a phenol or indole moiety enhance the antioxidant capacity of betaxanthins, which is overall much higher than that of their amino acid precursors and standard antioxidants, except for the cysteine-betaxanthin. The one-electron oxidation of amino acid betaxanthins produces radicals stabilized in multiple centers, as demonstrated by quantum chemical calculations.
RESUMO
In this study, we describe the semisynthesis of cost-effective photosensitizers (PSs) derived from chlorophyll a containing different substituents and using previously described methods from the literature. We compared their structures when used in photodynamic inactivation (PDI) against Staphylococcus aureus, Escherichia coli, and Candida albicans under different conditions. The PSs containing carboxylic acids and butyl groups were highly effective against S. aureus and C. albicans following our PDI protocol. Overall, our results indicate that these nature-inspired PSs are a promising alternative to selectively inactivate microorganisms using PDI.
Assuntos
Fotoquimioterapia , Fármacos Fotossensibilizantes , Candida albicans , Ácidos Carboxílicos , Clorofila A , Escherichia coli , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Staphylococcus aureus/fisiologiaRESUMO
Triterpenes α,ß-amyrin are naturally occurring molecules that can serve as building blocks for synthesizing new chemical entities. This study synthesized acyl, carboxyesther, NSAID, and nitrogenous derivatives and evaluated their antimicrobial activity. A cyclodextrin complexation method was developed to improve the solubility of the derivatives. Of the 17 derivatives tested, five exhibited activity against Trypanosoma cruzi, T. brucei, Leishmania infantum, Candida albicans, Staphylococcus aureus, and Escherichia coli. The 9a/9b mixture showed weak activity against the parasites (IC50 24.45-40.32 µM). However, it showed no activity for the other microorganisms. Derivatives 14a/14b exhibited potent activity against T. cruzi (IC50 2.0 nM) in this tested concentration did not show activity to the other microorganisms and were not cytotoxic. Derivatives 15a/15b and 16a/16b demonstrated relevant activity against the parasites (IC50 2.24-5.44 µM), but were also cytotoxic. Derivatives 17a/17b showed low activity against the tested parasites (IC50 21.70-22.79 µM), but they were selective since they did not show activity against other microorganisms. In docking studies, in general, all derivatives showed complementarity with the CYP51 binding site of the trypanosomatid mainly by hydrophobic interactions; thus, it is not conclusive that the molecules act by inhibiting this enzyme. Our results showed that triterpenes derivatives with antitrypanosomal activity could be synthesized by an inexpensive and rapid method.
Assuntos
Doença de Chagas , Leishmania infantum , Triterpenos , Trypanosoma cruzi , Humanos , Chumbo , Estrutura Molecular , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/farmacologiaRESUMO
Breast cancer has the highest incidence and mortality in females, while prostate cancer has the second-highest incidence in males. Studies have shown that compounds from Brazilian green propolis have antitumor activities and can selectively inhibit the AKR1C3 enzyme, overexpressed in hormone-dependent prostate and breast tumors. Thus, in an attempt to develop new cytotoxic inhibitors against these cancers, three prenylated compounds, artepillin C, drupanin and baccharin, were isolated from green propolis to synthesize new derivatives via coupling reactions with different amino acids. All obtained derivatives were submitted to antiproliferative assays against four cancer cells (MCF-7, MDA MB-231, PC-3, and DU145) and two normal cell lines (MCF-10A and PNT-2) to evaluate their cytotoxicity. In general, the best activity was observed for compound6e, derived from drupanin, which exhibited half-maximal inhibitory concentration (IC50) of 9.6 ± 3 µM and selectivity index (SI) of 5.5 against MCF-7 cells.In silicostudies demonstrated that these derivatives present coherent docking interactions and binding modes against AKR1C3, which might represent a possible mechanism of inhibition in MCF-7 cells.
Assuntos
Aminoácidos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Cinamatos/farmacologia , Fenilpropionatos/farmacologia , Própole/química , Tricotecenos/farmacologia , Aminoácidos/análise , Aminoácidos/síntese química , Antineoplásicos Fitogênicos/análise , Antineoplásicos Fitogênicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cinamatos/análise , Cinamatos/síntese química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenilpropionatos/análise , Fenilpropionatos/síntese química , Própole/análise , Própole/síntese química , Própole/farmacologia , Relação Estrutura-Atividade , Tricotecenos/análise , Tricotecenos/síntese químicaRESUMO
BACKGROUND: Natural products have been universally approached in the research of novel trends useful to detail the essential paths of the life sciences and as a strategy for pharmacotherapeutics. OBJECTIVE: This work focuses on further modification to the 6-hydroxy-flavanone building block aiming to obtain improved BCR-ABL kinase inhibitors. METHODS: Ether derivatives were obtained from Williamson synthesis and triazole from Microwave- assisted click reaction. Chemical structures were finely characterized through IR, 1H and 13C NMR and HRMS. They were tested for their inhibitory activity against BCR-ABL kinase. RESULTS: Two inhibitors bearing a triazole ring as a pharmacophoric bridge demonstrated the strongest kinase inhibition at IC50 value of 364 nM (compound 3j) and 275 nM (compound 3k). CONCLUSION: 6-hydroxy-flavanone skeleton can be considered as a promising core for BCR-ABL kinase inhibitors.
Assuntos
Flavonoides/síntese química , Flavonoides/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Brasilicardinâ A (1) consists of an unusual anti/syn/anti-perhydrophenanthrene skeleton with a carbohydrate side chain and an amino acid moiety. It exhibits potent immunosuppressive activity, yet its mode of action differs from standard drugs that are currently in use. Further pre-clinical evaluation of this promising, biologically active natural product is hampered by restricted access to the ready material, as its synthesis requires both a low-yielding fermentation process using a pathogenic organism and an elaborate, multi-step total synthesis. Our semi-synthetic approach included a) the heterologous expression of the brasilicardinâ A gene cluster in different non-pathogenic bacterial strains producing brasilicardinâ A aglycone (5) in excellent yield and b) the chemical transformation of the aglycone 5 into the trifluoroacetic acid salt of brasilicardinâ A (1 a) via a short and straightforward five-steps synthetic route. Additionally, we report the first preclinical data for brasilicardinâ A.
Assuntos
Aminoglicosídeos/metabolismo , Engenharia Genética , Imunossupressores/síntese química , Alquil e Aril Transferases/genética , Aminoglicosídeos/síntese química , Aminoglicosídeos/química , Aminoglicosídeos/farmacologia , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imunossupressores/química , Imunossupressores/metabolismo , Imunossupressores/farmacologia , Camundongos , Plasmídeos/genética , Plasmídeos/metabolismo , Streptomyces/genética , Streptomyces/metabolismo , Terpenos/químicaRESUMO
Neglected parasitic diseases are a group of infections currently considered as a worldwide concern. This fact can be attributed to the migration of these diseases to developed and developing countries, associated with therapeutic insufficiency resulted from the low investment in the research and development of new drugs. In order to overcome this situation, bioprospecting supports medicinal chemistry in the identification of new scaffolds with therapeutically appropriate physicochemical and pharmacokinetic properties. Among them, we highlight the nitrogenous heterocyclic compounds, as they are secondary metabolites of many natural products with potential biological activity. The objective of this work was to review studies within a 10-year timeframe (2009- 2019), focusing on the pharmacological application of nitrogen bioprospectives (pyrrole, pyridine, indole, quinoline, acridine, and their respective derivatives) against neglected parasitic infections (malaria, leishmania, trypanosomiases, and schistosomiasis), and their application as a template for semi-synthesis or total synthesis of potential antiparasitic agents. In our studies, it was observed that among the selected articles, there was a higher focus on the attempt to identify and obtain novel antimalarial compounds, in a way that an extensive amount of studies involving all heterocyclic nitrogen nuclei were found. On the other hand, the parasites with the lowest number of publications up until the present date have been trypanosomiasis, especially those caused by Trypanosoma cruzi, and schistosomiasis, where some heterocyclics have not even been cited in recent years. Thus, we conclude that despite the great biodiversity on the planet, little attention has been given to certain neglected tropical diseases, especially those that reach countries with a high poverty rate.
Assuntos
Bioprospecção , Leishmania , Doenças Negligenciadas , Doenças Parasitárias , Animais , Humanos , Doenças Negligenciadas/tratamento farmacológico , Nitrogênio , Doenças Parasitárias/tratamento farmacológicoRESUMO
Two new carotenoids, sapotexanthin 5,6-epoxide and sapotexanthin 5,8-epoxide, have been isolated from the ripe fruits of red mamey (Pouteria sapota). Sapotexanthin 5,6-epoxide was also prepared by partial synthesis via epoxidation of sapotexanthin, and the (5R,6S) and (5S,6R) stereoisomers were identified by high-performance liquid chromatography-electronic circular dichroism (HPLC-ECD) analysis. Spectroscopic data of the natural and semisynthetic derivatives obtained by acid-catalyzed rearrangement of cryptocapsin 5,8-epoxide stereoisomers were compared for structural elucidation.
Assuntos
Carotenoides/análise , Carotenoides/isolamento & purificação , Compostos de Epóxi/química , Pouteria/química , Carotenoides/química , EstereoisomerismoRESUMO
BACKGROUND: Effective cancer treatment is a major public health challenge. The limitations of current therapies and their adverse effects reduce the efficacy of treatment, leading to significant mortality rates worldwide. Moreover, natural product chemistry occupies a prominent role in the search for new treatment alternatives, by contributing a spectrum of chemical structures that may potentially yield new bioactive compounds. The compound [6]-gingerol (1) is the main active substance in ginger (Zingiber officinale) and several studies have shown it to produce beneficial effects, including antitumor activity. OBJECTIVE: This work aims to obtain new gingerol derivatives with cytotoxic activity. METHODS: [6]-gingerol was isolated and its derivatives were produced using click chemistry, obtaining eight new compounds. All chemical structures were determined by means of IR, NMR and HRMS data, and cytotoxicity was evaluated in the HCT 116 (colon carcinoma) and MCF-7 (breast carcinoma) cell lines at concentrations of 5 µmol L-1 and 50 µmol L-1. RESULTS: At 50 µmol L-1, more than 70% inhibition of cell growth was achieved with compounds 2e, 2g against HCT 116, and 2b, 2d, 2e, 2f and 2g against MCF-7. CONCLUSION: The obtained compounds showed only moderate cytotoxic activity. However, the products with substituents occupying the meta position in relation to the triazole ring showed increased cytotoxic properties. The brominated compound (2g) showed the strongest activity, inhibiting cell proliferation by 87%.
Assuntos
Antineoplásicos/farmacologia , Catecóis/farmacologia , Álcoois Graxos/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Catecóis/síntese química , Catecóis/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Álcoois Graxos/síntese química , Álcoois Graxos/química , Células HCT116 , Humanos , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
BACKGROUND/AIM: This study examined the potential role of natural triterpenoids lupeol, calenduladiol and heliantriol B2, and a set of 19 derivatives, as antiproliferative and antimetastatic agents against prostate cancer cells. MATERIALS AND METHODS: Natural triterpenoids were isolated from Chuqiraga erinaceae. Analogs were obtained by transformations of lupeol and calenduladiol. The effects of compounds on PC-3 and LNCaP cells were determined using the MTT assay. Compounds with half-maximal inhibitory concentration <70 µM were evaluated as antimetastatic agents by a wound-healing assay. RESULTS: Lupeol-3ß-sulfate, a new semisynthetic lupane, was the most active compound. In general, sulfated derivatives displayed higher activity than the lead against both cell lines. A new analog, calenduladiol-3ß-monosulfate, inhibited the migration of PC-3 cells; heliantriol B2 and 3ß-aminolupane inhibited the migration of LNCaP cells in a concentration-dependent manner. CONCLUSION: Our study provides novel agents with cytotoxic effects on prostate cancer cells, which may represent a potential new therapeutic approach for prostate cancer.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Triterpenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Cicatrização/efeitos dos fármacosRESUMO
We describe the in vitro activity of two natural isomeric ent-beyerene diterpenes, several derivatives and synthetic intermediates. Beyerenols 1 and 2 showed EC50 of 4.6⯱â¯9.4 and 5.3⯱â¯9.4⯵g/mL against amastigotes of L. (V) brazilensis, with SI of 5.1 and 7.7, respectively. Beyerenol 1 was synthesized from stevioside. In vivo experiments with bereyenols showed cure in 50% of hamsters infected with L. (V) brazilensis topically applied as Cream I (beyerenol 1, 0.81%, w/w) and Cream III (beyerenol 2, 1.96%, w/w). These results suggest that beyerenols are potential candidates for cutaneous leishmaniasis chemotherapy by topical application. In vitro assays of amastigotes of L. (V) brazilensis showed EC50 of 1.1⯱â¯0.1 and 1.3⯱â¯0.04⯵g/mL, with SI of 3.1 and 3.5 for hydrazone intermediates 10 and 11, respectively.
Assuntos
Diterpenos/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Tripanossomicidas/uso terapêutico , Animais , Linhagem Celular , Diterpenos/síntese química , Diterpenos/farmacologia , Diterpenos/toxicidade , Feminino , Humanos , Leishmania braziliensis/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Mesocricetus , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Tripanossomicidas/toxicidadeRESUMO
Trichomonas vaginalis and Leishmania spp. are protozoal species responsible for millions of cases of parasitic diseases worldwide. Considering the potential of natural products and the need for more effective and less toxic alternatives to treat trichomoniasis and leishmaniasis, this study aimed to evaluate the effect of two series of triterpenes derivatives with different modifications at C-3 and C-28 positions of the ursolic acid (UA) and betulinic acid (BA) against trophozoites of Trichomonas vaginalis and promastigotes forms of Leishmania (L.) amazonensis. The compounds modified just at C-3 were the most active. The 3β-acetyl betulinic acid (1b) reduced the trophozoites viability of T. vaginalis at 74%, followed by the 3-oxo ursolic acid and 3-oxo betulinic acid (3a and 3b) compounds (55% of reduction). The compound 3β-isobutyl ursolic acid (7a) inhibited the viability of L. amazonensis promastigotes by 55%. Therefore, analyzing the structure-activity relationship and the data of literature, it is possible to suppose that the inclusion of polar groups in the skeletons could improve the antiprotozoal activity. Overall, further studies are necessary to develop triterpenic derivatives with more powerful trichomonicidal and leishmanicidal properties.
RESUMO
Annonalide (3ß,20-epoxy-3α,16-dihydroxy-15-oxo-7-pimaren-19,6ß-olide, C20H26O6, 1) is the major (9ßH)-pimarane diterpene isolated from tubers of Cassimirella ampla, and it exhibits cytotoxic properties upon interaction with ctDNA. We have prepared new derivatives of 1 by modification of the (9ßH)-pimarane backbone and report here the semisynthesis and absolute configuration of a novel rearranged 19,20-δ-lactone (9ßH)-pimarane. Our approach was the reduction of the carbonyl groups of 1 with sodium borohydride, at positions C15 (no stereoselectivity) and C3 (stereoselective reduction), followed by rearrangement of the 6,19-γ-lactone ring into the six-membered 19,20-δ-lactone ring in 4a (3ß,6ß,16-trihydroxy-7-pimaren-19,20ß-olide monohydrate, C20H30O6·H2O). The absolute structure of the new compound, 4a, was determined unambiguously with a Flack parameter x of -0.01â (11), supporting the stereochemistry assignment of 1 redetermined here. Besides the changes in the pattern of covalent bonds caused by reduction and lactone rearrangement, the conformation of one of the three fused cyclohexane rings is profoundly different in 4a, adopting a chair conformation instead of the boat shape found in 1. Furthermore, the intramolecular hydrogen bond present in 1 is lost in new compound 4a, due to hydrogen bonding between the 3-OH group and the solvent water molecule.
RESUMO
The cytotoxic activity of the pimarane diterpene annonalide (1) and nine of its semisynthetic derivatives (2-10) was investigated against the human tumor cell lines HL-60 (leukemia), PC-3 (prostate adenocarcinoma), HepG2 (hepatocellular carcinoma), SF-295 (glioblastoma) and HCT-116 (colon cancer), and normal mouse fibroblast (L929) cells. The preparation of 2-10 involved derivatization of the side chain of 1 at C-13. Except for 2, all derivatives are being reported for the first time. Most of the tested compounds presented IC50s below 4.0⯵M, being considered potential antitumor agents. The structures of all new compounds were elucidated by spectroscopic analyses including 2D NMR and HRMS. Additionally, the interaction of annonalide (1) with ctDNA was evaluated using spectroscopic techniques, and the formation of a supramolecular complex with the macromolecule was confirmed. Competition assays with fluorescent probes (Hoechst and ethidium bromide) and theoretical studies confirmed that 1 interacts preferentially via DNA intercalation with stoichiometric ratio of 1:1 (1:ctDNA). The ΔG value was calculated as -28.24â¯kJâ¯mol-1, and indicated that the interaction process occurs spontaneously. Docking studies revealed that van der Walls is the most important interaction in 1-DNA and EB-DNA complexes, and that both ligands (1 and EB) interact with the same DNA residues (DA6, DA17 and DT19).
Assuntos
Ciclo-Octanos/química , DNA/química , Cetonas/química , Animais , Sítios de Ligação , Bovinos , Linhagem Celular Tumoral , Sobrevivência Celular , Ciclo-Octanos/síntese química , Ciclo-Octanos/toxicidade , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cetonas/síntese química , Cetonas/toxicidade , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Espectrofotometria , Eletricidade Estática , Termodinâmica , Temperatura de TransiçãoRESUMO
In this report, we describe the semisynthesis of two series of ursolic and betulinic acid derivatives through designed by modifications at the C-3 and C-28 positions and demonstrate their antimalarial activity against chloroquine-resistant P. falciparum (W2 strain). Structural modifications at C-3 were more advantageous to antimalarial activity than simultaneous modifications at C-3 and C-28 positions. The ester derivative, 3ß-butanoyl betulinic acid (7b), was the most active compound (IC50â¯=â¯3.4⯵M) and it did not exhibit cytotoxicity against VERO nor HepG2 cells (CC50â¯>â¯400⯵M), showing selectivity towards parasites (selectivity indexâ¯>â¯117.47). In combination with artemisinin, compound 7b showed an additive effect (CIâ¯=â¯1.14). While docking analysis showed a possible interaction of 7b with the Plasmodium protease PfSUB1, with an optimum binding affinity of -7.02â¯kcal/mol, the rather low inhibition displayed on a Bacillus licheniformis subtilisin A protease activity assay (IC50â¯=â¯93⯵M) and the observed accumulation of ring forms together with a delay of appearance of trophozoites in vitro suggests that the main target of 3ß-butanoyl betulinic acid on Plasmodium may be related to other molecules and processes pertaining to the ring stage. Therefore, compound 7b is the most promising compound for further studies on antimalarial chemotherapy. The results obtained in this study provide suitable information about scaffolds to develop novel antimalarials from natural sources.
Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/química , Células VeroRESUMO
The natural product lupeol 1 was isolated from aerial parts of Vernonia scorpioides with satisfactory yield, which made it viable to be used as starting material in semisynthetic approach. Ten lupeol derivatives 2-11 were prepared by classical procedures. Including, five new esters derivatives 7-11, which were obtained by structural modifications in the isopropylidene fragment. All semisynthetic compounds and lupeol 1-11 were confirmed by 1H NMR, 13C NMR and HRMS. Their antiprotozoal activity was evaluated in vitro against L. amazonensis and T. cruzi. Derivative 6 showed the best antitrypanosomal activity (IC50 = 12.48 µg/mL) and the lowest cytotoxic derivative (CC50 = 161.50 µg/mL). The mechanism of action of the most active derivatives (4, 6 and 11) is not dependent from the enzyme trypanothione reductase.
Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Triterpenos Pentacíclicos/química , Animais , Antiprotozoários/síntese química , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos/métodos , Concentração Inibidora 50 , Leishmania/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , NADH NADPH Oxirredutases/metabolismo , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Vernonia/químicaRESUMO
The effects of ten natural cadinane sesquiterpenoids isolated from Heterotheca inuloides on the pathways of the NF-κB, Nrf2 and STAT3 transcription factors were studied for the first time. The main constituent in this species, 7-hydroxy-3,4-dihydrocadalene (1), showed anti-NF-κB activity and activated the antioxidant Nrf2 pathway, which may explain the properties reported for the traditional use of the plant. In addition to the main metabolite, a structurally similar compound, 7-hydroxy-cadalene (2), also displayed anti-NF-κB activity. Thus, both natural compounds were used as templates for the preparation of a novel semi-synthetic derivative set, including esters and carbamates, which were evaluated for their potential in vitro antiproliferative activities against six human cancer cell lines. Carbamate derivatives 32 and 33 were found to exhibit potent activity against human colorectal adenocarcinoma and showed important selectivity in cancer cells. Among ester derivatives, compound 13 was determined to be a more potent NF-κB inhibitor and Nrf2 activator than its parent, 7-hydroxy-3,4-dihydrocadalene (1). Furthermore, this compound decreases levels of phospho-IκBα, a protein complex involved in the NF-κB activation pathway. Molecular simulations suggest that all active compounds interact with the activation loop of the IKKß subunit in the IKK complex, which is the responsible of IκBα phosphorylation. Thus, we identified two natural, and one semi-synthetic, NF-κB and Nrf2 modulators and two new promising cytotoxic compounds.