RESUMO
The secondary metabolites of clerodane diterpenoids have been found in several plant species from various families and in other organisms. In this review, we included articles on clerodanes and neo-clerodanes with cytotoxic or anti-inflammatory activity from 2015 to February 2023. A search was conducted in the following databases: PubMed, Google Scholar and Science Direct, using the keywords clerodanes or neo-clerodanes with cytotoxicity or anti-inflammatory activity. In this work, we present studies on these diterpenes with anti-inflammatory effects from 18 species belonging to 7 families and those with cytotoxic activity from 25 species belonging to 9 families. These plants are mostly from the Lamiaceae, Salicaceae, Menispermaceae and Euphorbiaceae families. In summary, clerodane diterpenes have activity against different cell cancer lines. Specific antiproliferative mechanisms related to the wide range of clerodanes known today have been described, since many of these compounds have been identified, some of which we barely know their properties. It is very possible that there are even more compounds than those described today, in such a way that makes it an open field to discover. Furthermore, some diterpenes presented in this review have already-known therapeutic targets, and therefore, their potential adverse effects can be predicted in some way.
Assuntos
Antineoplásicos , Diterpenos Clerodânicos , Diterpenos , Lamiaceae , Neoplasias , Humanos , Diterpenos Clerodânicos/farmacologia , Estrutura Molecular , Diterpenos/farmacologiaRESUMO
Bioassay-guided fractionation of dichloromethane extract from Athenaea velutina leaves led to the isolation of three withanolides, all being reported for the first time in this species. They were identified as withacnistin (1), withacnistin acetate (2) and a new withanolide, designated as withalutin (3). The structures were established by spectral data analysis, including MS, 1D and 2D NMR. In addition, in silico ADMET studies were employed to understand the pharmacokinetic properties of these withanolides. The withanolides isolated from A. velutina reduced cancer cell viability with IC50 values ranging from 1.52 to 5.39 µM. In silico prediction revealed that withanolides have good gastrointestinal absorption or oral bioavailability properties; and are not likely to be mutagenic or hepatotoxic. These findings revealed that A. velutina is an important source of cytotoxic withanolides.
Assuntos
Antineoplásicos , Solanaceae , Vitanolídeos , Vitanolídeos/química , Solanaceae/química , Lactonas/análise , Folhas de Planta/química , Antineoplásicos/análiseRESUMO
Previous studies revealed the potential of Labrenzia aggregata USBA 371 to produce cytotoxic metabolites. This study explores its metabolic diversity and compounds involved in its cytotoxic activity. Extracts from the extracellular fraction of strain USBA 371 showed high levels of cytotoxic activity associated with the production of diketopiperazines (DKPs). We purified two compounds and a mixture of two other compounds from this fraction. Their structures were characterized by 1D and 2D nuclear magnetic resonance (NMR). The purified compounds were evaluated for additional cytotoxic activities. Compound 1 (cyclo (l-Pro-l-Tyr)) showed cytotoxicity to the following cancer cell lines: breast cancer 4T1 (IC50 57.09 ± 2.11 µM), 4T1H17 (IC50 40.38 ± 1.94), MCF-7 (IC50 87.74 ± 2.32 µM), murine melanoma B16 (IC50 80.87 ± 3.67), human uterus sarcoma MES-SA/Dx5 P-pg (-) (IC50 291.32 ± 5.64) and MES-SA/Dx5 P-pg (+) (IC50 225.28 ± 1.23), and murine colon MCA 38 (IC50 29.85 ± 1.55). In order to elucidate the biosynthetic route of the production of DKPs and other secondary metabolites, we sequenced the genome of L. aggregata USBA 371. We found no evidence for biosynthetic pathways associated with cyclodipeptide synthases (CDPSs) or non-ribosomal peptides (NRPS), but based on proteogenomic analysis we suggest that they are produced by proteolytic enzymes. This is the first report in which the cytotoxic effect of cyclo (l-Pro-l-Tyr) produced by an organism of the genus Labrenzia has been evaluated against several cancer cell lines.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Rhodobacteraceae/química , Animais , Linhagem Celular Tumoral , DNA Bacteriano/genética , Dicetopiperazinas/química , Genômica , Humanos , Concentração Inibidora 50 , Células MCF-7 , Espectroscopia de Ressonância Magnética , Melanoma Experimental , Camundongos , Proteômica , RNA Ribossômico 16S/genéticaRESUMO
Abstract The chemical investigation of the n-hexane fraction of Salvadora persica L., Salvadoraceae, seeds afforded a new stearic acid ester, salvastearolide, together with five other phytosteroids identified as stigmasterol, β-sitosterol, Δ7-campesterol, Δ7-avenasterol and campesterol. Their structures were established on the basis of extensive spectroscopic methods including 1D and 2D NMR experiments and HRESI mass spectrometry. In addition, salvastearolide and the isolated fractions were tested for their cytotoxicity against human cancer cell lines MCF-7, MDA-MB-231 and HT-29. The n-hexane fraction exhibited significant anti-proliferative effect against human breast cancer cell line MCF-7 (IC50 50 µg/ml), while salvastearolide possessed a weak cytotoxic effect against MCF-7 cells with IC50 103.98 µg/ml.
RESUMO
The reaction of 2-acetyl- and 2-benzoyl-1,4-naphthoquinone with (Z)-methyl 3-(hydroxymethyl)aminocrotonate proceeds through a formal [3+3] process to yield the corresponding 1,2-dihydrobenzisoquinolinequinones in 63% and 72% yield, respectively. The reactions of 2-acyl-1,4-naphthoquinone with enaminones, derived from diverse l- and d-amino acid methyl esters, produced the corresponding naphthoquinone amino acids conjugates bonded through a vinyl spacer in the yields range 40-71%. The presence of not-separable isomers of the naphthoquinone amino acids conjugates in the ¹H- and 13C-NMR spectra is explained by the existence of conformational isomers generated by hindered rotation of the substituent bonded to the quinone double bond. These new naphthoquinone amino acids conjugates were screened in vitro on normal and cancer cell lines and showed moderate cytotoxic activities.
Assuntos
Aminoácidos/química , Antineoplásicos/química , Naftoquinonas/química , Compostos de Vinila/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Twelve Salpichroa taxa have been phytochemically analyzed. From the aerial parts of S. scandens, four known salpichrolides A, C, I, S, and an unreported withanolide named salpichrolide V (1), were isolated. In S. dependens, S. gayi, S. glandulosa subsp. glandulosa, S. glandulosa subps. weddellii, S. leucantha, S. micrantha, S. microloba, S. proboscidea, S. ramosissima, S. tristis var. tristis, and S. weberbauerii, no withanolides were found. The chemical content of ca. 85% of the Salpichroa taxa is in agreement with molecular studies, which suggest that Salpichroa and Jaborosa, a genus considered morphologically close to Salpichroa, are distant in the systematic of the Solanoideae subfamily. Moreover, the in vitro cytotoxic activity of a set of natural salpichrolides and derivatives was examined against two prostate carcinoma cell lines (PC3 and LNCaP) and two human breast cancer cell lines (MCF-7 and T47D). Several compounds showed moderate activity (IC50 = 64.91 - 29.97 µm).
Assuntos
Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Solanaceae/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia em Camada Fina , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Masculino , Compostos Fitoquímicos/isolamento & purificação , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Solanaceae/metabolismoRESUMO
One new chromone 3,3-dimethylallylspatheliachromene methyl ether (1), as well as five known chromones, 6-(3-methylbut-2-enyl) allopteroxylin methyl ether (2), 6-(3-methylbut-2-enyl) allopteroxylin (3), 3,3-dimethylallylspatheliachromene (4), 5-O-methylcneorumchromone K (5) and spatheliabischromene (6), two alkaloids, 8-methoxy-N-methylflindersine (7) and 8-methoxyflindersine (8), and two limonoids, limonin diosphenol (9) and rutaevin (10), were isolated from Dictyoloma vandellianum A. Juss (Rutaceae). Cytotoxic activities towards tumor cell lines B16-F10, HepG2, K562 and HL60 and non-tumor cells PBMC were evaluated for compounds 1 - 6. Compound 1 was the most active showing IC50 values ranging from 6.26 to 14.82 µg/ml in B16-F10 and K562 cell lines, respectively, and presented IC50 value of 11.65 µg/ml in PBMC cell line.
Assuntos
Cromonas/química , Rutaceae/química , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromonas/isolamento & purificação , Cromonas/toxicidade , Células HL-60 , Células Hep G2 , Humanos , Células K562 , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Limoninas/química , Limoninas/isolamento & purificação , Limoninas/toxicidade , Espectroscopia de Ressonância Magnética , Camundongos , Folhas de Planta/química , Folhas de Planta/metabolismo , Rutaceae/metabolismoRESUMO
A new bibenzyl, 2'-hydroxy-3,5-dimethoxy-4-methylbibenzyl (1) and four known compounds identified as 2'-hydroxy-3,5-dimethoxybibenzyl (2), liquiritigenin (3), guibourtinidol (4) and fisetinidol (5) were isolated from the roots of Bauhinia ungulata L. Phytochemical investigations of the stems of B. ungulata led to the isolation of the known compounds identified as liquiritigenin (3), guibourtinidol (4), fisetinidol (5), taraxerol (6), betulinic acid (7), taraxerone (8), glutinol (9), a mixture of sitosterol (10) and stigmasterol (11), pacharin (12), naringenin (13) and eriodictyol (14). The structures of these compounds were elucidated on the basis of their spectral data (IR, MS, 1D- and 2D-NMR). The cytotoxicity of the bibenzyl 1 has been evaluated against four human cancer cell lines, showing the IC50 values of 4.3 and 6.5 µg ml-1 against pro-myelocytic leukemia (HL-60) and cervical adenocarcinoma (HEP-2) cell lines, respectively. This article also registers for the first time the 13 C-NMR data of the known bibenzyl 2.
Assuntos
Compostos de Benzil/farmacologia , Fabaceae/química , Compostos de Benzil/química , Compostos de Benzil/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Saint Peter and Saint Paul's Archipelago is a collection of 15 islets and rocks remotely located in the equatorial Atlantic Ocean. In this particular site, the present project intended to assess the biodiversity and biotechnological potential of bacteria from the actinomycete group. This study presents the first results of this assessment. From 21 sediment samples, 268 strains were isolated and codified as BRA followed by three numbers. Of those, 94 strains were grown in liquid media and submitted to chemical extractions with AcOEt (A), BuOH (B), and MeOH (M). A total of 224 extracts were screened for their cytotoxic activity and 41 were significantly active against HCT-116 cancer cells. The obtained IC50 values ranged from 0.04 to 31.55 µg/ml. The HR-LC/MS dereplication analysis of the active extracts showed the occurrence of several known anticancer compounds. Individual compounds, identified using HR-MS combined with analysis of the AntiMarin database, included saliniketals A and B, piericidins A and C and glucopiericidin A, staurosporine, N-methylstaurosporine, hydroxydimethyl-staurosporine and N-carbamoylstaurosporine, salinisporamycin A, and rifamycins S and B. BRA-199, identified as Streptomyces sp., was submitted to bioassay-guided fractionation, leading to isolation of the bioactive piericidins A and C, glucopiericidin, and three known diketopiperazines, cyclo(l-Phe-trans-4-OH-l-Pro), cyclo(l-Phe-l-Pro), and cyclo(l-Trp-l-Pro).
Assuntos
Actinobacteria/química , Actinobacteria/isolamento & purificação , Antineoplásicos Fitogênicos/análise , Antineoplásicos Fitogênicos/farmacologia , Sedimentos Geológicos/microbiologia , Antineoplásicos Fitogênicos/química , Brasil , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
Complexes [Au(PyCT4BrPh)Cl]Cl (1), [Pt(PyCT4BrPh)Cl]0.5KCl (2), and [Pd(PyCT4BrPh)Cl]KCl (3) were obtained with 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone (HPyCT4BrPh). Although complexes (2) and (3) did not exhibit potent cytotoxic activity, HPyCT4BrPh and its gold(III) complex (1) proved to be highly cytotoxic against HL-60 (human promyelocytic leukemia) and THP-1 (human monocytic leukemia) cells, and against MDA-MB 231 and MCF-7 (human breast adenocarcinoma) solid tumor cells. Except for HL-60 cells, upon coordination to gold(III) a 2- to 3-fold increase in the cytotoxic effect was observed. An investigation on the possible biological targets of the gold(III) complex was carried out. Complex (1) but not the free thiosemicarbazone inhibits the enzymatic activity of thioredoxin reductase (TrxR). The affinity of 1 for TrxR suggests metal binding to a selenol residue in the active site of the enzyme. While HPyCT4BrPh was inactive, 1 was able to inhibit topoisomerase IB (Topo IB) activity. Hence, inhibition of TrxR and Topo IB could contribute to the mechanism of cytotoxic action of complex (1).
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiossemicarbazonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/metabolismo , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/químicaRESUMO
BACKGROUND: Volatile oils from fresh roots, stems, leaves and seeds of Piper klotzschianum (Piperaceae) were obtained by hydrodistillation and analysed by GC-FID and GC-MS. In total, 25 components, representing more than 95% of the examined oils, were identified. The essential oils were evaluated against Artemia salina Leach nauplii and fourth-instar Aedes aegypti larvae. RESULTS: The major chemical constituents that were identified from various parts of this plant were 1-butyl-3,4-methylenedioxybenzene and 2,4,5-trimethoxy-1-propenylbenzene in the root, 1-butyl-3,4-methylenedioxybenzene in the stems and leaves and 1-butyl-3,4-methylenedioxybenzene, limonene and α-phellandrene in the seeds. The biological activities of these essential oils generally exhibited high toxicity against A. salina, with LC50 values that ranged from 7.06 to 15.43 µg mL(-1), and significant larvicidal activity against fourth-instar A. aegypti larvae was observed in the essential oils from the seeds (LC50 of 13.27 µg mL(-1)) and roots (LC50 of 10.0 µg mL(-1)) of the plant. CONCLUSION: The present study indicates that both essential oil of P. klotzsdhianum and the isolate 1-butyl-3,4-methylenedioxybenzene are potential resources for A. aegypti larva control. This is the first report of the biological activities of the oil and isolated compound.