RESUMO
Rocaglaol, embedding a cyclopenta[b]benzofuran scaffold, was isolated mainly from the plants of Aglaia and exhibited nanomolar level antitumor activity. However, the drug-like properties of these compounds are poor. To improve the physicochemical properties of rocaglaol, 36 nitrogen-containing phenyl-substituted rocaglaol derivatives were designed and synthesized. These derivatives were tested for the inhibitory effects on three tumor cell lines, HEL, MDA-231, and SW480, using the MTT assay. Among them, 22 derivatives exhibited good cytotoxic activities with IC50 values between 0.11 ± 0.07 and 0.88 ± 0.02 µM. Fourteen derivatives exhibited stronger cytotoxicity than the positive control, adriamycin. In particular, a water-soluble derivative revealed selective cytotoxic effects on HEL cells (IC50 = 0.19 ± 0.01 µM). This compound could induce G1 cell cycle arrest and apoptosis in HEL cells. Western blot assays suggested that the water-soluble derivative could downregulate the expression of the marker proteins of apoptosis, PARP, caspase-3, and caspase-9, thus inducing apoptosis. Further CETSA and Western blot studies implied that this water-soluble derivative might be an inhibitor of friend leukemia integration 1 (Fli-1). This water-soluble derivative may serve as a potential antileukemia agent by suppressing the expression of Fli-1.
Assuntos
Antineoplásicos , Benzofuranos , Antineoplásicos/farmacologia , Apoptose , Doxorrubicina , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The strategy of bioactivity-guided isolation is widely used to obtain active compounds as quickly as possible. Thus, the inhibitory effects on human erythroleukemia cells (HEL) were applied to guide the isolation of the anti-leukemic compounds from Aglaia abbreviata. As a result, 19 compounds (16 steroids, two phenol derivatives, and a rare C12 chain nor-sesquiterpenoid), including 13 new compounds, were isolated and identified based on spectroscopic data analysis, single-crystal X-ray diffraction data, and electronic circular dichroism (ECD) calculations. Among them, 9 steroids exhibited good selective anti-leukemic activity against HEL and K562 (human chronic myeloid leukemia cells) cells with IC50 values between 2.29 ± 0.18 µM and 19.58 ± 0.13 µM. Notably, all the active compounds had relatively lower toxicity on the normal human liver cell line (HL-7702). Furthermore, five compounds (1, 4, 8, 10, and 19) displayed good anti-inflammatory effects, with IC50 values between 7.15 ± 0.16 and 27.1 ± 0.37 µM. An α,ß-unsaturated ketone or a 5,6Δ double bond was crucial for improving anti-leukemic effect from the structure-activity relationship analysis. The compound with the most potential, 14 was selected for the preliminary mechanistic study. Compound 14 can induce apoptosis and cause cell cycle arrest. The expression of the marker proteins, such as PARP and caspase 3, were notably effected by this compound, thus inducing apoptosis. In conclusion, our investigation implied that compound 14 may serve as a potential anti-leukemia agent.
Assuntos
Aglaia , Humanos , Aglaia/química , Apoptose , Bioensaio , Estrutura Molecular , Esteroides/farmacologia , Relação Estrutura-Atividade , Antineoplásicos/química , Antineoplásicos/farmacologiaRESUMO
Three new quinolizidine alkaloids (1 - 3), including one new naturally isoflavone and cytisine polymer (3), along with 6 known ones were isolated from the ethanol extract of Sophora tonkinensis Gagnep. Their structures were elucidated by comprehensive spectroscopic data analysis (IR, UV, HRESIMS, 1D and 2D NMR), combined with ECD calculations. The antifungal activity against Phytophythora capsica, Botrytis cinerea, Gibberella zeae, and Alternaria alternata of the compounds was evaluated in a mycelial inhibition assay. Biological tests indicated that compound 3 exhibited strong antifungal activity against P. capsica with EC50 values of 17.7 µg/ml.
Assuntos
Alcaloides , Sophora , Alcaloides Quinolizidínicos , Sophora/química , Antifúngicos/farmacologia , Raízes de Plantas/química , Alcaloides/química , Estrutura MolecularRESUMO
Belchinoids A-C (1-3), three unusual nor-sesquiterpenoids, along with a new isoflavone (4), were isolated from the roots of Belamcanda chinensis, a traditional Chinese medicine. To the best of our knowledge, compound 1 represents the first C13 nor-sesquiterpenoid with a five membered carbon ring. Compounds 2 and 3 are rare C14 chained nor-sesquiterpenoids. Their structures were fully characterized based on extensive spectroscopic data and quantum chemistry calculation. Three compounds (1, 2, and 4) showed potent inhibitory effects on lipid accumulation in an oleic acid-treated HepG2 cell model. In particular, compound 2 exhibited the most potent inhibitory effect on triglyceride accumulation at a low concentration of 2.5 µM, better than the positive control atorvastatin. The plausible biosynthetic pathway of the three nor-sesquiterpenoids (1-3) is also proposed.
Assuntos
Sesquiterpenos , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Raízes de Plantas/química , Análise Espectral , Lipídeos , Estrutura MolecularRESUMO
Phytochemical study of Magnolia grandiflora led to the isolation of 39 sesquiterpenoids, including 15 new compounds (1-15). Compounds 1 and 2 are discovered to be the first 13-norgermacrane type sesquiterpenoids in natural products. Compound 15 is a rare 5,6-seco-guaiane type sesquiterpene and its possible biogenic precursor is presumed to be compound 20. Subsequent structural modification for compound 28 led to 21 derivatives, among which 15 derivatives were new compounds. All compounds were tested for the inhibitory effects on three tumor cell lines, and 17 compounds were active with the IC50 values ranging from 1.91 ± 0.39 µM to 12.29 ± 1.68 µM. The structure-activity relationships implied that an α, ß-unsaturated lactone group was an important active group for the cytotoxicity. Two most active compounds (19 and 29) with low toxicity on normal human liver cell line were selected for further mechanism study. Compound 29 could induce apoptosis on Colo320DM cells through influencing the key apoptotic related proteins, such as PARP, Cleaved PARP, cleaved Caspase-3, and pro-Caspase 3. In addition, compound 19 with the best cytotoxic activity on HEL cells also could induce the apoptosis in dose- and time-dependent manners. In summary, our investigation implied that compounds 19 and 29 are two new potential anti-cancer candidates for ongoing study in the future.
Assuntos
Antineoplásicos , Magnolia , Sesquiterpenos , Humanos , Magnolia/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Proliferação de Células , Estrutura MolecularRESUMO
A new quinoline alkaloid, 5-hydroxy-6-methoxy-N-methyl-2-phenylquinoline-4-one (1), and seventeen known quinoline alkaloids (2-18) were isolated from the roots of Orixa japonica. The structure of 1 was determined by analysis of spectroscopic data. Among them, compounds 2, 3, and 13 were isolated from this plant for the first time. All isolates were screened for the anti-pathogenic fungi activities, including Rhizoctonia solani, Magnaporthe oryzae, and Phomopsis sp. The results showed that five compounds (4, 8, 10, 11, and 12) exhibited significant anti-pathogenic fungi effects at 50.0 µg/mL. In special, compound 10 exhibited the best antifungal activities toward R. solani and M. oryzae with the IC50 values of 37.86 and 44.72â µM, respectively, better than that of the positive control, hymexazol (IC50 121.21 and 1518.18â µM, respectively). Moreover, eleven new quinoline alkaloids derivatives (12a-12k) were designed and synthesized to investigate the structure-activity relationships (SARs). The SARs analysis indicated that the furo[2,3-b]quinoline skeleton and the methoxy at C-7 (compounds 8, 11, and 12) played a key role for improving the antifungal activities.
Assuntos
Alcaloides , Quinolinas , Antifúngicos/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Quinolinas/química , FungosRESUMO
To discover novel and effective antifungal candidates, a series of new curcumol derivatives were designed, synthesized, and evaluated their antifungal activity against five phytopathogenic fungi by the mycelium growth rate method. Derivatives c4, c22 and c23 exhibited excellent antifungal activity against Phomopsis sp. with EC50 values of 3.06, 3.07, and 3.16â µM, respectively. Specifically, compound c4 exhibited the strongest antifungal activity against Phomopsis sp., which was 44 times that of pyrimethanil (EC50 =134.37â µM). The results of scanning electron microscopy (SEM) and transmission electron microscopy (TEM) indicated that compound c4 could cause cell senescence and death of Phomopsis sp. by changing the normal hyphal morphology and disrupting the normal metabolism of hyphal cells. Moreover, compound c4 showed excellent curative effect against Phomopsis sp. on kiwifruit. These findings confirmed that compound c4 has great potential as a potent antifungal agent.
Assuntos
Antifúngicos , Sesquiterpenos , Antifúngicos/farmacologia , Relação Estrutura-Atividade , Fungos , Sesquiterpenos/farmacologiaRESUMO
Two new ursane-type triterpenes, eburnealactones A and B (1 and 2), one new flavonoid, eburneatin A (6), and one new phenylethanoid glycoside, chiritoside D (7), along with 9 known compounds (3-5, 8-13) were isolated from the whole plant of Primulina eburnea. Their structures were elucidated by comprehensive spectroscopic data analysis (IR, UV, NMR, and HR-ESI-MS). All the compounds were evaluated for their cytotoxic activities. Compound 1 showed significant cytotoxic activities against MKN-45 cell lines and 5637 cell lines with the IC50 values of 9.57â µM and 8.30â µM, respectively. Compound 1 exhibited moderate cytotoxic activities against A549 and PATU8988T cell lines with the IC50 values of 30.70â µM and 38.22â µM, respectively. Compound 6 exhibited moderate cytotoxic activities against MKN-45, HCT116, PATU8988T, 5637 and A-673 cell lines with the IC50 values of 19.69â µM, 16.44â µM, 18.07â µM, 11.51â µM and 18.15â µM, respectively. Compound 5 showed moderate cytotoxic activities against A549 cell lines with the IC50 values of 24.06â µM.
Assuntos
Antineoplásicos , Triterpenos , Humanos , Estrutura Molecular , Glicosídeos/química , Antineoplásicos/farmacologia , Flavonoides , Células A549 , Triterpenos/farmacologia , Triterpenos/químicaRESUMO
Two new isoflavones (1 and 2), as well as eight known ones were isolated from the roots of Sophora tonkinensis Gagnep. Compound 1 represents an unprecedented polymerization pattern constructed by isoflavone and cytisine. Their structures were elucidated by comprehensive spectroscopic data analysis, combined with ECD calculations. Compound 1 displayed significant anti-tobacco mosaic virus (TMV) activity compared with the positive control ningnanmycin. Moreover, compound 6 exhibited potent α-glucosidase inhibitory activity with IC50 value of 47.4 mg/L.
Assuntos
Alcaloides , Isoflavonas , Sophora , Isoflavonas/farmacologia , Sophora/química , Raízes de Plantas/química , Alcaloides/química , Quinolizinas/análiseRESUMO
Six novel Maillard reaction products (MRPs) (1-6) were isolated from the processed Thermopsis lanceolata R. Br. seed extract, along with one biogenetically related intermediate (7). Compounds 1-4 possessed three rare dimerization patterns constructed by cytisine, whereas compounds 5 and 6 represented the first example of the addition products of cytisine and 5,6-dihydroxy-4-hexanolide. Their structures were elucidated by comprehensive spectroscopic data analysis and quantum chemistry calculations including GIAO 13C{1H} NMR and ECD calculation, combined with single-crystal X-ray diffraction analysis. Biologically, compound 3 displayed significant anti-tobacco mosaic virus activity compared with the positive control ningnanmycin.
Assuntos
Vírus do Mosaico do Tabaco , Antivirais/química , Produtos Finais de Glicação Avançada , Extratos Vegetais/químicaRESUMO
Hyperpatone A (1), a highly oxidated polycyclic polyprenylated acylphloroglucinol (PPAP), along with a biosynthesized related PPAP (2) was isolated from Hypericum patulum under the guidance of LC-MS investigation. Architecturally, compound 1 represents the first PPAP with an unprecedented 8/6/5/6/5 pentacyclic skeleton and an intramolecular peroxy bridge, which might be derived from the [3.3.1]-type bicyclic polyprenylated acylphloroglucinol via the critical Baeyer-Villiger oxidation, decarboxylation, and intramolecular cyclization. The structures were established by extensive spectroscopic analysis, ACD software calculation, and quantum chemical computations. A plausible biogenetic pathway of 1 and 2 was also proposed. Importantly, both compounds exhibited moderate cytotoxic activities against the HEL cell line with the IC50 values ranging from 10.2 to 19.2 µM. Moreover, compound 1 showed an inhibitory effect on NO production in lipopolysaccharide-stimulated RAW264.7 cells at a lower concentration of 5 or 1 µM.
Assuntos
Hypericum , Estrutura Molecular , Hypericum/química , Floroglucinol/química , EsqueletoRESUMO
Eight rocaglaol derivatives with good cytotoxic activity (IC50: 0.013 â¼ 5.82 µM) were isolated from Aglaia odorata. Then, a series of novel derivatives with modifications on C3 of rocaglaol were designed, synthesized, and screened for their antitumor activities against three tumor cell lines (HEL, MDA-MB-231, and HCT116). A total of 44 derivatives exhibited significant cytotoxic activity with IC50 values lower than 1 µM. In particular, four derivatives (14, 20, 22j, and 22r) exhibited the best cytotoxic activity against HCT116 cells, with an IC50 value of 70 nM. Compound 22r with relatively low toxicity against normal cells and the best cytotoxic activity against HCT116 cells was selected for further study. Subsequent cellular mechanism studies showed that compound 22r induced apoptosis and G1 cell cycle arrest in HCT116 cells. Moreover, compound 22r inhibited both the Wnt/ß-catenin and MAPK signaling pathways via key proteins, such as the phosphorylation of p38 and JNK, GSK-3ß, Axin-2, etc. Therefore, our present results suggest that compound 22r is a potential candidate for developing novel anti-colorectal cancer agents in the future.
Assuntos
Antineoplásicos , Benzofuranos , Neoplasias Colorretais , Humanos , beta Catenina/metabolismo , Via de Sinalização Wnt , Glicogênio Sintase Quinase 3 beta/metabolismo , Benzofuranos/farmacologia , Linhagem Celular Tumoral , Apoptose , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologiaRESUMO
Three new compounds named cynansteroid A (1), cynansteroid B (2) and cynansteroid C (3), together with nine known C21 -steroidal pregnane sapogenins (4-12) were isolated from the hydrolytic extract of the roots of Cynanchum auriculatum. The structures of cynansteroid A-C (1-3) were ascertained via the detailed analysis of the HR-ESI-MS, 1D and 2D NMR, and the calculated and experimental ECD data of cynansteroid B (2). Compound 11 displayed moderate inhibitory activity toward Verticillium dahliae Kleb (IC50 =37.15â µM), furthermore, compounds 11 and 12 showed significant inhibitory activity against Phomopsis sp. (IC50 =16.49â µM and 17.62â µM, respectively).
Assuntos
Cynanchum , Sapogeninas , Cynanchum/química , Glicosídeos/química , Raízes de Plantas/química , Pregnanos/química , Pregnanos/farmacologiaRESUMO
Three new aglain derivatives (1-3), one known aglain derivative (4), two known rocaglamide derivatives (5 and 6), four known triterpenoids (7-10), and three steroids (11-13) were isolated from Aglaia odorata Lour. Their structures were established through the analysis of detailed spectroscopic data and electronic circular dichroism calculations. Five compounds (1 and 4-7) exhibited cytotoxic activities on human leukemia cells (HEL) and human breast cancer cells with IC50 values in the range of 0.03-8.40â µM. In particular, the cytotoxicity of compound 5 was six times stronger than that of the positive control (adriamycin) in HEL cell lines.
Assuntos
Aglaia , Antineoplásicos Fitogênicos , Antineoplásicos , Triterpenos , Aglaia/química , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Dicroísmo Circular , Humanos , Estrutura Molecular , Extratos Vegetais/química , Triterpenos/químicaRESUMO
Chronic myeloid leukemia accounts for human deaths worldwide and could enhance sevenfold by 2050. Thus, the treatment regimen for this disorder is highly crucial at this time. Flavaglines are a natural class of cyclopentane benzofurans exhibiting various bioactivities like anticancer action. Despite the antiproliferative activity of flavaglines against diverse cancer cells, their roles and mechanism of action in chronic myeloid leukemia (CML) remain poorly understood. Thus, this study examines the antiproliferative effect of a newly synthesized flavagline derivative, 1-chloracetylrocaglaol (A2074), on erythroleukemia K562 cells and the zebrafish xenograft model. The study revealed that A2074 could inhibit proliferation, promote apoptosis, and boost megakaryocyte differentiation of K562 cells. This flavagline downregulated c-MYC and miR-17-92 cluster genes, targeting upregulation of the apoptotic protein Bcl-2-like protein 11 (BIM). The work uncovered a critical role of the c-MYC-miR-17-92-BIM axis in the growth and survival of CML cells.
Assuntos
Leucemia Eritroblástica Aguda , Leucemia Mielogênica Crônica BCR-ABL Positiva , MicroRNAs , Animais , Humanos , Células K562 , Leucemia Eritroblástica Aguda/tratamento farmacológico , Leucemia Eritroblástica Aguda/genética , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , MicroRNAs/farmacologia , Relação Estrutura-Atividade , Apoptose , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proliferação de CélulasRESUMO
Two new (1 and 2) cytisine-type alkaloids that were chemically inseparable isomers (present in a 1:1 ratio) were identified from the seeds of Thermopsis lanceolata R. Br. Their structures were elucidated by comprehensive spectroscopic data analysis (IR, UV, NMR, HRESIMS) and ECD calculation. Compound 1 displayed significant anti-tobacco mosaic virus (TMV) activity, while compounds 1 and 2 displayed moderate insecticidal activities against Aphis fabae with LC50 value of 43.15 and 46.47 mg/L, respectively.
Assuntos
Alcaloides , Fabaceae , Estrutura Molecular , Quinolizinas/farmacologia , Alcaloides/farmacologia , Alcaloides/química , Azocinas , Sementes , Antivirais/químicaRESUMO
Hypermonins A-D (1-4), four rearranged nor-polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented skeletons, together with two new biosynthesis related PPAPs (5 and 6) were isolated and identified from the flowers of Hypericum monogynum. Hypermoins A-D represented the first examples of highly modified norPPAPs characterized by a rare 7/6/6/5-tetracyclic system. From the biogenic synthesis pathway analysis, all isolates shared the same biosynthetic intermediate, and the addition of two methyls or one methyl to this intermediate through methyltranferase could generate different types of PPAPs (1-7). Their planner structures as well as absolute configuration were confirmed via spectroscopic analysis, ECD calculation, and X-ray crystallography. All isolates potentially reversed multidrug resistance (MDR) activity in both two cancer cells, HepG2/ADR and MCF-7/ADR. Specifically, hypermoin E (5) and hyperielliptone HA (7) were found to be the best MDR modulators with the reversal fold ranging from 41 to 236, which is higher than the positive control verapamil.
Assuntos
Hypericum , Cristalografia por Raios X , Flores , Estrutura Molecular , Floroglucinol/farmacologiaRESUMO
Hypsampsone A (1) and hyperhexanone F (2), two novel seco-polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum sampsonii. Hypsampsone A (1) features the first spirocyclic system fused with 5/6/5/5 tetracyclic skeleton. Hyperhexanone F (2) represents the second novel 1,2-seco-bicyclo[3.3.1]-PPAP skeleton. Their structures were established by extensive spectroscopic analysis, computer-assisted structure elucidation software, and calculated electronic circular dichroism spectra. A plausible biogenetic pathway of 1 was also proposed. Compounds 1 and 2 showed moderate multidrug resistance reversal activity to adriamycin (ADR) resistant cancer cell lines, HepG2/ADR and MCF-7/ADR, with the fold-reversals ranging from 16 to 38 at noncytotoxic concentration of 10 µM.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Hypericum/química , Floroglucinol/química , Floroglucinol/farmacologia , Prenilação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células Hep G2 , Humanos , Células MCF-7 , Modelos Moleculares , Conformação MolecularRESUMO
A new polycyclic polyprenylated acylphloroglucinol (PPAP), hypermonin C (1), along with nine known PPAPs (2-10) were obtained from the leaves and twigs of Hypericum monogynum. The structures of the isolates were determined on the basis of extensive spectroscopic analysis. The neuroprotective effects of the isolates against several chemical-induced injuries in SH-SY5Y and PC12 cells were assessed, and most of the compounds exhibited significant protective effects at 10 µg/ml. Especially, three compounds (1, 3, and 7) showed excellent neuroprotective activity with a cell viability of 92.4% â¼ 95.8% in KCl-induced SH-SY5Y cell injury. Their preliminary structure-activity relationship was also discussed and the configuration of substituent in furohyperforin may be critical for the neuroprotective activity of PPAP derivatives.
Assuntos
Hypericum , Fármacos Neuroprotetores , Animais , Estrutura Molecular , Fármacos Neuroprotetores/farmacologia , Células PC12 , Floroglucinol/farmacologia , Folhas de Planta , RatosRESUMO
Two new compounds, including one new arylbenzofuran (1) and one new pterocarpanoid (2), along with nine known ones, were isolated from the seeds of Sophora tonkinensis. The structures of the new compounds were elucidated based on a comprehensive spectroscopic data analysis. Compounds 2 and 3 exhibited good anti-tobacco mosaic virus (TMV) activities with the protective inhibition rate of 69.62% and 68.72% respectively, at concentration of 100 µg/ml.