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1.
RSC Adv ; 14(32): 23109-23117, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39040697

RESUMO

A study of diterpenoids as active ingredients against cancer from the active roots extract of Casearia barteri Mast. (IC50 = 1.57 µg mL-1) led to the isolation of six new clerodane diterpenoids, named as barterins A-F (1-6) alongside seven known compounds, caseamembrin A, caseamembrin E, casearlucin A, graveospene G, N-trans-feruloyltyramine, N-cis-feruloytyramine and sitosterol-3-O-ß-D-(6-O-palmitoyl)-glucopyranoside. Their structures were elucidated based on NMR spectroscopic data and mass spectrometry. The absolute configurations of 1-6 were established by the time-dependent density functional theory (TDDFT), electronic circular dichroism (ECD) calculations and experimental data analysis. The cytotoxic effects of compounds 1-6 were evaluated against a human cervix carcinoma cell line KB-3-1. Barterins A-D (1-4) showed cytotoxic effects against the KB-3-1 cell line with IC50 values ranging from 1.34-4.73 µM.

2.
Molecules ; 28(3)2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36770745

RESUMO

A phytochemical investigation of the roots of Citrus × paradisi Macfad. (Rutaceae) led to the isolation of two new compounds, namely 1-formyl-5-hydroxy-N-methylindolin-1-ium (1) and decyloxycleomiscosin D (2), along with ten known compounds: 1,1-dimethylpyrrolidin-1-ium-2-carboxylate (3), furan-2,3-diol (4), 5-methoxyseselin (5), umbelliferone (6), scopoletin (7), citracridone I (8), citracridone II (9), citracridone III (10), limonin (11) and lupeol (12). The structures were determined through the comprehensive spectroscopic analysis of 1D and 2D NMR and EI- and ESI-MS, as well as a comparison with the published data. Notably, compounds 3 and 4 from the genus Citrus are reported here for the first time. In addition, the MeOH extract of the roots and compounds 1-7 were screened against the human adenocarcinoma alveolar basal epithelial cell line A549 and the Caucasian prostate adenocarcinoma cell line PC3 using the MTT assay. While the extract showed significant activity, with IC50 values of 35.2 and 38.1 µg/mL, respectively, compounds 1-7 showed weak activity, with IC50 values of 99.2 to 250.2 µM and 99.5 to 192.7 µM, respectively.


Assuntos
Adenocarcinoma , Citrus paradisi , Citrus , Rutaceae , Masculino , Humanos , Rutaceae/química , Extratos Vegetais/química , Alcaloides Indólicos/análise , Raízes de Plantas/química , Estrutura Molecular
3.
Chem Biodivers ; 19(7): e202101033, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35678514

RESUMO

The stem bark of Citrus × paradisi Macfad. (Rutaceae) gave (23S)-isolimonexic acid (1), limonin (2), citracridone II (3), citpressine II (4), citpressine I (5), grandisine (6), 2-hydroxynoracronycine (7), citracridone I (8), 5-methoxyseselin (9), umbelliferone (10), scopoletin (11), naringenin (12), apigenin (13), friedelin (14), agrostophyllinone (15) and stigmasterol-3-O-ß-D-glucopyranoside (16). The structures of the compounds were determined using NMR and MS spectroscopic data, and by comparison with published data. The relative configuration of 1 was proposed as (23S)-isolimonexic acid using NOE studies. Hydrogenation reaction of compound 3 led to the new derivative 3',4'-dihydrocitracridone II (3a). Cytotoxicity activities against the human adenocarcinoma alveolar basal epithelial cell lines A549 and the Caucasian prostate adenocarcinoma cell lines PC3, using the MTT assays showed that the methanol crude extract was significant with IC50 values of 30.1 and 31.7 µg/mL, respectively, with the positive control, doxorubicin giving an IC50 of 0.9 µM. In addition, compounds 3, 7 and 8 gave moderate cytotoxic activities with IC50 values of 33.1, 31.2 and 32.5 µM for A549 cells and 35.7, 33.8 and 34.9 µM for PC3 cells, respectively. The hydrogenated 3a was less active than 3, suggesting that the presence of the double bond in pyrans is important for structure-activity relationship.


Assuntos
Adenocarcinoma , Citrus paradisi , Citrus , Rutaceae , Humanos , Masculino , Casca de Planta/química , Extratos Vegetais/química , Rutaceae/química
4.
Nat Prod Res ; 36(18): 4661-4671, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34852702

RESUMO

Chemical investigation of Allophylus africanus P. Beauv fruits led to the isolation of a new δ-tocotrienol, 3α-hydroxy-δ-tocotrienol (1) together with eight known compounds (2-9). Compound (1) was allylated (1a) and prenylated (1 b and 1c) to give three new semi-synthesized derivatives which were fully characterized as: 6-O-allyl-3α-hydroxy-δ-tocotrienol (1a), 6-O-prenyl-3α-hydroxy-δ-tocotrienol (1 b) and 6-O,5-C-diprenyl-3α-hydroxy-δ-tocotrienol (1c). The structures of compounds were established using comprehensive spectroscopic analysis including UV, MS, 1 D NMR, 2 D NMR and by comparison with the corresponding literature data. Compound (1) and its semi-synthetic derivatives (1a-c) were tested for their antioxydant activity using DPPH radical scavenging assay and also for their cytotoxicity using human cervix carcinoma KB-3-1 cell lines. The results showed that compound (1) exhibited antioxidant activity with an IC50 value of 0.25 µM compared to the reference control trolox (26 µM); and good cytotoxic activity with IC50 values of 97 µM compared to the reference (+)-griseofulvin (IC50 between17-21 µM).


Assuntos
Antioxidantes , Sapindaceae , Antioxidantes/química , Antioxidantes/farmacologia , Feminino , Humanos , Sementes , Vitamina E/análogos & derivados
5.
Front Chem ; 9: 760083, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722462

RESUMO

Endophytes are prolific producers of privileged secondary metabolites with diverse therapeutic potential, although their anticancer and antimicrobial potential still have a room for further investigation. Herein, seven known secondary metabolites namely, arugosin C (1), ergosterol (2), iso-emericellin (3), sterigmatocystin (4), dihydrosterigmatocystin (5), versicolorin B (6), and diorcinol (7) were isolated from the rice culture of Aspergillus sp. retrieved from Tecoma stans (L.) Juss. ex Kunth leaves. Their anticancer and antimicrobial activities were evaluated in MTT and agar well diffusion assays, respectively. The cytotoxicity results showed that metabolite 3 displayed the best viability inhibition on the MCF-7 breast cancer cells with IC50 = 225.21 µM, while 5 on the HepG2 hepatocellular carcinoma cells with IC50 = 161.81 µM. 5 demonstrated a 60% apoptotic mode of cell death which is virtually correlated to its high docking affinity to Hsp90 ATP binding cleft (binding score -8.4 Kcal/mol). On the other side, metabolites 4 and 5 displayed promising antimicrobial activity especially on Pseudomonas aeruginosa with MIC = 125 µg/ml. The observed effect may be likely related to their excellent in silico inhibition of the bacterial DNA-gyrase kinase domain (binding score -10.28 Kcal/mol). To the best of our knowledge, this study is the first to report the promising cytotoxic and antibacterial activities of metabolites 3, 4, and 5 which needs further investigation and renovation to therapeutic leads.

6.
Z Naturforsch C J Biosci ; 76(7-8): 285-290, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34218550

RESUMO

The phytochemical investigation of Tarenna grandiflora led to the isolation of 18 known compounds of which were four flavones, three anthraquinones, one phenyl propanoic derivative, five triterpenoids, four steroids and a mixture of glucose. Luteolin (1) and soranjidiol (6) were allylated and/or prenylated to give four new semisynthesized derivatives which were fully characterized as 7,3',4'-O-triallylluteolin (1a), luteolin-7,3',4'-O-triprenyls (1b), luteolin-5,7,3',4'-O-tetraprenyls (1c) and 6-O-allylsoranjidiol (6a). Their structures were established using spectroscopic analysis including 1D, 2D NMR and MS data. The cytotoxic, antioxidant and antimicrobial activities of extracts, fractions, isolated compounds and semi-synthesized derivatives were evaluated. The petroleum ether and EtOAc extracts exhibited good cytotoxic potency on KB-3-1 cell line with IC50 of >0.1 and 0.025 mg/mL respectively, while compounds 1b and 11 were the most active (IC50 > 0.0001 M). Compounds 1 and 3 showed the best antioxidant activities (45.5 and 55.8 µM); while compounds 9 and 12 showed the best antibacterial activities with MICs values ranges from 8.55 to 132 µM.


Assuntos
Antibacterianos/isolamento & purificação , Antioxidantes/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Rubiaceae/química , Antibacterianos/química , Antibacterianos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Bactérias/classificação , Bactérias/efeitos dos fármacos , Compostos de Bifenilo/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia/métodos , Humanos , Espectrometria de Massas/métodos , Testes de Sensibilidade Microbiana/métodos , Estrutura Molecular , Oxirredução/efeitos dos fármacos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Picratos/metabolismo , Casca de Planta/química , Folhas de Planta/química , Caules de Planta/química
7.
Front Bioeng Biotechnol ; 9: 671321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937222

RESUMO

L-Carnitine is a bioactive compound derived from L-lysine and S-adenosyl-L-methionine, which is closely associated with the transport of long-chain fatty acids in the intermediary metabolism of eukaryotes and sought after in the pharmaceutical, food, and feed industries. The L-carnitine biosynthesis pathway has not been observed in prokaryotes, and the use of eukaryotic microorganisms as natural L-carnitine producers lacks economic viability due to complex cultivation and low titers. While biotransformation processes based on petrochemical achiral precursors have been described for bacterial hosts, fermentative de novo synthesis has not been established although it holds the potential for a sustainable and economical one-pot process using renewable feedstocks. This study describes the metabolic engineering of Escherichia coli for L-carnitine production. L-carnitine biosynthesis enzymes from the fungus Neurospora crassa that were functionally active in E. coli were identified and applied individually or in cascades to assemble and optimize a four-step L-carnitine biosynthesis pathway in this host. Pathway performance was monitored by a transcription factor-based L-carnitine biosensor. The engineered E. coli strain produced L-carnitine from supplemented L-N ε-trimethyllysine in a whole cell biotransformation, resulting in 15.9 µM carnitine found in the supernatant. Notably, this strain also produced 1.7 µM L-carnitine de novo from glycerol and ammonium as carbon and nitrogen sources through endogenous N ε-trimethyllysine. This work provides a proof of concept for the de novo L-carnitine production in E. coli, which does not depend on petrochemical synthesis of achiral precursors, but makes use of renewable feedstocks instead. To the best of our knowledge, this is the first description of L-carnitine de novo synthesis using an engineered bacterium.

8.
Green Chem Lett Rev ; 14(4): 578-599, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35821884

RESUMO

A metal-free, atom-economy and simple work-up domino amination-Knoevenagel condensation approach to construct new coumarin analogous (4a-f and 8a-e) was described. Further, new formyl (5a,d-f) and nitro (9a,d-f) coumarin derivatives were synthesized via C-N coupling reaction of various cyclic secondary amines and 4-chloro-3-(formyl-/nitro)coumarins (1a,c), respectively. The confirmed compounds were screened for their in vitro anti-proliferative activity against KB-3-1, A549 and PC3 human cancer cell lines using resazurin cellular-based assay. Among them, coumarin derivatives 4e and 8e displayed the best anti-cervical cancer potency (KB-3-1) with IC50 values of 15.5 ± 3.54 and 21 ± 4.24 µM, respectively. Also, 4e showed the most promising cytotoxicity toward A549 with IC50 value of 12.94 ± 1.51 µM. As well, 9d presented a more significant impact of potency against PC3 with IC50 7.31 ± 0.48 µM. Moreover, 8d manifested selectivity against PC3 (IC50 = 20.16 ± 0.07 µM), while 8e was selective toward KB-3-1 cell line (IC50 = 21 ± 4.24 µM). Matching with docking profile, the enzymatic assay divulged that 8e is a dual potent single-digit nanomolar inhibitor of VEGFR-2 and EGFR with IC50 values of 24.67 nM and 31.6 nM that were almost equipotent to sorafenib (31.08 nM) and erlotinib (26.79 nM), respectively.

9.
Nat Prod Res ; 35(21): 3830-3838, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32189530

RESUMO

The crystal structure and unambiguous absolute configuration of meleagrin (1) isolated from fungus Emericella dentata Nq45 is reported herein to first time on the bases of single crystal X-ray diffraction. Together with 1, haenamindole (2), isorugulosuvine (3), secalonic acid D (4), ergosterol (5) and cerebroside A (6) were obtained and their structures were determined by ESI MS and NMR data analysis. Diverse biological activity of meleagrin (1) was investigated. Compound 1 pronounced potent cytotoxicity against the human cervix carcinoma cell line KB-3-1 and its multidrug resistant sub-clone KB-V1 of IC50 3.07 and 6.07 µM, respectively, in comparison with the reference (+) - griseofulvin (IC50 19, 19.5 µM). Based on the antibiofilm activity, compound 1 displayed as well potent activity against Staphylococcus aureus with an MIC of 0.25 mg/mL. Isolation of the producing fungus and taxonomical characterization is stated as well.


Assuntos
Emericella , Ovomucina/farmacologia , Organismos Aquáticos/química , Linhagem Celular Tumoral , Emericella/química , Humanos , Estrutura Molecular , Ovomucina/química , Staphylococcus aureus/efeitos dos fármacos
10.
Bioorg Chem ; 97: 103678, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32120076

RESUMO

In this study, a series of novel N-feruloyl dipeptides (10-17) have been synthesized through the coupling of N-feruloyl amino acids (6-9) with glycine/alanine methyl ester hydrochloride. Structures of the peptides were assigned using 1D and 2D NMR and HRESIMS. According to initial in vitro cytotoxic screening against the cervix carcinoma cell line KB-3-1, aromatic dipeptides (12, 13, 16, 17) were the most potent ones among all tested feruloyl dipeptides. Accordingly, these peptides were further intensively investigated as potential anticancer agents against a panel of ten cancer cell lines from different tissue origin. Based on that, compound 17 showed the strongest cytotoxic efficiency towards the whole panel of tested cell lines with IC50 values from 2.1 to 7.9 µM. By contrast, the dipeptides 12, 13 and 16 showed moderate to weak cytotoxicity (IC50 16.1-28.3 or >30, 5.7-21.9 and 3.9-21.2 or ≥30 µM, respectively). Mechanistically, compound 17 induced a strong dissipation of the mitochondrial transmembrane potential and an early activation of caspase 3/7 in the triple-negative MDA-MB-231 breast cancer cell line. In an in vivo model, compound 17 inhibited growth, proliferation and induced apoptosis in MDA-MB-231 xenografted onto the chick chorioallantoic membrane. All the synthesized compounds were also tested against a set of pathogenic bacterial strains, displaying no potential activity.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Dipeptídeos/química , Dipeptídeos/farmacologia , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Dipeptídeos/síntese química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo
11.
Steroids ; 156: 108584, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31982421

RESUMO

Two new ergostane-type steroids named tiamenones A and B (1-2) were isolated from the bark of Entandrophragma angolense (Meliaceae) along with ten known compounds identified as 20S-hydroxy-4,6,24(28)-ergostatrien-3-one (3), 3ß,7α,20ß-trihydroxyergosta-5,24(28)-diene (4), 3ß,5α-dihydroxyergosta-7,22-diene (5), stigmasterol, ß-sitosterol, ß-amyrin, oleanolic acid, asperphenamate, sucrose and daucosterol. The structures of the isolated compounds have been established using NMR spectroscopic and mass spectrometric analyses. The assignment of relative and absolute configurations of compound 1 was achieved by a NOESY experiment and comparison of its NMR data with those of known compound reported in literature. Compounds 1-3, ß-amyrin and asperphenamate were evaluated for their antibacterial potencies against five bacterial model strains viz. Escherichia coli DSMZ 1058, Pseudomonas agarici DSMZ 11810, Bacillus subtilis DSMZ 704, Micrococcus luteus DMSZ 1605 and Staphylococcus warneri DSMZ 20036 and their cytotoxicity on two cell lines KB3-1 and HT-29. No potencies were exhibited by the tested compounds even at the highest concentration of 0.5 mg/mL. Compounds 1-3 were found to be potential HIV-1 inhibitors based on their molecular docking analyses.


Assuntos
Ergosterol/análogos & derivados , Meliaceae/química , Extratos Vegetais/química , Esteroides/química , Linhagem Celular Tumoral , Ergosterol/química , Ergosterol/isolamento & purificação , Células HT29 , Humanos , Conformação Molecular , Extratos Vegetais/isolamento & purificação , Esteroides/isolamento & purificação
12.
Nat Prod Res ; 34(8): 1080-1090, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30663363

RESUMO

Isoshamixanthone (1), a new stereoisomeric pyrano xanthone together with the previously known fungal metabolites, epiisoshamixanthone (2), sterigmatocystin (3), arugosin C (4), norlichexanthone (5), diorcinol (6), ergosterol and methyllinoleate, were obtained from the endophytic fungal strain Aspergillus sp. ASCLA isolated from leaf tissues of the medicinal plant Callistemon subulatus. The chemical structure of the new xanthone (1) was elucidated by extensive 1D, 2D NMR, and ESI HR mass measurements, and by comparison with literature data. The constitutions and absolute configurations of 1 and epiisoshamixanthone (2) were additionally confirmed by X-ray crystallography. Compounds 1,2 were evaluated for their potential anticancer activity using the human cervix carcinoma cell line (KB-3-1). The antimicrobial activities of the fungal extract and compounds 1,2 were studied using a panel of pathogenic microorganisms as well.


Assuntos
Aspergillus/química , Plantas Medicinais/microbiologia , Xantonas/isolamento & purificação , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Aspergillus/isolamento & purificação , Linhagem Celular Tumoral , Cristalografia por Raios X , Ergosterol , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular
13.
Nat Prod Res ; 34(7): 965-974, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30602325

RESUMO

Terretonin O (1), a new meroterpenoid, was isolated individually from both methanolic extracts of thermophilic Aspergillus terreus TM8 and marine Aspergillus terreus LGO13. The recently reported terretonins M (2) and N (3) were further isolated from the fungus LGO13 along with nine known compounds, terrelumamide A (4), terrein (5), methyl-3,4,5-trimethoxyl-2-[2-(nicotinamide)benzamido] benzoate (6), butyrolactones I-III (7-9), aspulvinone O (10), ergosterol, ergost-4-ene-3-one and methyl linoleate. Structure of terretonin O (1) was established on the bases of HRESIMS, 1D and 2D NMR spectra and comparison with its analogues in literatures. The relative stereochemistry of 1 was assigned on the basis of NOESY spectra and comparison with reported configuration of its congener compounds 2 and 3. The antimicrobial and cytotoxic activities of the fungal extracts and obtained compounds were assayed using a set of microorganisms, and cervix carcinoma cell line (KB-3-1), respectively. Isolation and taxonomical characterization of the producing strains are reported.


Assuntos
Aspergillus/química , Terpenos/isolamento & purificação , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Linhagem Celular Tumoral , Citotoxinas/química , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Estereoisomerismo , Terpenos/química , Terpenos/farmacologia
14.
ChemistryOpen ; 8(6): 737-742, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31275795

RESUMO

RGD-cryptophycin and isoDGR-cryptophycin conjugates were synthetized by combining peptidomimetic integrin ligands and cryptophycin, a highly potent tubulin-binding antimitotic agent across lysosomally cleavable Val-Ala or uncleavable linkers. The conjugates were able to effectively inhibit binding of biotinylated vitronectin to integrin αvß3, showing a binding affinity in the same range as that of the free ligands. The antiproliferative activity of the novel conjugates was evaluated on human melanoma cells M21 and M21-L with different expression levels of integrin αvß3, showing nanomolar potency of all four compounds against both cell lines. Conjugates containing uncleavable linker show reduced activity compared to the corresponding cleavable conjugates, indicating efficient intracellular drug release in the case of cryptophycin-based SMDCs. However, no significant correlation between the in vitro biological activity of the conjugates and the integrin αvß3 expression level was observed, which is presumably due to a non-integrin-mediated uptake. This reveals the complexity of effective and selective αvß3 integrin-mediated drug delivery.

15.
J Antibiot (Tokyo) ; 72(10): 729-735, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31289369

RESUMO

The first calcium complex from nature, Coumamarin (1), 7-hydroxy-3-methoxy-2-oxo-2H-chromene-6-carboxylate Ca(II) complex, was isolated from Aspergillus sydowii ASTI, together with diorcinol (2), violaceol I (3), hydroxysydonic acid (4), cyclo (Trp-Phe), kojic acid, ergosterol, and uracil. The producing strain was isolated from marine water sample collected from Tiran Island, Red Sea, Egypt. Structure 1 was assigned by intensive 1D, 2D NMR, HR-ESIMS, and X-ray crystallography as well. Coumamarin is potentially active against certain tested bacteria and yeasts, while showing no cytotoxic activity against human cervix carcinoma cell line (KB-3-1). Taxonomically, the fungus was identified by phylogenetic analysis of its 18S rRNA gene sequence.


Assuntos
Aspergillus/química , Produtos Biológicos/isolamento & purificação , Aspergillus/classificação , Aspergillus/genética , Aspergillus/isolamento & purificação , Produtos Biológicos/química , Análise por Conglomerados , DNA Fúngico/química , DNA Fúngico/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Egito , Oceano Índico , Estrutura Molecular , Filogenia , RNA Ribossômico 18S/genética , Água do Mar/microbiologia , Análise de Sequência de DNA , Análise Espectral
16.
Z Naturforsch C J Biosci ; 74(11-12): 283-288, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31246580

RESUMO

In the search for bioactive secondary metabolites from terrestrial fungi, four compounds, namely, 3-methyl-3H-quinazolin-4-one (1), aurantiomide C (2), 3-O-methylviridicatin (3), and dehydrocyclopeptine (4), were isolated from Penicillium sp. 8PKH, fungal strain, isolated from deteriorated rice straws. The structures of the isolated compounds were identified by extensive NMR and mass analyses and comparison with literature data. This is the first report of the structure of 3-methyl-3H-quinazolin-4-one (1) with full NMR spectral data having been previously identified by GC-MS from Piper beetle. Analysis of the non-polar fractions of the strain extract by GC-MS revealed the presence of additional eight compounds: methyl-hexadecanoate, methyl linoleate, methyl-9 (Z)-octadecenoate, methyl-octadecanoate, cis-9-oxabicyclo (6.1.0) nonane, 9,12-octadecadienal (9E,12E), ethyl-(E)-9-octadecenoate, and 3-buten-2-ol. The isolated compounds were evaluated for their antimicrobial and cytotoxic activities and exhibited little or no inhibitory activities against the test strains. The taxonomical characterisation and fermentation of the fungal strain were reported as well.


Assuntos
Oryza/microbiologia , Penicillium/isolamento & purificação , Penicillium/metabolismo , Metabolismo Secundário , Bactérias , Linhagem Celular Tumoral , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Testes de Sensibilidade Microbiana , Penicillium/química
17.
Pharmaceutics ; 11(5)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067748

RESUMO

Tumor targeting has emerged as an advantageous approach to improving the efficacy and safety of cytotoxic agents or radiolabeled ligands that do not preferentially accumulate in the tumor tissue. The somatostatin receptors (SSTRs) belong to the G-protein-coupled receptor superfamily and they are overexpressed in many neuroendocrine tumors (NETs). SSTRs can be efficiently targeted with octreotide, a cyclic octapeptide that is derived from native somatostatin. The conjugation of cargoes to octreotide represents an attractive approach for effective tumor targeting. In this study, we conjugated octreotide to cryptophycin, which is a highly cytotoxic depsipeptide, through the protease cleavable Val-Cit dipeptide linker using two different self-immolative moieties. The biological activity was investigated in vitro and the self-immolative part largely influenced the stability of the conjugates. Replacement of cryptophycin by the infrared cyanine dye Cy5.5 was exploited to elucidate the tumor targeting properties of the conjugates in vitro and in vivo. The compound efficiently and selectively internalized in cells overexpressing SSTR2 and accumulated in xenografts for a prolonged time. Our results on the in vivo properties indicate that octreotide may serve as an efficient delivery vehicle for tumor targeting.

18.
Pharmaceutics ; 11(4)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939768

RESUMO

Cryptophycins are potent tubulin polymerization inhibitors with picomolar antiproliferative potency in vitro and activity against multidrug-resistant (MDR) cancer cells. Because of neurotoxic side effects and limited efficacy in vivo, cryptophycin-52 failed as a clinical candidate in cancer treatment. However, this class of compounds has emerged as attractive payloads for tumor-targeting applications. In this study, cryptophycin was conjugated to the cyclopeptide c(RGDfK), targeting integrin αvß3, across the protease-cleavable Val-Cit linker and two different self-immolative spacers. Plasma metabolic stability studies in vitro showed that our selected payload displays an improved stability compared to the parent compound, while the stability of the conjugates is strongly influenced by the self-immolative moiety. Cathepsin B cleavage assays revealed that modifications in the linker lead to different drug release profiles. Antiproliferative effects of Arg-Gly-Asp (RGD)⁻cryptophycin conjugates were evaluated on M21 and M21-L human melanoma cell lines. The low nanomolar in vitro activity of the novel conjugates was associated with inferior selectivity for cell lines with different integrin αvß3 expression levels. To elucidate the drug delivery process, cryptophycin was replaced by an infrared dye and the obtained conjugates were studied by confocal microscopy.

19.
Z Naturforsch C J Biosci ; 74(5-6): 131-137, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-30645191

RESUMO

As a continuation of our earlier research concerning the investigation of microbial bioactive secondary metabolites from the terrestrial Penicillium sp.KH Link 1809 isolate KHMM, the fungus was re-cultivated on a large scale to explore its bioactive compounds intensively. Fifteen compounds, including seven alkaloids (1-7), one sesquiterpene (8), an acetylenic system (9), two sterols, and sphengolipid, were identified. Their structures were established on the bases of extensive one- and two-dimensional nuclear magnetic resonance and mass measurements, and by comparison with literature data. The antimicrobial activity of the fungal extract and the corresponding compounds were studied using a panel of pathogenic microorganisms, and their in vitro cytotoxicity against the human cervix carcinoma cell line (KB-3-1) was reported as well. The molecular docking of the isolated compounds showed promising affinities for the alkaloidal compounds 4-6 towards α, ß tubulins.


Assuntos
Alcaloides/química , Anti-Infecciosos/química , Antineoplásicos/química , Simulação de Acoplamento Molecular , Penicillium/química , Policetídeos/química , Moduladores de Tubulina/química , Alcaloides/farmacologia , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Humanos , Policetídeos/farmacologia , Ligação Proteica , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia
20.
Beilstein J Org Chem ; 14: 1281-1286, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29977395

RESUMO

Cryptophycins are naturally occurring cytotoxins with great potential for chemotherapy. Since targeted therapy provides new perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to homing devices are required. We describe the design, synthesis and biological evaluation of three new unit B cryptophycin analogues. The O-methyl group of the unit B D-tyrosine analogue was replaced by an O-(allyloxyethyl) moiety, an O-(hydroxyethyl) group, or an O-(((azidoethoxy)ethoxy)ethoyxethyl) substituent. While the former two maintain cytotoxicity in the subnanomolar range, the attachment of the triethylene glycol spacer with a terminal azide results in a complete loss of activity. Docking studies of the novel cryptophycin analogues to ß-tubulin provided a rationale for the observed cytotoxicities.

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