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1.
Molecules ; 29(11)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38893527

RESUMO

Natural products contribute substantially to anticancer therapy; the plant kingdom provides an important source of molecules. Conofolidine is a novel Aspidosperma-Aspidosperma bisindole alkaloid isolated from the Malayan plant Tabernaemontana corymbosa. Herein, we report conofolidine's broad-spectrum anticancer activity together with that of three other bisindoles-conophylline, leucophyllidine, and bipleiophylline-against human-derived breast, colorectal, pancreatic, and lung carcinoma cell lines. Remarkably, conofolidine was able to induce apoptosis (e.g., in MDA-MB-468 breast) or senescence (e.g., in HT-29 colorectal) in cancer cells. Annexin V-FITC/PI, caspase activation, and PARP cleavage confirmed the former while positive ß-gal staining corroborated the latter. Cell cycle perturbations were evident, comprising S-phase depletion, accompanied by downregulated CDK2, and cyclins (A2, D1) with p21 upregulation. Confocal imaging of HCT-116 cells revealed an induction of aberrant mitotic phenotypes-membrane blebbing, DNA-fragmentation with occasional multi-nucleation. DNA integrity assessment in HCT-116, MDA-MB-468, MIAPaCa-2, and HT-29 cells showed increased fluorescent γ-H2AX during the G1 cell cycle phase; γ-H2AX foci were validated in HCT-116 and MDA-MB-468 cells by confocal microscopy. Conofolidine increased oxidative stress, preceding apoptosis- and senescence-induction in most carcinoma cell lines as seen by enhanced ROS levels accompanied by increased NQO1 expression. Collectively, we present conofolidine as a putative potent anticancer agent capable of inducing heterogeneous modes of cancerous cell death in vitro, encouraging further preclinical evaluations of this natural product.


Assuntos
Apoptose , Senescência Celular , Humanos , Apoptose/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Alcaloides/farmacologia , Alcaloides/química , Linhagem Celular Tumoral , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/química , Tabernaemontana/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Células HT29
2.
Int J Mol Sci ; 24(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36674548

RESUMO

Adaptation to a wide variety of habitats allows fungi to develop unique abilities to produce diverse secondary metabolites with diverse bioactivities. In this study, 30 Ascomycetes fungi isolated from St. John's Island, Singapore were investigated for their general biosynthetic potential and their ability to produce antimicrobial secondary metabolites (SMs). All the 30 fungal isolates belong to the Phylum Ascomycota and are distributed into 6 orders and 18 genera with Order Hypocreales having the highest number of representative (37%). Screening for polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) genes using degenerate PCR led to the identification of 23 polyketide synthases (PKSs) and 5 nonribosomal peptide synthetases (NRPSs) grouped into nine distinct clades based on their reduction capabilities. Some of the identified PKSs genes share high similarities between species and known reference genes, suggesting the possibility of conserved biosynthesis of closely related compounds from different fungi. Fungal extracts were tested for their antimicrobial activity against S. aureus, Methicillin-resistant S. aureus (MRSA), and Candida albicans. Bioassay-guided fractionation of the active constituents from two promising isolates resulted in the isolation of seven compounds: Penilumamides A, D, and E from strain F4335 and xanthomegnin, viomellein, pretrichodermamide C and vioxanthin from strain F7180. Vioxanthin exhibited the best antibacterial activity with IC50 values of 3.0 µM and 1.6 µM against S. aureus and MRSA respectively. Viomellein revealed weak antiproliferative activity against A549 cells with an IC50 of 42 µM. The results from this study give valuable insights into the diversity and biosynthetic potential of fungi from this unique habitat and forms a background for an in-depth analysis of the biosynthetic capability of selected strains of interest with the aim of discovering novel fungal natural products.


Assuntos
Ascomicetos , Staphylococcus aureus Resistente à Meticilina , Singapura , Staphylococcus aureus Resistente à Meticilina/metabolismo , Staphylococcus aureus/metabolismo , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Ascomicetos/genética , Peptídeo Sintases/genética , Peptídeo Sintases/metabolismo , Fungos/metabolismo , Filogenia
3.
Int J Mol Sci ; 21(22)2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33202690

RESUMO

Sortase A (SrtA) is a membrane-associated enzyme that anchors surface-exposed proteins to the cell wall envelope of Gram-positive bacteria such as Staphylococcus aureus. As SrtA is essential for Gram-positive bacterial pathogenesis but dispensable for microbial growth or viability, SrtA is considered a favorable target for the enhancement of novel anti-infective drugs that aim to interfere with key bacterial virulence mechanisms, such as biofilm formation, without developing drug resistance. Here, we used virtual screening to search an in-house natural compound library and identified two natural compounds, N1287 (Skyrin) and N2576 ((4,5-dichloro-1H-pyrrol-2-yl)-[2,4-dihydroxy-3-(4-methyl-pentyl)-phenyl]-methanone) that inhibited the enzymatic activity of SrtA. These compounds also significantly reduced the growth of S. aureus but possessed moderate mammalian toxicity. Furthermore, S. aureus strains treated with these compounds exhibited reduction in adherence to host fibrinogen, as well as biofilm formation. Hence, these compounds may represent an anti-infective therapy without the side effects of antibiotics.


Assuntos
Aminoaciltransferases , Antibacterianos , Proteínas de Bactérias , Biofilmes/efeitos dos fármacos , Cisteína Endopeptidases , Inibidores Enzimáticos , Staphylococcus aureus/fisiologia , Células A549 , Aminoaciltransferases/antagonistas & inibidores , Aminoaciltransferases/química , Aminoaciltransferases/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Biofilmes/crescimento & desenvolvimento , Simulação por Computador , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Células Hep G2 , Humanos
4.
Microb Cell Fact ; 19(1): 71, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32192516

RESUMO

Notonesomycin A is a 32-membered bioactive glycosylated macrolactone known to be produced by Streptomyces aminophilus subsp. notonesogenes 647-AV1 and S. aminophilus DSM 40186. In a high throughput antifungal screening campaign, we identified an alternative notonesomycin A producing strain, Streptomyces sp. A793, and its biosynthetic gene cluster. From this strain, we further characterized a new more potent antifungal non-sulfated analogue, named notonesomycin B. Through CRISPR-Cas9 engineering of the biosynthetic gene cluster, we were able to increase the production yield of notonesomycin B by up to 18-fold as well as generate a strain that exclusively produces this analogue.


Assuntos
Antifúngicos/isolamento & purificação , Macrolídeos/isolamento & purificação , Streptomyces/genética , Antifúngicos/metabolismo , Clonagem Molecular , Macrolídeos/metabolismo , Família Multigênica , Streptomyces/metabolismo
5.
BMC Genomics ; 20(1): 374, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088369

RESUMO

BACKGROUND: Phomafungin is a recently reported broad spectrum antifungal compound but its biosynthetic pathway is unknown. We combed publicly available Phoma genomes but failed to find any putative biosynthetic gene cluster that could account for its biosynthesis. RESULTS: Therefore, we sequenced the genome of one of our Phoma strains (F3723) previously identified as having antifungal activity in a high-throughput screen. We found a biosynthetic gene cluster that was predicted to synthesize a cyclic lipodepsipeptide that differs in the amino acid composition compared to Phomafungin. Antifungal activity guided isolation yielded a new compound, BII-Rafflesfungin, the structure of which was determined. CONCLUSIONS: We describe the NRPS-t1PKS cluster 'BIIRfg' compatible with the synthesis of the cyclic lipodepsipeptide BII-Rafflesfungin [HMHDA-L-Ala-L-Glu-L-Asn-L-Ser-L-Ser-D-Ser-D-allo-Thr-Gly]. We report new Stachelhaus codes for Ala, Glu, Asn, Ser, Thr, and Gly. We propose a mechanism for BII-Rafflesfungin biosynthesis, which involves the formation of the lipid part by BIIRfg_PKS followed by activation and transfer of the lipid chain by a predicted AMP-ligase on to the first PCP domain of the BIIRfg_NRPS gene.


Assuntos
Antifúngicos/química , Depsipeptídeos/química , Proteínas Fúngicas/genética , Saccharomycetales/genética , Sequência de Aminoácidos , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Vias Biossintéticas , Depsipeptídeos/biossíntese , Depsipeptídeos/farmacologia , Genômica , Estrutura Molecular , Família Multigênica , Saccharomycetales/metabolismo , Sequenciamento Completo do Genoma
6.
Sci Rep ; 9(1): 710, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679518

RESUMO

We have isolated Hypoculoside, a new glycosidic amino alcohol lipid from the fungus Acremonium sp. F2434 belonging to the order Hypocreales and determined its structure by 2D-NMR (Nuclear Magnetic Resonance) spectroscopy. Hypoculoside has antifungal, antibacterial and cytotoxic activities. Homozygous profiling (HOP) of hypoculoside in Saccharomyces cerevisiae (budding yeast) revealed that several mutants defective in vesicular trafficking and vacuolar protein transport are sensitive to hypoculoside. Staining of budding yeast cells with the styryl dye FM4-64 indicated that hypoculoside damaged the vacuolar structure. Furthermore, the propidium iodide (PI) uptake assay showed that hypoculoside disrupted the plasma membrane integrity of budding yeast cells. Interestingly, the glycosidic moiety of hypoculoside is required for its deleterious effect on growth, vacuoles and plasma membrane of budding yeast cells.


Assuntos
Acremonium/química , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Membrana Celular/química , Citotoxinas/farmacologia , Glicosídeos/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Esfingosina/análogos & derivados , Antibacterianos/química , Antifúngicos/química , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Citotoxinas/química , Genes Fúngicos , Glicosídeos/química , Saccharomyces cerevisiae/crescimento & desenvolvimento , Esfingosina/química , Esfingosina/farmacologia , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo
7.
J Nat Prod ; 79(10): 2709-2717, 2016 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-27759387

RESUMO

Examination of the EtOH extract of the Malayan Tabernaemontana corymbosa resulted in the isolation of three new alkaloids, viz., cononuridine (1), an unusual hexacyclic, iboga-derived, monoterpenoid indole characterized by contraction of the tetrahydroazepine C-ring and incorporation of an additional isoxazolidine ring, taberisidine (2), a seco-corynanthean alkaloid, and conofolidine (3), an Aspidosperma-Aspidosperma bisindole that showed pronounced in vitro growth inhibitory activity against an array of human cancer cell lines, including KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, HT-29, and HCT 116 cells. The structures and absolute configurations of 1 and 3 and the absolute configuration of the novel pyridopyrimidine indole alkaloid vernavosine (4) were confirmed by X-ray diffraction analysis. A reasonable biosynthesis route to cononuridine starting from an iboga precursor is presented.


Assuntos
Antineoplásicos Fitogênicos , Alcaloides Indólicos , Monoterpenos , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Aspidosperma/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HT29 , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Células KB , Estrutura Molecular , Monoterpenos/isolamento & purificação , Monoterpenos/farmacologia , Tabernaemontana/química , Vincristina/farmacologia
8.
J Nat Prod ; 79(5): 1388-99, 2016 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-27077800

RESUMO

Ten new indole alkaloids (1-10) comprising five ibogan, two aspidosperman, one vincamine, and two bisindole alkaloids, in addition to 32 known alkaloids, were isolated from the stem-bark extract of a Malayan Tabernaemontana corymbosa. The structures of these alkaloids were determined based on analysis of the NMR and MS data and, in five instances (1, 3, 5, 6, 8), confirmed by X-ray diffraction analysis. Two of the iboga alkaloids, conodusines B (2) and C (3), and the iboga-containing bisindole tabernamidine B (10) are notable for the presence of an α-substituted acetyl group at C-20 of the iboga carbon skeleton. The iboga alkaloid (+)-conodusine E (5) had MS and NMR data that were identical to those of (-)-ervatamine I, recently isolated from Ervatamia hainanensis. Establishment of the absolute configuration of (+)-conodusine E (5) was based on analysis of the ECD data, correlation with (-)-heyneanine, and X-ray analysis, which showed that (+)-5 belongs to the same enantiomeric series as exemplified by (-)-coronaridine. The configuration at C-20' of the previously reported Tabernaemontana bisindole alkaloid 19'-oxotabernamine (renamed tabernamidine B) required revision based on the present results. Several of the bisindoles showed pronounced in vitro growth inhibitory activity against drug-sensitive and vincristine-resistant KB cells.


Assuntos
Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ibogaína/análogos & derivados , Células KB , Conformação Molecular , Estrutura Molecular , Casca de Planta/química , Folhas de Planta/química , Estereoisomerismo , Relação Estrutura-Atividade , Tabernaemontana/química , Vincamina/química , Vincamina/isolamento & purificação , Vincamina/farmacologia , Vincristina/farmacologia
9.
Org Lett ; 16(24): 6330-3, 2014 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-25454201

RESUMO

Two new indole alkaloids characterized by previously unencountered natural product skeletons, viz., criofolinine (1), incorporating a pyrroloazepine motif within a pentacyclic ring system, and vernavosine (2, isolated as its ethyl ether derivative 3, which on hydrolysis regenerated the putative precursor alkaloid 2), incorporating a pyridopyrimidine moiety embedded within a pentacyclic carbon framework, were isolated from a Malayan Tabernaemontana species. The structures and absolute configuration of these alkaloids were determined on the basis of NMR and MS analysis and confirmed by X-ray diffraction analysis.


Assuntos
Azepinas/química , Alcaloides Indólicos/química , Pirimidinas/química , Tabernaemontana/química , Ioimbina/química , Alcaloides Indólicos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Folhas de Planta , Estereoisomerismo , Difração de Raios X
10.
J Nat Prod ; 77(11): 2504-12, 2014 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-25333996

RESUMO

Seven new indole alkaloids (1-7) comprising four vobasine, two tacaman, and one corynanthe-tryptamine bisindole alkaloid were isolated from the stem-bark extract of a Malayan Tabernaemontana. Two of the new vobasine alkaloids (1, 3), as well as 16-epivobasine (15) and 16-epivobasenal (17), showed appreciable cytotoxicity toward KB cells (IC50 ca. 5 µg/mL). The structure of the known Tabernaemontana alkaloid tronoharine (8) was revised based on newly acquired NMR data, as well as X-ray diffraction analysis.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Plantas Medicinais/química , Tabernaemontana/química , Antineoplásicos Fitogênicos/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Indóis/química , Indóis/isolamento & purificação , Indóis/farmacologia , Malásia , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Pausinystalia , Triptaminas/química , Triptaminas/isolamento & purificação , Triptaminas/farmacologia
11.
Org Lett ; 15(18): 4774-7, 2013 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-23991636

RESUMO

Two new indole alkaloids, voatinggine (1) and tabertinggine (2), which are characterized by previously unencountered natural product skeletons, were isolated from a Malayan Tabernaemontana species. The structures and absolute configuration of these alkaloids were determined using NMR and MS analysis, and X-ray diffraction analysis. A possible biogenetic pathway to these novel alkaloids from an iboga precursor, and via a common cleavamine-type intermediate, is presented.


Assuntos
Alcaloides Indólicos/síntese química , Tabernaemontana/química , Cristalografia por Raios X , Alcaloides Indólicos/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Estereoisomerismo
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