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1.
J Nat Prod ; 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35522580

RESUMO

Five new minor sesterterpenoids, ansellones H (4), I (5), J (6), and K (7) and phorone C (8), have been isolated from a Phorbas sp. marine sponge collected in British Columbia. Their structures have been elucidated by detailed analysis of NMR and MS data. Ansellone J (6) and phorone C (8) are potent in vitro HIV-1 latency reversal agents that are more potent than the reference compound and control protein kinase C activator prostratin (3). The most potent Phorbas sesterterpenoid, ansellone J (6), was evaluated for HIV latency reversal in a primary cell context using CD4+ T cells obtained directly from four combination antiretroviral therapy-suppressed donors with HIV. To a first approximation, ansellone J (6) induced HIV latency reversal at levels similar to prostratin (3) ex vivo, but at a 10-fold lower concentration.

2.
Nat Prod Res ; : 1-5, 2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35176917

RESUMO

A new C-benzylated flavone, uvariaruflavone (1), along with 13 known compounds (2-14) were isolated from the twig and leaf extracts of Uvaria rufa Blume. Their structures were established by extensive spectroscopic methods. Flavones (5-8) and cyclohexene (10) were isolated from U. rufa for the first time. Most of the isolated compounds were evaluated for their α-glucosidase and α-amylase inhibitory activities. Of these, uvariaruflavone (1) showed the highest α-glucosidase inhibitory activity with an IC50 value of 44.3 µM, while ferrudiol (12) displayed the highest α-amylase inhibitory activity with an IC50 value of 73.5 µM.

3.
J Antibiot (Tokyo) ; 75(4): 213-225, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35091665

RESUMO

Screening of a marine derived crude natural product extract library, followed by bioactivity guided fractionation, has led to isolation and structural elucidation of 10 natural products as hits active against Mycobacterium tuberculosis (Mtb). Among them, three (3, 4 and 5) were identified for the first time and the remaining 7 compounds (1, 2, 6, 7, 8, 9 and 10) were previously reported, but now assigned with anti-mycobacterial activity. Among identified hits, the oligo cyclic depsipeptide discodermin B (7) exhibited the highest potency with an MIC90 value of 0.5 µM. The polysufide alkaloid lissoclinotoxin F (1) displayed a good balance of anti Mtb potency (MIC90 = 2.6 µM) and selectivity (SI = 19 in HEK293 cells). Lissoclinotoxin F (1) was found to be active against intracellular Mtb as well as non-replicating forms of Mtb, with higher activity against Mtb compared to other gram-negative and gram-positive bacteria. Consequently, lissoclinotoxin F (1) could be used as a lead compound for development of new TB drugs. Details regarding screening techniques, structural elucidation and preliminary structural activity relationships (SAR) of the isolated hits are discussed.


Assuntos
Antituberculosos , Invertebrados , Mycobacterium tuberculosis , Animais , Antituberculosos/química , Células HEK293 , Humanos , Invertebrados/química , Testes de Sensibilidade Microbiana
4.
Cell Chem Biol ; 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34520745

RESUMO

The pathogen Mycobacterium tuberculosis (Mtb) evades the innate immune system by interfering with autophagy and phagosomal maturation in macrophages, and, as a result, small molecule stimulation of autophagy represents a host-directed therapeutics (HDTs) approach for treatment of tuberculosis (TB). Here we show the marine natural product clionamines activate autophagy and inhibit Mtb survival in macrophages. A yeast chemical-genetics approach identified Pik1 as target protein of the clionamines. Biotinylated clionamine B pulled down Pik1 from yeast cell lysates and a clionamine analog inhibited phosphatidyl 4-phosphate (PI4P) production in yeast Golgi membranes. Chemical-genetic profiles of clionamines and cationic amphiphilic drugs (CADs) are closely related, linking the clionamine mode of action to co-localization with PI4P in a vesicular compartment. Small interfering RNA (siRNA) knockdown of PI4KB, a human homolog of Pik1, inhibited the survival of Mtb in macrophages, identifying PI4KB as an unexploited molecular target for efforts to develop HDT drugs for treatment of TB.

5.
Mol Biol Rep ; 48(7): 5459-5471, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34304367

RESUMO

BACKGROUND: The Canadian prairie ecosystem presents a rich source of natural products from plants that are subjected to herbivory by grazing mammals. This type of ecological competition may contribute to the production of natural products of interest in cell biology and medical research. We provide the first biological description of the sesquiterpene lactone, pulchelloid A, which we isolated from the prairie plant, Gaillardia aristata (Asteraceae) and report that it inhibits mitosis in human cells. METHODS AND RESULTS: We found that G. aristata (Blanket flower) extracts were cytotoxic to human cell lines and used phenotypic assays to characterize the bioactivity of extracts. Before dying, cells were characterized by a rounded morphology, phospho-histone H3 signals, mitotic spindles, and active Cdk1. By biology-guided fractionation of Gaillardia extracts, we isolated a sesquiterpene lactone named pulchelloid A. We used immunofluorescence microscopy and observed that cells treated with pulchelloid A have phospho-histone H3 positive chromosomes and a mitotic spindle, confirming that they were in mitosis. Treated cells arrest with an unusual phenotype; they enter a prolonged mitotic arrest in which the spindles become multipolar and the chromosomes acquire histone γH2AX foci, a hallmark of damaged DNA. CONCLUSIONS: We propose that pulchelloid A, a natural product present in the prairie plant Gaillardia aristata, delays cells in mitosis. There is a growing body of evidence that a small number of members of the sesquiterpene lactone chemical family may target proteins that regulate mitosis.


Assuntos
Asteraceae/química , Extratos Vegetais/química , Fuso Acromático/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Células HT29 , Humanos , Mitose/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/genética
6.
Nat Prod Res ; : 1-9, 2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34096406

RESUMO

Three new indole diterpenoids, aculeatupenes A-C (1-3), together with four known compounds (4-7), were isolated from the mycelium of Aspergillus aculeatus KKU-CT2. Their structures were established by spectroscopic evidence and absolute configurations of 1-3 were determined by comparison of their experimental and calculated ECD spectra. Compounds 1, 2, and emindole SB (4) showed weak cytotoxicity against HelaS3, KB, HepG2, MCF-7, and A549 cancer cell lines with IC50 values in the range of 11.12-67.81 µM. Compound 3 showed weak cytotoxicity against HelaS3 cell lines with an IC50 value of 17.48 µM but non-cytotoxicity against Vero cell line. In addition, compound 1 exhibited weak antibacterial activity against Bacillus cereus.

7.
Heliyon ; 7(5): e07131, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34095597

RESUMO

We are investigating plants from the prairie ecological zone of Canada to identify natural products that inhibit mitosis in cancer cells. Investigation of plant parts from the Canadian plant species Hymenoxys richardsonii (Asteraceae) revealed that leaf extracts (PP-360A) had anti-mitotic activity on human cancer cell lines. Cells treated with leaf extracts acquired a rounded morphology, similar to that of cells in mitosis. We demonstrated that the rounded cells contained mitotic spindles and phospho-histone H3 using the techniques of immunofluorescence microscopy. By biology-guided fractionation of H. richardsonii leaves, we isolated a sesquiterpene lactone named hymenoratin, which had not been previously assigned a biological activity. Cells treated with hymenoratin have phospho-histone H3 positive chromosomes, a mitotic spindle, and enter a prolonged mitotic arrest in which the spindles become distorted. By Western blot analysis, hymenoratin treated cells acquire high levels of cyclin B and dephosphorylated Cdk1. There is a growing body of evidence that select members of the sesquiterpene lactone chemical family have anti-mitotic activity.

8.
Mol Biol Cell ; 32(15): 1374-1392, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34038161

RESUMO

Sterols are important lipid components of the plasma membrane (PM) in eukaryotic cells, but it is unknown how the PM retains sterols at a high concentration. Phospholipids are asymmetrically distributed in the PM, and phospholipid flippases play an important role in generating this phospholipid asymmetry. Here, we provide evidence that phospholipid flippases are essential for retaining ergosterol in the PM of yeast. A mutant in three flippases, Dnf1-Lem3, Dnf2-Lem3, and Dnf3-Crf1, and a membrane protein, Sfk1, showed a severe growth defect. We recently identified Sfk1 as a PM protein involved in phospholipid asymmetry. The PM of this mutant showed high permeability and low density. Staining with the sterol probe filipin and the expression of a sterol biosensor revealed that ergosterol was not retained in the PM. Instead, ergosterol accumulated in an esterified form in lipid droplets. We propose that ergosterol is retained in the PM by the asymmetrical distribution of phospholipids and the action of Sfk1. Once phospholipid asymmetry is severely disrupted, sterols might be exposed on the cytoplasmic leaflet of the PM and actively transported to the endoplasmic reticulum by sterol transfer proteins.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Adenosina Trifosfatases/metabolismo , Ergosterol/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Repressoras/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Membrana Celular/metabolismo , Proteínas de Transferência de Fosfolipídeos/metabolismo , Saccharomyces cerevisiae/enzimologia
9.
Heliyon ; 7(2): e06180, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33665411

RESUMO

Four new compounds, (+)-(2S)-desmosdumosone (1), (+)-(2R)-7,8-dimethoxy-5-hydroxyflavanone (7), (+)-(2R)-7-methoxychamanetin (9), and (+)-(1'R,2'R)-phebalosin (18), and 25 known compounds were isolated from the twig and leaf extracts of Desmos dumosus. Compounds (±)-7 and (±)-9 were isolated as racemates and their enantiomers were separated by chiral HPLC. Their structures were elucidated by spectroscopic methods as well as comparisons made from the literature. The absolute configuration of (+)-(1'R,2'R)-18 was established by X-ray diffraction analysis using Cu Kα radiation and electronic circular dichroism (ECD) spectoscopy. In contrast, the absolute configuration of compounds (+)-(2S)-1, (+)-(2R)-7, and (+)-(2R)-9 were identified by comparing their ECD spectra and specific rotations with those of reported known compounds. Compounds 9, 11, 13, 14, 22, 25, and 28 showed α-glucosidase inhibitory activities with IC50 values ranging from 5.3-52.7 µM, much better than that of standard control (acarbose, IC50 value 83.5 µM). Compound 13 was the most active with an IC50 value of 5.3 µM.

10.
Toxins (Basel) ; 13(2)2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673235

RESUMO

We are investigating plant species from the Canadian prairie ecological zone by phenotypic cell assays to discover toxins of biological interest. We provide the first report of the effects of extracts prepared from the shrub Symphoricarpos occidentalis in several human cell lines. S. occidentalis (Caprifoliaceae) extracts are cytotoxic, and, strikingly, treated cells undergo light-dependent vacuolation near the nucleus. The range of irradiation is present in standard ambient light and lies in the visible range (400-700 nm). Vacuolization in treated cells can be induced with specific wavelengths of 408 or 660 nm at 1 J/cm2 energies. Vacuolated cells show a striking phenotype of a large perinuclear vacuole (nuclear associated vacuole, NAV) that is distinct from vesicles observed by treatment with an autophagy-inducing agent. Treatment with S. occidentalis extracts and light induces an intense lamin A/C signal at the junction of a nuclear vacuole and the nucleus. Further study of S. occidentalis extracts and vacuolation provide chemical tools that may contribute to the understanding of nuclear envelope organization and human cell biology.


Assuntos
Núcleo Celular/efeitos dos fármacos , Extratos Vegetais/toxicidade , Plantas Tóxicas/toxicidade , Symphoricarpos/toxicidade , Toxinas Biológicas/toxicidade , Vacúolos/efeitos dos fármacos , Células A549 , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Núcleo Celular/efeitos da radiação , Células HT29 , Humanos , Lamina Tipo A/metabolismo , Luz , Extratos Vegetais/isolamento & purificação , Toxinas Biológicas/isolamento & purificação , Vacúolos/metabolismo , Vacúolos/patologia , Vacúolos/efeitos da radiação
11.
Future Med Chem ; 13(5): 487-504, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33565317

RESUMO

Oceans harbor a vast biodiversity that is not represented in terrestrial habitats. Marine sponges have been the richest source of marine natural products reported to date, and sponge-derived natural products have served as inspiration for the development of several drugs in clinical use. However, many promising sponge-derived drug candidates have been stalled in clinical trials due to lack of efficacy, off-target toxicity, metabolic instability or poor pharmacokinetics. One possible solution to this high clinical failure rate is to design drug delivery systems that deliver drugs in a controlled and specific manner. This review critically analyzes drugs/drug candidates inspired by sponge natural products and the potential use of drug delivery systems as a new strategy to enhance the success rate for translation into clinical use.


Assuntos
Produtos Biológicos/química , Portadores de Fármacos/química , Poríferos/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Herpesviridae/efeitos dos fármacos , Imunoconjugados/química , Imunoconjugados/metabolismo , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico
12.
J Nat Prod ; 84(3): 797-813, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33124806

RESUMO

Synthetic analogues of the marine natural product sintokamides have been prepared in order to investigate the structure-activity relationships for the androgen receptor N-terminal domain (AR NTD) antagonist activity of the sintokamide scaffold. An in vitro LNCaP cell-based transcriptional activity assay with an androgen-driven luciferase (Luc) reporter was used to monitor the potency of analogues. The data have shown that the chlorine atoms on the leucine side chains are essential for potent activity. Analogues missing the nonchlorinated methyl groups of the leucine side chains (C-1 and C-17) are just as active and in some cases more active than the natural products. Analogues with the natural R configuration at C-10 and the unnatural R configuration at C-4 are most potent. Replacing the natural propionamide N-terminus cap with the more sterically hindered pivaloylamide N-terminus cap leads to enhanced potency. The tetramic acid fragment and the methyl ether on the tetramic acid fragment are essential for activity. The SAR optimized analogue 76 is more selective, easier to synthesize, more potent, and presumed to be more resistant to proteolysis than the natural sintokamides.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Pirrolidinonas/farmacologia , Antagonistas de Receptores de Andrógenos/química , Animais , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Dysidea/química , Humanos , Masculino , Estrutura Molecular , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirrolidinonas/química , Relação Estrutura-Atividade
13.
ACS Omega ; 5(40): 25593-25604, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33073085

RESUMO

The marine natural product latonduine A (1) shows F508del-cystic fibrosis transmembrane regulator (CFTR) corrector activity in cell-based assays. Pull-down experiments, enzyme inhibition assays, and siRNA knockdown experiments suggest that the F508del-CFTR corrector activities of latonduine A and a synthetic analogue MCG315 (4) result from simultaneous inhibition of PARP3 and PARP16. A library of synthetic latonduine A analogs has been prepared in an attempt to separate the PARP3 and PARP16 inhibitory properties of latonduine A with the goal of discovering selective small-molecule PARP3 and PARP16 inhibitory cell biology tools that could confirm the proposed dual-target F508del-CFTR corrector mechanism of action. The structure activity relationship (SAR) study reported herein has resulted in the discovery of the modestly potent (IC50 3.1 µM) PARP3 selective inhibitor (±)-5-hydroxy-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (5) that shows 96-fold greater potency for inhibition of PARP3 compared with its inhibition of PARP16 in vitro and the potent (IC50 0.362 µM) PARP16 selective inhibitor (±)-7,8-dichloro-5-hydroxy-4-(pyridin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (6) that shows 205-fold selectivity for PARP16 compared with PARP3 in vitro. At 1 or 10 µM, neither 5 or 6 alone showed F508del-CFTR corrector activity, but when added together at 1 or 10 µM each, the combination exhibited F508del-CFTR corrector activity identical to 1 or 10 µM latonduine A (1), respectively, supporting its novel dual PARP target mechanism of action. Latonduine A (1) showed additive in vitro corrector activity in combination with the clinically approved corrector VX809, making it a potential new partner for cystic fibrosis combination drug therapies.

14.
Mol Oncol ; 14(10): 2455-2470, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32734688

RESUMO

Resistance of castration-resistant prostate cancer (CRPC) to enzalutamide and abiraterone involves the expression of constitutively active, truncated androgen receptor (AR) splice variants (AR-Vs) that lack a C-terminal ligand-binding domain (LBD). Both full-length AR and truncated AR-Vs require a functional N-terminal domain (NTD) for transcriptional activity thereby providing rationale for the development of ralaniten (EPI-002) as a first-in-class antagonist of the AR-NTD. Here, we evaluated the antitumor effect of a next-generation analog of ralaniten (EPI-7170) as a monotherapy or in combination with enzalutamide in prostate cancer cells that express AR-V7 that were resistant to enzalutamide. EPI-7170 had 8-9 times improved potency compared to ralaniten. Enzalutamide increased levels of AR-V7 and expression of its target genes. Knockdown of AR-V7 restored sensitivity to enzalutamide, indicating a role for AR-V7 in the mechanism of resistance. EPI-7170 inhibited expression of genes transcriptionally regulated by full-length AR and AR-V7. A combination of EPI-7170 and enzalutamide resulted in synergistic inhibition of proliferation of enzalutamide-resistant cells that was consistent with results from cell cycle and clonogenic assays. In addition, this drug enhanced the antitumor effect of enzalutamide in enzalutamide-resistant CRPC preclinical models. Thus, a combination therapy targeting both the NTD and LBD of AR, and thereby blocking both full-length AR and AR-Vs, has potential for the treatment of enzalutamide-resistant CRPC.


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/uso terapêutico , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/química , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Benzamidas/farmacologia , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Domínios Proteicos , Transcrição Genética/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
iScience ; 23(8): 101433, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32823063

RESUMO

The anti-inflammatory actions of interleukin-10 (IL10) are thought to be mediated primarily by the STAT3 transcription factor, but pro-inflammatory cytokines such as interleukin-6 (IL6) also act through STAT3. We now report that IL10, but not IL6 signaling, induces formation of a complex between STAT3 and the inositol polyphosphate-5-phosphatase SHIP1 in macrophages. Both SHIP1 and STAT3 translocate to the nucleus in macrophages. Remarkably, sesquiterpenes of the Pelorol family, which we previously described as allosteric activators of SHIP1 phosphatase activity, could induce SHIP1/STAT3 complex formation in cells and mimic the anti-inflammatory action of IL10 in a mouse model of colitis. Using crystallography and docking studies we identified a drug-binding pocket in SHIP1. Our studies reveal new mechanisms of action for both STAT3 and SHIP1 and provide a rationale for use of allosteric SHIP1-activating compounds, which mimic the beneficial anti-inflammatory actions of IL10. VIDEO ABSTRACT.

16.
Molecules ; 25(12)2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32599753

RESUMO

The increasing prevalence of drug-resistant influenza viruses emphasizes the need for new antiviral countermeasures. The M2 protein of influenza A is a proton-gated, proton-selective ion channel, which is essential for influenza replication and an established antiviral target. However, all currently circulating influenza A virus strains are now resistant to licensed M2-targeting adamantane drugs, primarily due to the widespread prevalence of an M2 variant encoding a serine to asparagine 31 mutation (S31N). To identify new chemical leads that may target M2(S31N), we performed a virtual screen of molecules from two natural product libraries and identified chebulagic acid as a candidate M2(S31N) inhibitor and influenza antiviral. Chebulagic acid selectively restores growth of M2(S31N)-expressing yeast. Molecular modeling also suggests that chebulagic acid hydrolysis fragments preferentially interact with the highly-conserved histidine residue within the pore of M2(S31N) but not adamantane-sensitive M2(S31). In contrast, chebulagic acid inhibits in vitro influenza A replication regardless of M2 sequence, suggesting that it also acts on other influenza targets. Taken together, results implicate chebulagic acid and/or its hydrolysis fragments as new chemical leads for M2(S31N) and influenza-directed antiviral development.


Assuntos
Antivirais/farmacologia , Benzopiranos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Glucosídeos/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Proteínas da Matriz Viral/antagonistas & inibidores , Amantadina/química , Amantadina/farmacologia , Animais , Antivirais/química , Cães , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Histidina/química , Vírus da Influenza A/fisiologia , Células Madin Darby de Rim Canino , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/genética , Replicação Viral/efeitos dos fármacos
17.
Cancers (Basel) ; 12(7)2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32708219

RESUMO

Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.

18.
Phytochemistry ; 177: 112439, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32562917

RESUMO

Three undescribed spirosteroids, asparacemosones A-C, an undescribed spiro-21-norsteroid, asparacemosone D, along with seven known compounds were isolated from Thai herbal plant Asparagus racemosus Willd. roots. Their structures were elucidated by spectroscopic analysis including NMR, UV, IR and mass spectrometry. The absolute configurations of asparacemosones A, B, and D were determined by single crystal X-ray diffraction using CuKα radiation. Among the isolated compounds, the norlignan nyasol and three acetylenic norlignans demonstrated potent α-glucosidase inhibition, with IC50 values ranging from 0.003 to 0.004 µM which is 5 × 104 fold more potent than the standard acarbose.


Assuntos
Asparagus (Planta) , alfa-Glucosidases , Extratos Vegetais , Raízes de Plantas
19.
J Antibiot (Tokyo) ; 73(8): 568-573, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32404991

RESUMO

Crude extracts of the marine sponge Chelonaplysilla sp. collected in Samoa, that were obtained from the NCI Open Repository (NCS 21903), inhibited Mycobacterium tuberculosis growth. Assay-guided fractionation of the extract led to the isolation and structural elucidation of the known diterpenoid macfarlandin D (1) and three new diterpenoids macfarlandins F (2), G (3), and H (4). Macfarlandin D (1) exhibited potent antimicrobial activity against M. tuberculosis with an MIC of 1.2 ± 0.4 µg mL-1. Macfarlandins F (2), G (3), and H (4) exhibited significantly weaker antitubercular activities, revealing SAR for the macfarlandin antitubercular pharmacophore. The structures of compounds 2, 3, and 4 were elucidated via detailed analysis of NMR and MS data.


Assuntos
Diterpenos/química , Diterpenos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Poríferos/química , Animais , Antituberculosos/química , Antituberculosos/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Testes de Sensibilidade Microbiana/métodos
20.
Bioorg Med Chem ; 28(10): 115462, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32247751

RESUMO

The first phytochemical investigation of Polyalthia cinnamomea led to the isolation and identification of two new oxoprotoberberine alkaloids, (-)-(13aS)-polyalthiacinnamines A and B, together with eleven known compounds. The structures of the new compounds were elucidated by extensive spectroscopic methods. The absolute configuration of miliusacunine E and consanguine B was established by X-ray diffraction analysis using Cu Kα radiation and ECD spectra, whereas the absolute configurations of polyalthiacinnamines A and B were established by comparison of their ECD spectra and specific rotations with those of miliusacunine E and consanguine B. Compounds 1-4, 6, and 8 exhibited α-glucosidase inhibitory activities (IC50 values ranging from 11.3 to 57.9 µM) better than a positive control (acarbose, IC50 83.5 µM). Compound 2 also exhibited NO production inhibitory activity with an IC50 value of 24.4 µM (indomethacin, a positive control, IC50 = 32.2 µM).


Assuntos
Alcaloides/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Óxido Nítrico/antagonistas & inibidores , Extratos Vegetais/farmacologia , Polyalthia/química , alfa-Glucosidases/metabolismo , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Camundongos , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico/biossíntese , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Células RAW 264.7 , Relação Estrutura-Atividade , Árvores/química
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