RESUMEN
The isolation, structure determination, and biological evaluation of constituents from the organic extract of Turraea delphinensis Wahlert (Meliaceae) resulted in the isolation of 51 secondary metabolites, including 14 new terpenoids (six cycloartanes, four tirucallanes/euphanes, three limonoids, and a 7-keto sterol). Among the new compounds, 1 is the first triterpenoid with a trioxaspiro[4.4]nonane side chain, while 11-13 are the first 17-γ-lactone tetranortriterpenoids with four oxygenated functional groups at C-1, -3, -6, and -7. The isolated compounds were evaluated for antiproliferative activity against five human tumor cell lines, including a vinblastine-resistant cell line.
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Antineoplásicos Fitogénicos , Ensayos de Selección de Medicamentos Antitumorales , Meliaceae , Terpenos , Triterpenos , Humanos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Terpenos/farmacología , Terpenos/química , Terpenos/aislamiento & purificación , Estructura Molecular , Meliaceae/química , Triterpenos/farmacología , Triterpenos/química , Triterpenos/aislamiento & purificación , Línea Celular Tumoral , Limoninas/farmacología , Limoninas/química , Limoninas/aislamiento & purificación , Proliferación Celular/efectos de los fármacosRESUMEN
Eight vilasinin-class limonoids, including the unusually chlorinated rubescins K-M (1-3), the 2,3-epoxylated rubescin N (4), and rubescins O-R (5-8), were newly isolated from Trichilia rubescens. The structures of the isolated compounds were determined through spectroscopic and spectrometric analyses, as well as ECD calculations. The natural occurrence of chlorinated limonoids 1-3 was confirmed by chemical methods and HPLC analysis of a roughly fractionated portion of the plant extract. Eight selected limonoids, including previously known and new compounds, were evaluated for antiproliferative activity against five human tumor cell lines. All tested limonoids, except 8, exhibited significant potency, with IC50 values of <10 µM; in particular, limonoid 14 strongly inhibited tumor cell growth, with IC50 values of 0.54-2.06 µM against all tumor cell lines, including multi-drug-resistant cells.
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Limoninas , Meliaceae , Humanos , Limoninas/química , Línea Celular Tumoral , Meliaceae/química , Estructura MolecularRESUMEN
Four cytotoxic heptacyclic caged-xanthones [gambogefic acids B-E (1-4)], a cytotoxic hexacyclic caged-xanthone [garcilatelic acid (5)], and four biphenyl derivatives [garcilatelibiphenyls A-D (6-9)] were newly isolated in a phytochemical study of a 50% MeOH/CH2Cl2 extract of Garcinia lateriflora (Clusiaceae). The isolated compounds were evaluated for antiproliferative activity against five human tumor cell lines including a vincristine-resistant line. The new caged-xanthones displayed potent activity with IC50 values from 0.5 to 6.7 µM against all tested tumor cell lines.
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Antineoplásicos Fitogénicos , Garcinia , Xantonas , Humanos , Compuestos de Bifenilo , Línea Celular Tumoral , Xantonas/farmacología , Estructura Molecular , Antineoplásicos Fitogénicos/farmacologíaRESUMEN
Increasing evidence implicates the tumor microbiota as a factor that can influence cancer progression. In patients with colorectal cancer (CRC), we found that pre-resection antibiotics targeting anaerobic bacteria substantially improved disease-free survival by 25.5%. For mouse studies, we designed an antibiotic silver-tinidazole complex encapsulated in liposomes (LipoAgTNZ) to eliminate tumor-associated bacteria in the primary tumor and liver metastases without causing gut microbiome dysbiosis. Mouse CRC models colonized by tumor-promoting bacteria (Fusobacterium nucleatum spp.) or probiotics (Escherichia coli Nissle spp.) responded to LipoAgTNZ therapy, which enabled more than 70% long-term survival in two F. nucleatum-infected CRC models. The antibiotic treatment generated microbial neoantigens that elicited anti-tumor CD8+ T cells. Heterologous and homologous bacterial epitopes contributed to the immunogenicity, priming T cells to recognize both infected and uninfected tumors. Our strategy targets tumor-associated bacteria to elicit anti-tumoral immunity, paving the way for microbiome-immunotherapy interventions.
RESUMEN
Chemotherapy refers principally to the use of small molecules to treat cancer, and natural product derivatives have been main sources of clinically using anticancer drugs. While the coumarin skeleton does not inhibit cell growth, its derivatives are often active, and numerous coumarins have been examined for antiproliferative activity against human cancer cell lines. In this study, 16 novel coumarin derivatives (1, 1a-5a, 1b, 2b, 6b, 7b, 8-13) with attached N-heterocycles, including aminopyrrolidine, aminopiperidine, aminoazepane, and indoline, were prepared and ultimately esterified or amidated with alcohols or amines, respectively. All synthesized N-heterocycles containing coumarin derivatives with alcohols, amines, and carboxylic acids were assessed for antiproliferative activity against several human cancer cell lines, containing triple-negative breast cancer (TNBC) as well as a P-glycoprotein (P-gp) overexpressing multidrug-resistant (MDR) KB subline KB-VIN. Five coumarin derivatives (3a-5a, 12, 13) showed no effect (IC50 >40 µM) against all tested cell lines. In contrast, derivative 1a showed broad-spectrum activity against four cell lines, while 1b and 10 were nearly twice as selective for KB-VIN cells as the parent KB. The coumarin derivatives 1a, 1b, and 10 were optimal for antiproliferative activity in this study and could provide a new avenue for overcoming MDR tumors. Derivatives 1a, 1b, and 10 showed MDR cell-selective antiproliferative activity, indicating that N-heterocycle-coumarins exert previously unexplored bioactivity with selective action on MDR cancer cells.
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Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Proliferación Celular , Ciclo Celular , Cumarinas/farmacología , Línea Celular Tumoral , Relación Estructura-ActividadRESUMEN
Six new Pd(II), Pt(II) and Ag(I) complexes, (1);{Pd (L1)]2C6H4}2Cl4} (2); Pt(L2)(DMSO)Cl; 3; {PtL5]2C6H4}2·PhCOO-â 11NO3-; 4; {[Pt(L4)]2C6H4}; the binuclear cyclometalated complex the polymer chain (5); {[PtL5]C6H4}·NO3-}; and the polymeric silver species (6); Zn(L6)2·AgNO3·CHCl3 were synthesized and thoroughly characterized using X-ray diffraction and spectroscopic techniques (L1=(S,S)-1,4-i-PrOx]2C6H4}2Cl4, L2=Di(2,2-bis(4R-isopropyl-4,5-dihydro-oxazol-2-yl)acetonitrile) zinc (II) (BR1);L3= 1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)benzene (AR2); L4= 1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)benzeneï¼L5=1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)-benzeneï¼L6=Di(2,2-bis(4S-isopropyl-4,5-dihydrooxazol-2-yl)acetonitrile) zinc (II). Complexes 1-6 showed cytotoxic effects against human tumour cell lines, including a multidrug-resistant subline. Oxazoline and Pd complex 1 induced apoptosis in A549 cells. DFT calculations were also performed to exhibit the excellent bioactivity of complex 1 against A549, MDA-MB-231, and KB cells. Complex 1, with the best docking score and a stable interaction network within the binding site of the G-quadruplex, could stably interact with the G-quadruplex. Additionally, complex 1 was further used in the animal experiment of human lung adenocarcinoma cells in nude mice. By comparing with the model control group, the tumour volume, relative tumour volume and relative tumour proliferation rate T/C decreased significantly in the cisplatin group and compound 1 (complex 1) group.
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Antineoplásicos , Platino (Metal) , Animales , Ratones , Humanos , Platino (Metal)/farmacología , Platino (Metal)/química , Simulación del Acoplamiento Molecular , Paladio/farmacología , Paladio/química , Plata/farmacología , Teoría Funcional de la Densidad , Benceno , Ratones Desnudos , Línea Celular Tumoral , Antineoplásicos/química , ZincRESUMEN
Aims: Emerging evidence suggests that modulating redox homeostasis through targeting mitochondrial functions may be a useful strategy for suppressing triple-negative breast cancer (TNBC) activities. However, whether there are specific microRNAs (miRNAs) involved in regulating oxidative stress-associated mitochondrial functions that can act as therapeutic targets to suppress TNBC activities remains unclear. Here, we aimed to identify the role of redox-associated miRNAs in TNBC and investigated their potential as therapeutic targets. Results: We identified oxidative stress-responsive differentially expressed miRNAs (DEMs) regulated by phytosesquiterpene lactone deoxyelephantopin (DET) and its novel derivative DETD-35, which are known to inhibit TNBC growth and metastasis in vitro and in vivo, using comparative miRNA microarray analysis and reactive oxygen species (ROS) scavenging approaches. Mitochondrial dysfunction was identified as a major biological function regulated by a few specific DEMs. In particular, miR-4284 was identified to play a role in DET- and DETD-35-mediated ROS production, mitochondrial basal proton leak, and antiproliferation activity in TNBC cells. Moreover, DET- and DETD-35-induced mitochondrial DNA damage was observed in TNBC cells and xenograft tumors. miR-4284 was also identified to play a role in oxidative DNA damage in TNBC tumors. Innovation: We identified a novel role for miR-4284 in regulating mitochondrial basal proton leak in TNBC cells, and highlighted its significance in TNBC tumor oxidative DNA damage, and its direct correlation with TNBC patient survival. Conclusion: We used DET and DETD-35 as proof of concept to demonstrate that activities of anticancer agents can involve regulation of multiple miRNAs playing different roles in cancer progression. Antioxid. Redox Signal. 38, 198-214.
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MicroARNs , Mitocondrias , Neoplasias de la Mama Triple Negativas , Humanos , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Lactonas/farmacología , MicroARNs/genética , Protones , Especies Reactivas de Oxígeno , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Animales , Sesquiterpenos/farmacología , Mitocondrias/patologíaRESUMEN
Four new diterpene esters, shirakindicans A-D (1-4), along with eight related known diterpene esters (5-12), were isolated from the fruits of the Bangladeshi medicinal plant Shirakiopsis indica. The structures of 1-4 were elucidated by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Shirakindican A (1) was assigned as a tigliane-type diterpene ester possessing an unusual 6ß-hydroxy-1,7-dien-3-one structure, while shirakindican B (2) exhibits a tiglia-1,5-dien-3,7-dione structure. The anti-HIV activities of the isolated diterpene esters were evaluated and showed significant activities for sapintoxins A (5) and D (11), with EC50 values of 0.0074 and 0.044 µM, respectively, and TI values of 1â¯100 and 5â¯290. Sapatoxin A (12) also exhibited anti-HIV activity with an EC50 value of 0.13 µM and a TI value of 161.
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Fármacos Anti-VIH , Euphorbiaceae , VIH , Ésteres del Forbol , Euphorbiaceae/química , Frutas/química , Estructura Molecular , VIH/efectos de los fármacos , Ésteres del Forbol/química , Ésteres del Forbol/aislamiento & purificación , Ésteres del Forbol/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/aislamiento & purificación , Fármacos Anti-VIH/farmacología , Línea Celular , HumanosRESUMEN
Although many diterpenoid alkaloids have been evaluated recently for antiproliferative activity against human cancer cell lines, little data have been offered relating to the antiproliferative effects of hetisine-type C20-diterpenoid alkaloids, such as kobusine (1), likewise as their derivatives. A total of 43 novel diterpenoid alkaloid derivatives (2-10, 2b, 3a, 3b, 6a-16a, 7b, 9b, 10b, 13, 15-26, 15b, 18a, 23a, 27a) were prepared by C-11 and -15 esterification of 1. Antiproliferative effects of the natural parent compound (1) and all synthesized kobusine derivatives against human cancer cell lines, including a triple-negative breast cancer (TNBC) cell line as well as a P-glycoprotein overexpressing multidrug-resistant subline, were assessed. The structure-based design strategy resulted in the lead derivative 11,15-dibenzoylkobusine (3; average IC50 7.3 µM). Several newly synthesized kobusine derivatives (particularly, 5-8, 10, 13, 15-26) exhibited substantial suppressive effects against all tested human cancer cell lines. In contrast, kobusine (1), 11,15-O-diacetylkobusine (2), 11-acylkobusine derivatives (3a, 6a, 9a, 11a, 12a, 15a, 27a), and 15-acylkobusine derivatives (2b, 3b, 7b, 9b, 10b, 15b) showed no effect. The most active kobusine derivatives primarily had two specific substitution patterns, C-11,15 and C-11. Notably, 11,15-diacylkobusine derivatives (3, 6-10, 13, 15, 16, 18, 23) were more potent compared with 11- and 15-acylkobusine derivatives (3a, 3b, 6a-10a, 7b, 9b, 10b, 13a, 15a, 15b, 16a, 18a, 23a). Derivatives 13 and 25 induced MDA-MB-231 cells to the sub-G1 phase within 12 h. 11,15-Diacylation of kobusine (1) appears to be crucial for inducing antiproliferative activity in this alkaloid class and could introduce a new avenue to overcome TNBC using natural product derivatives.
RESUMEN
C4 variation of 4'-O-demethyl-epipodophyllotoxin (DMEP) is an effective approach to optimize the antitumor spectra of this compound class. Accordingly, two series of novel DMEP derivatives were synthesized, and as expected, the antitumor spectra of these derivatives varied with different C4 substituents. Notably, most compounds showed significant inhibition against the etoposide (2)-resistant KBvin cells. Four of the compounds (11, 18, 27 and 28) induced protein-linked DNA break (PLDB) levels higher than those of GL-331 (6) and 2, and are assumed to be topoisomerase II (topo II) poisons more potent than 6 and 2. Compound 28, a potent topo II poison highly effective against KBvin cells, was further evaluated with a panel of tumor cells and was most active against HepG2. This compound also exhibited apparent in vivo antitumor efficacy in hepatoma 22 (H22) mouse model. The results indicated that C4 derivation of DMEP is a feasible approach to identify potent topo II inhibitors with optimized antitumor profiles.
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Antineoplásicos , Podofilotoxina , Animales , Antineoplásicos/farmacología , ADN-Topoisomerasas de Tipo II/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Ratones , Podofilotoxina/farmacología , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/farmacologíaRESUMEN
The pharmacological activities of C19-diterpenoid alkaloids are related to their basic skeletons (e.g., aconitine-type or lycoctonine-type). Also, few studies have been reported on the chemosensitizing effects of diterpenoid alkaloids. Consequently, this study was aimed at determining the chemosensitizing effects of synthetic derivatives of lycoctonine-type C19-diterpenoid alkaloids on a P-glycoprotein (P-gp)-overexpressing multidrug-resistant (MDR) cancer cell line KB-VIN. The acyl-derivatives of delpheline and delcosine showed moderate cytotoxicity against chemosensitive cancer cell lines. Among non-cytotoxic synthetic analogs (1-14), several derivatives effectively and significantly sensitized MDR cells by interfering with the drug transport function of P-gp to three anticancer drugs, vincristine, paclitaxel, and doxorubicin. The chemosensitizing effect of derivatives 2, 4, and 6 on KB-VIN cells against vincristine were more potent than 5 µM verapamil, and derivatives 4 and 13 were more effective than 5 µM verapamil for paclitaxel. Among them, 2 in particular increased the sensitivity of KB-VIN cells to vincristine by 253-fold.
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Alcaloides , Diterpenos , Neoplasias , Alcaloides/farmacología , Diterpenos/farmacología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Humanos , Paclitaxel/farmacología , Verapamilo/farmacología , Vincristina/farmacologíaRESUMEN
Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted scientific and popular interest worldwide since the 19th century. More than 600 compounds have been isolated from nature to date. To build on our two prior reviews, we reexamined the promising molecules described in previous reports and provided updated literature on novel quinoline and quinazoline alkaloids isolated over the past 5 years. This chapter reviews and discusses 205 molecules with a broad range of bioactivities, including antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, and other effects. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.
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Alcaloides , Quinolinas , Alcaloides/farmacología , Antiinflamatorios , Biología , Quinazolinas/farmacología , Quinolinas/farmacologíaRESUMEN
Acquired resistance to vemurafenib (PLX4032) is a thorny issue in BRAFV600E mutant melanoma therapy. Ferroptotic programmed cell death is a potential strategy for combating therapy-resistant cancers. This study uncovers the adaptation and abnormal upregulation of PUFAs and bioactive oxylipin metabolism in PLX4032 resistant melanoma cells. Phyto-sesquiterpene lactone, DET, and its derivative, DETD-35, induced lipid ROS accumulation and triggered ferroptotic cell death in PLX4032 sensitive (A375) and resistant (A375-R) BRAFV600E melanoma cells by reprogramming glutathione and primary metabolisms, lipid/oxylipin metabolism, and causing mitochondrial damage in which DETD-35 showed superior efficiency to DET. We discovered that DET and DETD-35 are a new type of GPX4 enzyme inhibitor through non-covalent binding. This study provides new insight into the therapeutic mechanisms of both DET and DETD-35 to combat PLX4032 sensitive/resistant BRAFV600E mutant melanomas via targeting GPX4 and ferroptosis.
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Ferroptosis , Melanoma , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Sesquiterpenos , Línea Celular Tumoral , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/farmacología , Ferroptosis/efectos de los fármacos , Humanos , Indoles/farmacología , Lactonas/farmacología , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/metabolismo , Oxilipinas/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Sesquiterpenos/farmacología , Sulfonamidas/farmacología , Vemurafenib/farmacologíaRESUMEN
Four series of molecular hybrids (37 final products) of neo-tanshinlactone, a natural product extracted from Salvia miltiorrhiza Bunge, and known PD-1/PD-L1 interaction inhibitors were prepared as possible chemotherapeutic agents against triple negative breast cancer. Screening using a homogenous time-resolved fluorescence method resulted in three lead compounds (MZ52 IC50 74 ± 4 nM; MZ58 IC50 134 ± 17 nM; MZ61 IC50 225 ± 19 nM). With less T cell cytotoxicity and effects in activating CD8+ T cells in a T cell proliferation assay and a functionality experiment, MZ58 was selected as the best candidate for animal experiments. MZ58 exhibited antitumor effects in a subcutaneous transplantation tumor model as well as effects in reducing T cell exhaustion. In conclusion, after in vivo and in vitro experiments, we successfully acquired an effective candidate (MZ58) showing antitumor effects with low cytotoxicity toward T cells as well as the ability to activate CD8+ T cells and reduce T cell exhaustion.
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Antineoplásicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Diseño de Fármacos , Furanos/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Pironas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Furanos/síntesis química , Furanos/química , Humanos , Inhibidores de Puntos de Control Inmunológico/síntesis química , Inhibidores de Puntos de Control Inmunológico/química , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Receptor de Muerte Celular Programada 1/metabolismo , Pironas/síntesis química , Pironas/química , Relación Estructura-ActividadRESUMEN
Diterpenoid alkaloids, the main components of plants of the genera Aconitum, Delphinium, and Garrya, are a group of natural products with notable chemical properties and biological activities. Several C19-diterpenoid alkaloid components from Delphinium elatum cv. Pacific Giant, as well as their derivatives, exhibited cytotoxic activity against lung, prostate, cervical, and vincristine-resistant cervical cancer cell lines. In the current phytochemical investigation on the seeds of D. elatum cv. Pacific Giant, eleven new C19-diterpenoid alkaloids, elapaciline (1), meladine (2), melapacitine (3), iminoeladine (4), 19-oxopaciline (5), 19-oxopacinine (6), N-deethyldelpheline (7), N-deethylpacinine (8), N-deethyl-19-oxoeladine (9), N-deethyl-N-formyleladine (10), and N-deethyl-N-formyldelpheline (11), together with 15 known C19-diterpenoid alkaloids were isolated. Their structures were elucidated by extensive spectroscopic methods including NMR (1D and 2D), IR, and MS (HRMS). Three known diterpenoid alkaloids, 6-dehydrodelcorine (12), delelatine (23), and 6-dehydroeldelidine (24), were isolated for the first time from this plant. Six of the new C19-diterpenoid alkaloids (2, 4-7, and 11) and three of the known diterpenoid alkaloids (18, 23, and 24) were evaluated for cytotoxic activity against five human tumor cell lines.
Asunto(s)
Aconitum , Alcaloides , Delphinium , Diterpenos , Alcaloides/farmacología , Línea Celular Tumoral , Humanos , Estructura Molecular , Raíces de PlantasRESUMEN
Phenanthrene-based tylophorine-1 (PBT-1) was identified previously as a lead compound in an anticancer drug discovery effort based on natural Tylophora alkaloids. An expanded structural optimization using a new more efficient synthetic route provided 14 PBT-derivatives. Eleven compounds displayed obvious antiproliferative activities in cellular assays (GI50 0.55-9.32 µM). The most potent compounds 9c, 9g, and 9h (GI50 < 1 µM) contained a 7-hydroxy group on the phenanthrene B-ring in addition to a pendant piperidine E-ring with different 4-substituents. Compound 9h with NH2 as the piperidine substituent was at least 4-fold more potent against triple-negative breast cancer MDA-MB-231 than estrogen-responsible breast cancer MCF-7 cell growth. In further biological evaluations, the new active compounds induced cell cycle accumulation in the late S and G2/M phase without interfering with microtubule formation or cell morphology. These results on the optimization of the B- and E-rings of PBT-1 should benefit further development of novel antitumor agents.
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The HIV-1 Capsid (CA) is considered as a promising target for the development of potent antiviral drugs, due to its multiple roles during the viral life cycle. Herein, we report the design, synthesis, and antiviral activity evaluation of series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors. Among them, 4-methoxy-N-methylaniline substituted phenylalanine (II-13c) and indolin-5-amine substituted phenylalanine (V-25i) displayed exceptional anti-HIV-1 activity with the EC50 value of 5.14 and 2.57 µM respectively, which is slightly weaker than that of lead compound PF-74 (EC50 = 0.42 µM). Besides, surface plasmon resonance (SPR) binding assay demonstrated II-13c and V-25i prefer to combine with CA hexamer rather than monomer, which is similar to PF-74. Subsequently, molecular dynamics simulation (MD) revealed potential interactions between representative compounds with HIV-1 CA hexamer. Overall, this work laid a solid foundation for further structural optimization to discover novel promising HIV-1 CA inhibitors.
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Fármacos Anti-VIH/farmacología , Proteínas de la Cápside/antagonistas & inhibidores , Diseño de Fármacos , VIH-1/efectos de los fármacos , Fenilalanina/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Proteínas de la Cápside/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , VIH-1/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Simulación de Dinámica Molecular , Estructura Molecular , Fenilalanina/síntesis química , Fenilalanina/química , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Structurally diverse tigliane diterpenoids have drawn significant research interest for drug discovery over many decades. Using LC-MS-guided fractionation and separation, the first phytochemical investigation on Wikstroemia lamatsoensis led to the isolation of eight tiglianes (1-8), including two new compounds, wikstrocin D (1) and wikstrocin E (2). The new structures were elucidated based on extensive physicochemical and spectroscopic analyses. The characteristic ESIMS/MS fragmentations of tiglianes 1-8 were also summarized. Among the isolated tiglianes, three compounds (8, 5, and 7) showed the most potent anti-HIV activity, with IC50 values of 0.18, 3.8, and 12.8 nM, respectively.
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Fármacos Anti-VIH/química , Diterpenos/química , Forboles/química , Wikstroemia/química , Fármacos Anti-VIH/farmacología , Línea Celular , China , Diterpenos/farmacología , VIH-1/efectos de los fármacos , Humanos , Estructura Molecular , Forboles/farmacología , Fitoquímicos/química , Fitoquímicos/farmacologíaRESUMEN
Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four series of tigliane-type diterpenoids. We synthesized and evaluated 29 new phorbol ester derivatives for anti-HIV activity and for cytotoxicity against human tumor cell lines. Among them, three derivatives, two phorbol-13-monoesters (5d and 5e) and a phorbol-12,13-diester (6a), showed significant anti-HIV activity. We found that better anti-HIV activity was often associated with a shorter acyl ester at C-13. Particularly, compounds with a phenyl ring in the ester side chain exhibited excellent anti-HIV activity and had good safety indexes. Due to its significant anti-HIV potency with a high selectivity index, phorbol-12,13-dicinnamoate (6a) was chosen as the potential candidate for further preclinical trials.
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Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , VIH-1/fisiología , Ésteres del Forbol/química , Ésteres del Forbol/farmacología , Replicación Viral/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Macrocyclic daphnane orthoesters (MDOs) have attracted significant research interest for the drug discovery to cure HIV infection based on the "Shock and Kill" strategy. In the present study, the first chemical study on Wikstroemia ligustrina (Thymelaeaceae) was carried out by LC-MS analysis and phytochemical investigation. Nine daphnane diterpenoids (1-9) including seven MDOs were detected by LC-MS analysis. Further phytochemical investigation resulted in the isolation and structural elucidation of five daphnanes (1, 2, 5, 8, and 9) with potent anti-HIV activity. Taking the isolated MDO (1) as a model compound, the MS/MS fragmentation pathway was also elucidated.