RESUMEN
BACKGROUND: Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within and around transplanted organs. However, tacrolimus also suppresses T-cell function in the skin, contributing to a high incidence of skin cancer and associated mortality and morbidity in solid organ transplant recipients. Here, we aimed to identify a compound capable of re-establishing antitumor T-cell control in the skin despite the presence of tacrolimus. METHODS: In this study, we performed time-resolved fluorescence resonance energy transfer to identify molecules capable of antagonizing the interaction between tacrolimus and FKBP12. The capacity of these molecules to rescue mouse and human T-cell function in the presence of tacrolimus was determined in vitro, and the antitumor effect of the lead compound, Q-2361, was assessed in "regressor" models of skin cancer in immunosuppressed mice. Systemic CD8 T-cell depletion and analyses of intratumoral T-cell activation markers and effector molecule production were performed to determine the mechanism of tumor rejection. Pharmacokinetic studies of topically applied Q-2361 were performed to assess skin and systemic drug exposure. RESULTS: Q-2361 potently blocked the interaction between tacrolimus and FKBP12 and reversed the inhibition of the nuclear factor of activated T cells activation by tacrolimus following T-cell receptor engagement in human Jurkat cells. Q-2361 rescued T-cell function in the presence of tacrolimus, rapamycin, and everolimus. Intratumoral injection of Q-2361-induced tumor regression in mice systemically immune suppressed with tacrolimus. Mechanistically, Q-2361 treatment permitted T-cell activation, proliferation, and effector function within tumors. When CD8 T cells were depleted, Q-2361 could not induce tumor regression. A simple solution-based Q-2361 topical formulation achieved high and sustained residence in the skin with negligible drug in the blood. CONCLUSIONS: Our findings demonstrate that the local application of Q-2361 permits T-cells to become activated driving tumor rejection in the presence of tacrolimus. The data presented here suggests that topically applied Q-2361 has great potential for the reactivation of T-cells in the skin but not systemically, and therefore represents a promising strategy to prevent or treat skin malignancies in immunosuppressed organ transplant recipients.
Asunto(s)
Neoplasias Cutáneas , Tacrolimus , Humanos , Animales , Ratones , Tacrolimus/farmacología , Tacrolimus/uso terapéutico , Proteína 1A de Unión a Tacrolimus , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Huésped InmunocomprometidoRESUMEN
A chemoinformatic method was developed to extract nonflat scaffolds embedded in natural products within the Dictionary of Natural Products (DNP). The cedrane scaffold was then chosen as an example of a nonflat scaffold that directs substituents in three-dimensional (3D) space. A cedrane scaffold that has three orthogonal handles to allow generation of 1D, 2D, and 3D libraries was synthesized on a large scale. These libraries would cover more than 50% of the natural diversity of natural products with an embedded cedrane scaffold. Synthesis of three focused natural product-like libraries based on the 3D cedrane scaffold was achieved. A phenotypic assay was used to test the biological profile of synthesized compounds against normal and Parkinson's patient-derived cells. The cytological profiles of the synthesized analogues based on the cedrane scaffold revealed that this 3D scaffold, prevalidated by nature, can interact with biological systems as it displayed various effects against normal and Parkinson's patient-derived cell lines.
Asunto(s)
Productos Biológicos/química , Materiales Biomiméticos/química , Materiales Biomiméticos/síntesis química , Diseño de Fármacos , Informática , Materiales Biomiméticos/farmacología , Línea Celular , Técnicas de Química Sintética , Humanos , Modelos Moleculares , Conformación Molecular , FenotipoRESUMEN
Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product-based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy-nine (79) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain.
Asunto(s)
Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Evaluación Preclínica de Medicamentos/métodos , Espectrometría de Masas/métodos , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/crecimiento & desarrollo , Unión Proteica , Proteínas Protozoarias/metabolismoRESUMEN
(1)H NMR fingerprints were used as the guiding principle for the isolation of minor compounds related to the l-type amino acid transporter inhibitors venulosides A (1) and B (2). Two new monoterpene glycosides, namely, venulosides C (3) and D (4), were isolated from a Queensland collection of the plant Pittosporum venulosum. Compounds 3 and 4 were found to inhibit l-leucine transport in LNCaP cells with IC50 values of 11.47 and 39.73 µM, respectively. The venulosides are the first reported natural product inhibitors of leucine transport in prostate cancer cells, and the isolation of the minor compounds provides some early SAR information.
Asunto(s)
Sistemas de Transporte de Aminoácidos/química , Aminoácidos/metabolismo , Glicósidos/química , Glicósidos/aislamiento & purificación , Glicósidos/farmacología , Leucina/metabolismo , Monoterpenos/química , Monoterpenos/aislamiento & purificación , Monoterpenos/farmacología , Rosales/química , Transporte Biológico , Humanos , Transportador de Aminoácidos Neutros Grandes 1 , Masculino , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Relación Estructura-ActividadRESUMEN
A series of amide (832, 4045) and urea (33, 34, 3639) analogues based on the thiaplakortone A natural product scaffold were synthesised and screened for in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine- and mefloquine-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50 <500 nM) and good selectivity for P. falciparum versus human neonatal foreskin fibroblast cells (selectivity index >100). Two of these compounds, 8 and 33, exhibited good aqueous solubility and metabolic stability, and when administered subcutaneously to mice (32 mg kg(-1)), plasma concentrations remained above 0.2 µM for at least 8 h. Both 8 and 33 were well tolerated in mice after subcutaneous administration of 32 mg kg(-1) twice daily for 4 days. Using this regimen blood stage P. berghei was suppressed by 52% for 8 and 26% for 33, relative to the vehicle control.
Asunto(s)
Amidas/química , Antimaláricos/química , Antimaláricos/farmacología , Productos Biológicos/química , Triazinas/química , Triazinas/farmacología , Urea/química , Animales , Antimaláricos/efectos adversos , Antimaláricos/farmacocinética , Atovacuona/farmacología , Línea Celular , Técnicas de Química Sintética , Resistencia a Medicamentos/efectos de los fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Malaria/tratamiento farmacológico , Masculino , Ratones , Plasmodium berghei/efectos de los fármacos , Plasmodium berghei/fisiología , Plasmodium falciparum/efectos de los fármacos , Relación Estructura-Actividad , Triazinas/efectos adversos , Triazinas/farmacocinéticaRESUMEN
The first total synthesis of the potent and selective human blood coagulation factor XIa inhibitor clavatadine A (1) is described. Direct, early-stage guanidinylation enabled rapid, convergent access to an immediate clavatadine A precursor. Concomitant lactone hydrolysis and guanidine deprotection with aqueous acid cleanly provided clavatadine A (1) in only four steps (longest linear sequence, 41-43% overall yield).
Asunto(s)
Factor XIa/antagonistas & inhibidores , Guanidinas/síntesis química , Fenilacetatos/síntesis química , Animales , Guanidinas/química , Guanidinas/farmacología , Humanos , Lactonas/química , Estructura Molecular , Fenilacetatos/química , Fenilacetatos/farmacología , Poríferos/químicaRESUMEN
Well over a hundred years ago, Professor Julius Bredt embarked on a career pursuing and critiquing bridged bicyclic systems that contained ring strain induced by the presence of a bridgehead olefin. These endeavors founded what we now know as Bredt's rule (Bredtsche Regel). Physical, theoretical, and synthetic organic chemists have intensely studied this premise, pushing the boundaries of such systems to arrive at a better understood physical phenomenon. Mother nature has also seen fit to construct molecules containing bridgehead double bonds that encompass Bredt's rule. For the first time, this topic is reviewed in a natural product context.
Asunto(s)
Productos Biológicos/química , Estructura MolecularRESUMEN
Inhibition of FASN has emerged as a promising therapeutic target in cancer, and numerous inhibitors have been investigated. However, severe pharmacological limitations have challenged their clinical testing. The synthetic FASN inhibitor triclosan, which was initially developed as a topical antibacterial agent, is merely affected by these pharmacological limitations. Yet, little is known about its mechanism in inhibiting the growth of cancer cells. Here we compared the cellular and molecular effects of triclosan in a panel of eight malignant and non-malignant prostate cell lines to the well-known FASN inhibitors C75 and orlistat, which target different partial catalytic activities of FASN. Triclosan displayed a superior cytotoxic profile with a several-fold lower IC50 than C75 or orlistat. Structure-function analysis revealed that alcohol functionality of the parent phenol is critical for inhibitory action. Rescue experiments confirmed that end product starvation was a major cause of cytotoxicity. Importantly, triclosan, C75 and orlistat induced distinct changes to morphology, cell cycle, lipid content and the expression of key enzymes of lipid metabolism, demonstrating that inhibition of different partial catalytic activities of FASN activates different metabolic pathways. These finding combined with its well-documented pharmacological safety profile make triclosan a promising drug candidate for the treatment of prostate cancer.
Asunto(s)
Reposicionamiento de Medicamentos , Acido Graso Sintasa Tipo I/antagonistas & inhibidores , Inhibidores de la Síntesis de Ácidos Grasos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Triclosán/farmacología , Células 3T3 , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacología , Animales , Antiinfecciosos Locales/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Lactonas/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Orlistat , Relación Estructura-ActividadRESUMEN
Thiaplakortone A (3a), an antimalarial natural product, was prepared by an operationally simple and scalable synthesis. In our efforts to deliver a lead compound with improved potency, metabolic stability, and selectivity, the synthesis was diverted to access a series of analogues. Compounds 3a-d showed nanomolar activity against the chloroquine-sensitive (3D7) Plasmodium falciparum line and were more active against the chloroquine- and mefloquine-resistant (Dd2) P. falciparum line. All compounds are "Rule-of-5" compliant, and we show that metabolic stability can be enhanced via modification at either the primary or pyrrole nitrogen. These promising results lay the foundation for the development of this structurally unprecedented natural product.
RESUMEN
The NMR spectrum of a mixture of small molecules is a fingerprint of all of its components. Herein, we present an NMR fingerprint method that takes advantage of the fact that fractions contain simplified NMR profiles, with minimal signal overlap, to allow the identification of unique spectral patterns. The approach is exemplified in the identification of a novel natural product, iotrochotazineâ A (1), sourced from an Australian marine sponge Iotrochotaâ sp. Compound 1 was used as a chemical probe in a phenotypic assay panel based on human olfactory neurosphere-derived cells (hONS) from idiopathic Parkinson's disease patients. Compound 1 at 1â µM was not cytotoxic but specifically affected the morphology and cellular distribution of lysosomes and early endosomes.
Asunto(s)
Productos Biológicos/química , Compuestos Heterocíclicos con 3 Anillos/química , Animales , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular/métodos , Mucosa Olfatoria/efectos de los fármacos , Mucosa Olfatoria/patología , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/patología , Poríferos/químicaRESUMEN
The L-type amino acid transporter (LAT) family consists of four members (LAT1-4) that mediate uptake of neutral amino acids including leucine. Leucine is not only important as a building block for proteins, but plays a critical role in mTORC1 signaling leading to protein translation. As such, LAT family members are commonly upregulated in cancer in order to fuel increased protein translation and cell growth. To identify potential LAT-specific inhibitors, we established a function-based high-throughput screen using a prefractionated natural product library. We identified and purified two novel monoterpene glycosides, ESK242 and ESK246, sourced from a Queensland collection of the plant Pittosporum venulosum. Using Xenopus laevis oocytes expressing individual LAT family members, we demonstrated that ESK246 preferentially inhibits leucine transport via LAT3, while ESK242 inhibits both LAT1 and LAT3. We further show in LNCaP prostate cancer cells that ESK246 is a potent (IC50 = 8.12 µM) inhibitor of leucine uptake, leading to reduced mTORC1 signaling, cell cycle protein expression and cell proliferation. Our study suggests that ESK246 is a LAT3 inhibitor that can be used to study LAT3 function and upon which new antiprostate cancer therapies may be based.
Asunto(s)
Sistemas de Transporte de Aminoácidos Básicos/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Glicósidos/farmacología , Transportador de Aminoácidos Neutros Grandes 1/química , Leucina/metabolismo , Monoterpenos/química , Neoplasias de la Próstata/patología , Rosales/química , Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Transporte Biológico , Western Blotting , Femenino , Humanos , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Monoterpenos/farmacología , Complejos Multiproteicos/metabolismo , Oocitos/citología , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Células Tumorales Cultivadas , Xenopus laevis/crecimiento & desarrollo , Xenopus laevis/metabolismoRESUMEN
In this tutorial review, recent advances in the synthesis of cyclopropane-containing natural products are discussed, highlighting the application of novel synthetic methodologies and innovative synthetic strategies in the construction of highly functionalized cyclopropanes. The examples showcased herein aim to inspire students and practitioners of organic synthesis to seek further advances in the chemical synthesis of cyclopropanes, both in the context of target-oriented syntheses and method developments.
Asunto(s)
Productos Biológicos/síntesis química , Técnicas de Química Sintética/métodos , Ciclopropanos/síntesis química , Productos Biológicos/química , Catálisis , Ciclopropanos/química , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Rutenio/químicaRESUMEN
With their fascinating biological profiles and stunningly complex molecular architectures, the polycyclic polyprenylated acylphloroglucinols (PPAPs) have long provided a fertile playing field for synthetic organic chemists. In particular, the recent advent of innovative synthetic methods and strategies together with C-C bond-forming reactions and asymmetric catalysis have revitalized this field tremendously. Consequently, PPAP targets which once seemed beyond reach have now been synthesized. This Review aims to highlight the recent achievements in the total synthesis of PPAPs, as well as notable methods developed for the construction of the bicyclo[3.3.1] core of these chemically and biologically intriguing molecules.
Asunto(s)
Floroglucinol/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Catálisis , Ciclización , Floroglucinol/síntesis química , Prenilación , Selenio/químicaRESUMEN
In the long lasting battle against cancer, Nature sometimes gives a helping hand to researchers to find new drugs for the treatment of diseases and improvement of patients' well-being. Englerin A has emerged as a promising anticancer candidate as well as being an exciting synthetic challenge for organic chemists. This focus review summarizes the total syntheses reported to date and the synthetic approaches toward analogues of this fascinating natural product.
Asunto(s)
Antineoplásicos/síntesis química , Sesquiterpenos de Guayano/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Sesquiterpenos de Guayano/química , Sesquiterpenos de Guayano/farmacología , Relación Estructura-ActividadRESUMEN
A direct synthetic approach to the spiro-γ-lactone clerodane ring system has been investigated. This work builds on that of Jung and highlights the inherent difficulties associated with the otherwise obvious Diels-Alder approach.
Asunto(s)
Diterpenos de Tipo Clerodano/química , Modelos Moleculares , Estructura Molecular , Compuestos de Espiro/químicaRESUMEN
Secondary alcohols modified as tosylates, PEG-sulfonates, or quisylates undergo inversion of configuration at the reacting center when treated with lithium halide in acetone at reflux, where the PEG-sulfonates and quisylates are substantially more reactive. In sterically hindered cases, elimination is a competing process. In contrast, when treated with TiCl(4), simple secondary sulfonates give chloride products with partial inversion of configuration. Any observed retention of configuration in a given alkyl sulfonate substrate under these conditions is likely due to neighboring group participation or diastereoselective attack on a carbocation (or ion pair) rather than an S(N)i mechanism.
RESUMEN
Ring-closing metathesis was used to construct the strained 11-membered ring of obtusallenes II (and IV). Bromonium ion induced transannular oxonium ion formation-fragmentation gave the macrocyclic carbon skeleton of obtusallene VII with a bromine atom at C-13, in line with a previously published hypothesis. An additional brominated [5.5.1]bicyclotridecane adduct that must arise from a bromonium ion induced transannular oxonium ion formation-fragmentation could also be isolated, suggesting that this adduct represents the core of an as yet undiscovered natural product. An authentic sample of obtusallene V was studied by NMR spectroscopy, and the position of the halogens at C-7 and C-13 was reassigned on the basis of a (13)C NMR chlorine induced isotopic shift. This revised structure was subsequently confirmed by X-ray crystallography. These findings allow us to confidently conclude that the structures of obtusallenes VII and VI should also be reassigned.
Asunto(s)
Bromo/química , Éteres Cíclicos/química , Oxígeno/química , Ciclización , Éteres Cíclicos/síntesis química , Iones/química , Modelos Moleculares , Conformación Molecular , EstereoisomerismoRESUMEN
Enantiopure bromonium ions may be generated from enantiopure bromohydrins and derivatives, they can be trapped with an in situ nucleophile to give enantiomerically pure products.
Asunto(s)
Alcoholes/química , Bromuros/química , Bromuros/síntesis química , EstereoisomerismoRESUMEN
Herein we describe a novel stereoselective synthesis of cis-vinylstannanes employing the widely established Li/Te exchange pathway. In contrast to previously reported methods of cis-selective hydrostannation (i.e., ZrCl4), this method demonstrates compatibility toward oxygenated substrates.