RESUMO
Progress toward a convergent approach for the enantioselective synthesis of the Veratrum alkaloid jervine is presented. The two requisite fragments were stereoselectively and efficiently fashioned from economical and readily available reagents. Key reactions include (a) a highly diastereoselective Ireland-Claisen rearrangement to establish the necessary cis-relationship between the amine and methyl group on the tetrahydrofuran E-ring; (b) a diastereoselective selenoetherification reaction that enabled the assembly of the D/E oxaspiro[4.5]decene in the needed configuration; and (c) an enzymatic desymmetrization of an abundant achiral diol en route to a key four-carbon building block as a practical alternative to a protected Roche ester reduction.
Assuntos
Alcaloides de Veratrum/síntese química , Técnicas de Química Sintética/métodos , Ciclização , Estereoisomerismo , Alcaloides de Veratrum/químicaRESUMO
An efficient synthetic strategy for three natural seco-type cholestane alkaloids isolated from the Veratrum plants, based on commercially available naturally occurring and abundant (-)-diosgenin (1), as exemplified in the concise asymmetric synthesis of (-)-verazine (4), (-)-veramiline (5) (proposed structure), and its 22-epimer, (-)-oblonginine (6), is presented. This work highlights the application of a cascade ring-switching process of (-)-diosgenin to achieve the E-ring opening and construction of chiral six-membered lactone challenges in seco-type cholestane alkaloid synthesis. This approach enables the synthesis of related natural and nature-like novel cholestane alkaloids, opening up opportunities for more extensive exploration of cholestane alkaloid biology.
Assuntos
Alcaloides de Veratrum/síntese química , Conformação Molecular , Estereoisomerismo , Veratrum/química , Alcaloides de Veratrum/químicaRESUMO
The Hedgehog (Hh) signaling pathway plays a critical role in controlling patterning, growth and cell migration during embryonic development. Aberrant activation of Hh signaling has been linked to tumorigenesis in various cancers, such as basal cell carcinoma (BCC) and medulloblastoma. As a key member of the Hh pathway, the Smoothened (Smo) receptor, a member of the G protein-coupled receptor (GPCR) family, has emerged as an attractive therapeutic target for the treatment and prevention of human cancers. The recent determination of several crystal structures of Smo in complex with different antagonists offers the possibility to perform structure-based virtual screening for discovering potent Smo antagonists with distinct chemical scaffolds. In this study, based on the two Smo crystal complexes with the best capacity to distinguish the known Smo antagonists from decoys, the molecular docking-based virtual screening was conducted to identify promising Smo antagonists from ChemDiv library. A total of 21 structurally novel and diverse compounds were selected for experimental testing, and six of them exhibited significant inhibitory activity against the Hh pathway activation (IC50â¯<â¯10⯵M) in a GRE (Gli-responsive element) reporter gene assay. Specifically, the most potent compound (compound 20: 47â¯nM) showed comparable Hh signaling inhibition to vismodegib (46â¯nM). Compound 20 was further confirmed to be a potent Smo antagonist in a fluorescence based competitive binding assay. Optimization using substructure searching method led to the discovery of 12 analogues of compound 20 with decent Hh pathway inhibition activity, including four compounds with IC50 lower than 1⯵M. The important residues uncovered by binding free energy calculation (MM/GBSA) and binding free energy decomposition were highlighted and discussed. These findings suggest that the novel scaffold afforded by compound 20 can be used as a good starting point for further modification/optimization and the clarified interaction patterns may also guide us to find more potent Smo antagonists.
Assuntos
Compostos de Boro/farmacologia , Descoberta de Drogas , Corantes Fluorescentes/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Alcaloides de Veratrum/farmacologia , Animais , Compostos de Boro/síntese química , Compostos de Boro/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Células NIH 3T3 , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade , Alcaloides de Veratrum/síntese química , Alcaloides de Veratrum/químicaRESUMO
Organocatalyzed enantioselective allylation of 2-iodocyclohexenone followed by methylation and oxy-Cope rearrangement delivered enantiomerically enriched 2-methyl 3-allyl cyclohexanone, which engaged in acid-catalyzed Robinson annulation to give the bicyclic enone. Subsequent elaboration of the pendant allyl group into an α-diazo ß-keto ester set the stage for Rh-mediated cyclization to deliver the tricyclic A-B-C core of the Veratrum alkaloids.
Assuntos
Alcaloides de Veratrum/síntese química , Ciclização , Cicloexanonas/química , Estrutura Molecular , Alcaloides de Veratrum/químicaRESUMO
A practical approach to the synthesis of the A, B and C-ring subunit of cyclopamine has been developed. This synthetic tactic highlights the utility of mandelate acetal-mediated resolution of the fused ring ketone (±)-4 and IBX-mediated oxidation cascades from 12 to 9. The availability of advanced intermediates from enantiomerically pure (+)-4 and 2 could provide efficient access to biologically active and structurally diverse C-nor-D-homo-steroidal alkaloids such as cyclopamine.
Assuntos
Técnicas de Química Sintética/métodos , Alcaloides de Veratrum/síntese química , Estrutura Molecular , Fenômenos de Química Orgânica , Estereoisomerismo , Esteroides/química , Alcaloides de Veratrum/químicaRESUMO
A convenient and efficient one-pot synthesis of cyclopamine from peimisine is described. The key steps involve one-pot hydrazination and subsequent Bamford-Stevens reaction. The mild reaction conditions, high overall yield as well as an easy purification indicate this process can potentially be used for the scale-up preparation of cyclopamine.
Assuntos
Alcaloides/química , Fritillaria/química , Alcaloides de Veratrum/síntese química , Medicamentos de Ervas Chinesas/química , Alcaloides de Veratrum/químicaRESUMO
The Veratrum alkaloid cyclopamine, an inhibitor of cancer stem cell growth, was used as a representative scaffold to evaluate the inhibitory impact of glycosylation with a group of nonmetabolic saccharides, such as d-threose. In a five-step divergent process, a 32-member glycoside library was created and assayed to determine that glycosides of such sugars notably improved the GI50 value of cyclopamine while metabolic sugars, such as d-glucose, did not.
Assuntos
Glucose/química , Alcaloides de Veratrum/química , Glicosilação , Humanos , Estrutura Molecular , Tetroses/química , Alcaloides de Veratrum/síntese química , Alcaloides de Veratrum/farmacologiaRESUMO
A Veratrum piperidine chiron was prepared over 11 steps (7.9% yield) from (-)-citronellal. Three methods for the installation of the propargylic side chain onto a cyclic enamide are presented.
Assuntos
Caprilatos/síntese química , Piperidinas/química , Piperidinas/síntese química , Sulfonamidas/química , Alcaloides de Veratrum/química , Alcaloides de Veratrum/síntese química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
We prepared a new glucuronide prodrug of cyclopamine designed to target selectively the Hedgehog signalling pathway of cancer cells. This prodrug includes a novel self-immolative linker bearing a hydrophilic side chain that can be easily introduced via"click chemistry". With this design, the prodrug exhibits reduced toxicity compared to the free drug on U87 glioblastoma cells. However, in the presence of ß-glucuronidase, the prodrug conducts to the quick release of cyclopamine thereby restoring its antiproliferative activity.
Assuntos
Antineoplásicos/farmacologia , Glucuronídeos/farmacologia , Pró-Fármacos/farmacologia , Alcaloides de Veratrum/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Química Click , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glucuronídeos/síntese química , Glucuronídeos/química , Humanos , Cinética , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Transdução de Sinais , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Alcaloides de Veratrum/síntese química , Alcaloides de Veratrum/químicaRESUMO
The combination of theoretical and computational studies with organic synthesis and biological investigations has led to exo-cyclopamine. This stable and highly potent derivative of cyclopamine promises big potential as an experimental drug against several types of human cancer.
Assuntos
Proteínas Hedgehog/metabolismo , Transdução de Sinais/efeitos dos fármacos , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacologia , Animais , Desenho de Fármacos , Estabilidade de Medicamentos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Alcaloides de Veratrum/síntese químicaRESUMO
All four diastereomers of the trisubstituted piperidine-alkaloids of the veratramine and jervine type were synthesized with complete stereocontrol starting from enantiopure citronellic acids. The flexible, high-yielding, and scalable route described here will facilitate convergent syntheses and give access to analogues of cyclopamine and other biologically active and diverse steroid alkaloids.
Assuntos
Produtos Biológicos/síntese química , Piperidinas/síntese química , Alcaloides de Veratrum/síntese química , Produtos Biológicos/química , Catálise , Estrutura Molecular , Piperidinas/química , Estereoisomerismo , Alcaloides de Veratrum/químicaAssuntos
Antineoplásicos/síntese química , Biomimética/métodos , Alcaloides de Veratrum/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacologiaRESUMO
The synthesis and biological evaluation of structurally simplified, metabolically stable cyclopamine-like Sonic Hedgehog (SHH) signaling inhibitors, i.e., 5, is described in four chemical steps from commercially available steroidal precursors. Biological evaluation of this cyclopamine analogue in two different systems establishes the high potency of 5 as a SHH signaling inhibitor. This approach provides important new lead structures for the development of new cancer chemotherapeutic agents based on the inhibition on SHH signaling.
Assuntos
Desenho de Fármacos , Proteínas Hedgehog/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Alcaloides de Veratrum/síntese química , Estrona/análogos & derivados , Estrona/síntese química , Estrona/química , Estrona/farmacologia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacologiaRESUMO
Herein is reported the synthesis of a novel class of hedgehog antagonists derived from cyclopamine. The acid sensitive D-ring of cyclopamine was homologated utilizing a sequence of chemoselective cyclopropanation and stereoselective acid-catalyzed rearrangement. Further modification of the A/B-ring homoallylic alcohol to the conjugated ketone led to the discovery of new cyclopamine analogues with improved pharmaceutical properties and in vitro potency (EC 50) ranging from 10 to 1000 nM.
Assuntos
Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Transdução de Sinais/efeitos dos fármacos , Alcaloides de Veratrum/síntese química , Administração Oral , Estrutura Molecular , Relação Estrutura-Atividade , Alcaloides de Veratrum/administração & dosagem , Alcaloides de Veratrum/químicaRESUMO
A diversity-oriented synthesis has been developed for facile construction of a library of carbohydrate-cyclopamine conjugates. The synthetic protocol is suitable for generating cyclopamine derivatives with various structural motifs for exploring the desired activity. From this initial library, we have observed one derivative that exhibits improved activity against lung cancer cell as compared to cyclopamine.