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1.
Eur J Med Chem ; 185: 111806, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31677446

RESUMO

In this work, 35 new derivatives of betulonic, dihydrobetulonic and ursonic acid were prepared including 30 aminothiazoles and all of them were tested for their in vitro cytotoxic activity in eight cancer cell lines and two non-cancer fibroblasts. Compounds with the IC50 below 5 µM in CCRF-CEM cells and low toxicity in non-cancer fibroblasts (4m, 5c, 5m, 6c, 6m, 7b, and 7c) were further subjected to tests of pharmacological parameters yielding the final set for advanced biological evaluation (4m, 5m, 6m, and 7b). It was proved by several methods, that all of them trigger apoptosis via the intrinsic pathway and derivatives 5m and 7b are the most effective (IC50 2.4 µM and 3.6 µM). They are the best candidates to become potentially new anticancer drugs and will be subjected to in vivo tests in mice. In addition, compounds 6b and 6c deserve more attention because their activity is not limited only to chemosensitive CCRF-CEM cell line. Specifically, compound 6b is highly active against K562 leukemic cell line (0.7 µM) and its IC50 activity in colon cancer HCT116 cell line is 1.0 µM. Compound 6c is active in both normal K562 and resistant K562-TAX cell lines (IC50 3.4 µM and 5.4 µM) and both colon cancer cell lines (HCT116 and HCT116p53-/-, IC50 3.5 µM and 3.4 µM).


Assuntos
Antineoplásicos/farmacologia , Ácido Oleanólico/análogos & derivados , Terpenos/farmacologia , Tiazóis/farmacologia , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microssomos/química , Microssomos/metabolismo , Estrutura Molecular , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Relação Estrutura-Atividade , Terpenos/síntese química , Terpenos/química , Tiazóis/síntese química , Tiazóis/química , Triterpenos/química
2.
J Enzyme Inhib Med Chem ; 35(1): 152-164, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31742469

RESUMO

Overexpression of protein tyrosine phosphatase 1B (PTP1B) induces insulin resistance in various basic and clinical research. In our previous work, a synthetic oleanolic acid (OA) derivative C10a with PTP1B inhibitory activity has been reported. However, C10a has some pharmacological defects and cytotoxicity. Herein, a structure-based drug design approach was used based on the structure of C10a to elaborate the smaller tricyclic core. A series of tricyclic derivatives were synthesised and the compounds 15, 28 and 34 exhibited the most PTP1B enzymatic inhibitory potency. In the insulin-resistant human hepatoma HepG2 cells, compound 25 with the moderate PTP1B inhibition and preferable pharmaceutical properties can significantly increase insulin-stimulated glucose uptake and showed the insulin resistance ameliorating effect. Moreover, 25 showed the improved in vivo antihyperglycaemic potential in the nicotinamide-streptozotocin-induced T2D. Our study demonstrated that these tricyclic derivatives with improved molecular architectures and antihyperglycaemic activity could be developed in the treatment of T2D.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Terpenos/farmacologia , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células Hep G2 , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Relação Estrutura-Atividade , Terpenos/síntese química , Terpenos/química
3.
Am J Chin Med ; 47(6): 1193-1221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31488038

RESUMO

Veronica is the largest genus in the flowering plant family Plantaginaceae and comprises approximately 500 species. The genus was formerly placed in the Scrophulariaceae family, some species of which have been used in traditional medicine for the treatment of influenza, respiratory diseases, hemoptysis, laryngopharyngitis, cough, hernia, cancer, edema, and wounds. This review comprehensively summarizes the current information on the traditional uses, phytochemistry, and pharmacology of the genus Veronica on the basis of articles published from 1970 to 2018. More than 260 compounds have been isolated, and chemotaxonomic investigations of Veronica have revealed that iridoid glucosides - including aucubin, catalpol, and 6-O-catalpol derivatives - are characteristic of this genus. Modern pharmacological studies and clinical practice have demonstrated that extracts or monomeric compounds from Veronica have several pharmacological actions, such as anti-inflammatory, anti-oxidative, anticancer, antibacterial, anti-angiogenic, antineurodegenerative, neuroprotective, and hepatoprotective effects both in vivo and in vitro.


Assuntos
Glucosídeos Iridoides/isolamento & purificação , Glucosídeos Iridoides/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Veronica/química , Inibidores da Angiogênese , Animais , Antibacterianos , Anti-Inflamatórios , Antineoplásicos Fitogênicos , Antioxidantes , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Humanos , Glucosídeos Iridoides/química , Medicina Tradicional , Conformação Molecular , Fármacos Neuroprotetores , Fitoterapia , Terpenos/síntese química , Terpenos/isolamento & purificação , Terpenos/farmacologia
4.
Molecules ; 24(11)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31195609

RESUMO

Recently, the methylene-cycloakylacetate (MCA) scaffold has been reported as a potential pharmacophore for neurite outgrowth activity. In this work, natural diterpenes that embed MCA fragments are reviewed, as they are major components of Halimium viscosum: ent-halimic acid, the prototype for these bioactive compounds. Herein, structures, sources, and activities for the natural diterpenes, as well as their synthetic derivatives of interest, are reviewed.


Assuntos
Acetatos/química , Acetatos/farmacologia , Terpenos/química , Terpenos/farmacologia , Alcaloides Diterpenos/química , Diterpenos/síntese química , Diterpenos/química , Diterpenos/farmacologia , Glicerol/química , Sesquiterpenos/química , Terpenos/síntese química
5.
Nat Commun ; 10(1): 2448, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164645

RESUMO

Natural product and natural product-like molecules continue to be important for the development of pharmaceutical agents, as molecules in this class play a vital role in the pipeline for new therapeutics. Among these, tetracyclic terpenoids are privileged, with >100 being FDA-approved drugs. Despite this significant pharmaceutical success, there remain considerable limitations to broad medicinal exploitation of the class due to lingering scientific challenges associated with compound availability. Here, we report a concise asymmetric route to forging natural and unnatural (enantiomeric) C19 and C20 tetracyclic terpenoid skeletons suitable to drive medicinal exploration. While efforts have been focused on establishing the chemical science, early investigations reveal that the emerging chemical technology can deliver compositions of matter that are potent and selective agonists of the estrogen receptor beta, and that are selectively cytotoxic in two different glioblastoma cell lines (U251 and U87).


Assuntos
Neoplasias Encefálicas , Receptor beta de Estrogênio/agonistas , Glioblastoma , Terpenos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenvolvimento de Medicamentos , Humanos , Células-Tronco Neurais/efeitos dos fármacos , Estereoisomerismo , Terpenos/farmacologia
6.
Nature ; 569(7758): 703-707, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31022719

RESUMO

The presence of a quaternary centre-a carbon with four other carbons bonded to it-in any given molecule can have a substantial chemical and biological impact. In many cases, it can enable otherwise challenging chemistry. For example, quaternary centres induce large rate enhancements in cyclization reactions-known as the Thorpe-Ingold effect-which has application in drug delivery for molecules with modest bioavailability1. Similarly, the addition of quaternary centres to a drug candidate can enhance both its activity and its metabolic stability2. When present in chiral ligands3, catalysts4 and auxiliaries5, quaternary centres can guide reactions toward both improved and unique regio-, stereo- and/or enantioselectivity. However, owing to their distinct steric congestion and conformational restriction, the formation of quaternary centres can be achieved reliably by only a few chemical transformations6,7. For particularly challenging cases-for example, the vicinal all-carbon8, oxa- and aza-quaternary centres9 in molecules such as azadirachtin10,11, scopadulcic acid A12,13 and acutumine14-the development of target-specific approaches as well as multiple functional-group and redox manipulations is often necessary. It is therefore desirable to establish alternative ways in which quaternary centres can positively affect and guide synthetic planning. Here we show that if a synthesis is designed such that each quaternary centre is deliberately leveraged to simplify the construction of the next-either through rate acceleration or blocking effects-then highly efficient, scalable and modular syntheses can result. This approach is illustrated using the conidiogenone family of terpenes as a representative case; however, this framework provides a distinct planning logic that is applicable to other targets of similar synthetic complexity that contain multiple quaternary centres.


Assuntos
Técnicas de Química Sintética , Terpenos/química , Terpenos/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise , Diterpenos/síntese química , Diterpenos/química , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química
7.
Z Naturforsch C J Biosci ; 74(3-4): 63-70, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30645192

RESUMO

Biocatalysis has developed enormously in the last decade and now offers solutions for the sustainable production of chiral and highly functionalised asset molecules. Products generated by enzymatic transformations are already being used in the food, feed, chemical, pharmaceutical and cosmetic industry, and the accessible compound panoply is expected to expand even further. In particular, the combination of stereo-selective enzymes in linear cascade reactions is an elegant strategy toward enantiomeric pure compounds, as it reduces the number of isolation and purification steps and avoids accumulation of potentially unstable intermediates. Here, we present the set-up of an enzyme cascade to selectively convert citral to (-)-iso-isopulegol by combining an ene reductase and a squalene hopene cyclase. In the initial reaction step, the ene reductase YqjM from Bacillus subtilis selectively transforms citral to (S)-citronellal, which is subsequently cyclised exclusively to (-)-iso-isopulegol by a mutant of the squalene hopene cyclase from Alicyclobacillus acidocaldarius (AacSHC). With this approach, we can convert citral to an enantiopure precursor for isomenthol derivatives.


Assuntos
Alicyclobacillus/enzimologia , Bacillus subtilis/enzimologia , Proteínas de Bactérias/genética , FMN Redutase/genética , Transferases Intramoleculares/genética , Terpenos/síntese química , Aldeídos/química , Aldeídos/metabolismo , Alicyclobacillus/genética , Bacillus subtilis/genética , Proteínas de Bactérias/metabolismo , Biocatálise , Clonagem Molecular , Ciclização , Escherichia coli/enzimologia , Escherichia coli/genética , FMN Redutase/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Microbiologia Industrial/métodos , Transferases Intramoleculares/metabolismo , Cinética , Monoterpenos/síntese química , Monoterpenos/química , Monoterpenos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Terpenos/metabolismo
8.
Nat Prod Rep ; 36(2): 263-288, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30215657

RESUMO

Covering: January 2012 to January 2018 Sesterterpenoids are a small family of terpenes that often possess intriguing biological profiles and complicated chemical structures. Their total syntheses are usually remarkably challenging, requiring methodological and strategic innovation. In this review, we summarize and discuss the total syntheses of sesterterpenoids published during the coverage period, and the key chemical transformations are highlighted.


Assuntos
Terpenos/síntese química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/síntese química , Compostos Bicíclicos com Pontes/síntese química , Estrutura Molecular , Sesquiterpenos/síntese química , Sesterterpenos/síntese química
9.
Molecules ; 24(1)2018 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-30586854

RESUMO

In the present study, we developed a green epoxidation approach for the synthesis of the diastereomers of (-)-isopulegol benzyl ether epoxide using molecular oxygen as the oxidant and a hybrid manganese(III)-porphyrin magnetic reusable nanocomposite as the catalyst. High activity, selectivity, and stability were obtained, with up to four recycling cycles without the loss of activity and selectivity for epoxide. The anticancer effect of the newly synthesized isopulegol epoxide diastereomers was evaluated on a human osteosarcoma cell line (MG-63); both diastereomers showed similar in vitro potency. The measured IC50 values were significantly lower than those reported for other monoterpene analogues, rendering these epoxide isomers as promising anti-tumor agents against low prognosis osteosarcoma.


Assuntos
Antineoplásicos/farmacologia , Biomimética , Fenômenos Magnéticos , Metaloporfirinas/química , Nanocompostos/química , Osteossarcoma/patologia , Antineoplásicos/síntese química , Antineoplásicos/química , Varredura Diferencial de Calorimetria , Catálise , Linhagem Celular Tumoral , Compostos de Epóxi/síntese química , Compostos de Epóxi/química , Humanos , Manganês/química , Nanocompostos/ultraestrutura , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo , Terpenos/síntese química , Terpenos/química , Terpenos/farmacologia , Termogravimetria
10.
Nat Chem Biol ; 14(12): 1090-1098, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30429605

RESUMO

One application of synthetic biology is the redesign of existing biological systems to acquire new functions. In this context, expanding the chemical code underlying key biosynthetic pathways will lead to the synthesis of compounds with new structures and potentially new biological activities. Terpenoids are a large group of specialized metabolites with numerous applications. Yet, being synthesized from five-carbon units, they are restricted to distinct classes that differ by five carbon atoms (C10, C15, C20, etc.). To expand the diversity of terpenoid structures, we engineered yeast cells to synthesize a noncanonical building block with 11 carbons, and produced 40 C11 terpene scaffolds that can form the basis for an entire terpenoid class. By identifying a single-residue switch that converts C10 plant monoterpene synthases to C11-specific enzymes, we engineered dedicated synthases for C11 terpene production. This approach will enable the systematic expansion of the chemical space accessed by terpenoids.


Assuntos
Alquil e Aril Transferases/genética , Engenharia Metabólica/métodos , Saccharomyces cerevisiae/metabolismo , Terpenos/síntese química , Alquil e Aril Transferases/metabolismo , Cianobactérias/enzimologia , Cianobactérias/genética , Difosfatos/metabolismo , Diterpenos/metabolismo , Engenharia de Proteínas/métodos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/genética , Biologia Sintética/métodos , Terpenos/metabolismo
11.
Int J Mol Sci ; 19(11)2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30413128

RESUMO

A library of isopulegol-based ß-amino acid derivatives has been developed from commercially-available (-)-isopulegol. Michael addition of primary and secondary amines towards α,ß-unsaturated γ-lactones was accomplished resulting in ß-aminolactones in highly-stereoselective reactions. Ring-opening of ß-aminolactones with different amines furnished excellent yields of ß-aminoamides. Moreover, the applicability of aminolactones in peptide synthesis was examined by opening the lactone ring with α- and ß-aminoesters, providing dipeptides as promising chiral substrates for the synthesis of foldamers. The antiproliferative activities of ß-aminolactones and ß-aminoamides were explored, and the structure-activity relationships were studied from the aspects of the stereochemistry of the monoterpene ring and the substituent effects on the ß-aminoamide ring system. The N-unsubstituted (-)-isopulegol-based ß-aminoamides exhibited considerable antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF7 and MDA-MB-231).


Assuntos
Lactonas/química , Neoplasias/tratamento farmacológico , Terpenos/química , Amidas/química , Proliferação de Células/efeitos dos fármacos , Células HeLa , Humanos , Lactonas/síntese química , Lactonas/farmacologia , Peptídeos/síntese química , Peptídeos/química , Estereoisomerismo , Relação Estrutura-Atividade , Terpenos/síntese química , Terpenos/farmacologia
12.
J Am Chem Soc ; 140(40): 12770-12774, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30261724

RESUMO

A short, enantioselective synthesis of (-)-nodulisporic acid C is described. The route features two highly diastereoselective polycyclizations en route to the terpenoid core and the indenopyran fragment and a highly convergent assembly of a challenging indole moiety. Application of this chemistry allows for a 12-step synthesis of the target indoloterpenoid from commercially available material.


Assuntos
Indóis/síntese química , Técnicas de Química Combinatória/métodos , Ciclização , Reação de Cicloadição/métodos , Indóis/química , Estereoisomerismo , Terpenos/síntese química , Terpenos/química
13.
J Nat Prod ; 81(9): 2010-2017, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30207477

RESUMO

The efficient synthesis and antifungal exploration of (+)-yahazunol and related natural products are described. Central to this strategy is the Barton decarboxylative coupling, comprising a one-pot radical decarboxylation and quinone addition cascade. The scalable synthesis of (+)-yahazunol was accomplished in five longest linear sequences (LLS) starting from commercially available and inexpensive (-)-sclareol. The divergent translational potential of (+)-yahazunol was demonstrated by the expedient preparation of (-)-zonarone, (-)-isozonarone, (-)-zonarol, (-)-isozonarol, (+)-chromazonarol, and (+)-yahazunone. This approach also enables the formal synthesis of puupehenol, puupehedione, and hongoquercin A. Antifungal evaluation was performed, and this represents the first biological profiles for (+)-yahazunone, (+)-8- O-acetylyahazunone, and (+)-8- O-acetylyahazunol. (+)-Chromazonarol and (+)-yahazunone are promising candidates against Sclerotinia scleotiorum, with EC50 values of 24.1 and 28.7 µM, respectively, demonstrating advantages over the original model (DM) and synthesized heterocyclic mimic (3a) of meroterpenoids. This will favor the establishment of a chemical repertoire in the management of different plant diseases.


Assuntos
Antifúngicos/síntese química , Terpenos/síntese química , Antifúngicos/farmacologia , Terpenos/farmacologia
14.
J Org Chem ; 83(18): 11323-11326, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-29969566

RESUMO

An operationally simple protocol for the conversion of geranyl acetate to 8-hydroxygeraniol is reported. The convenient two-step procedure relies on an efficient, chemo- and regioselective SeO2-promoted oxidation, followed by straightforward deacetylation. This facile means to prepare 8-hydroxygeraniol is expected to enable biosynthetic studies pertaining to thousands of monoterpene indole alkaloids.


Assuntos
Terpenos/química , Terpenos/síntese química , Técnicas de Química Sintética , Estereoisomerismo
15.
J Org Chem ; 83(15): 8716-8723, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-29869493

RESUMO

An iodine-promoted sunlight-induced olefin Z/ E isomerization reaction together with a palladium-catalyzed direct cross-coupling reaction of a drimanal hydrazone and an iodobenzaldehyde, without touching the aromatic aldehyde group, facilitated a divergent and expeditious access to bioactive marine natural products siphonodictyal B, corallidictyals C/D, and liphagal based on the early presence of an aldehyde group instead of a late-stage introduction.


Assuntos
Aldeídos/química , Hidroquinonas/química , Hidroquinonas/síntese química , Sesquiterpenos/química , Sesquiterpenos/síntese química , Terpenos/química , Terpenos/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise , Técnicas de Química Sintética , Paládio/química , Estereoisomerismo
16.
Molecules ; 23(6)2018 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-29865273

RESUMO

Naturally occurring terpenes were combined by click reactions to generate sixteen hybrid molecules. The diterpene imbricatolic acid (IA) containing an azide group was used as starting compound for the synthesis of all the derivatives. The alkyne group in the terpenes cyperenoic acid, dehydroabietinol, carnosic acid γ-lactone, ferruginol, oleanolic acid and aleuritolic acid was obtained by esterification using appropriate alcohols or acids. The hybrid compounds were prepared by combining the IA azide function with the different terpene-alkynes under click chemistry conditions. The cytotoxic activity of the terpene hybrids 1⁻16 was assessed against Vero cells and tumour cell lines (HEP-2, C6 and Raw 264.7). Compounds 1, 2, 3 and 7 showed cytotoxic activity against the tested cell lines. The antiviral activity of the compounds was evaluated against HSV-1 KOS, Field and B2006 strain. For the pairs of hybrid compounds formed between IA-diterpene (compounds 3⁻8, except for compound 7), a moderate activity was observed against the three HSV-1 strains with an interesting selectivity index (SI ≥10, SI = CC50/CE50) for some compounds.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Química Click , Terpenos/síntese química , Terpenos/farmacologia , Animais , Antineoplásicos/química , Antivirais/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Herpesvirus Humano 1/efeitos dos fármacos , Humanos , Camundongos , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7 , Espectrometria de Massas por Ionização por Electrospray , Terpenos/química
17.
J Org Chem ; 83(11): 6066-6085, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29728045

RESUMO

(+)-Psiguadial B is a diformyl phloroglucinol meroterpenoid that exhibits antiproliferative activity against the HepG2 human hepatoma cancer cell line. This full account details the evolution of a strategy that culminated in the first enantioselective total synthesis of (+)-psiguadial B. A key feature of the synthesis is the construction of the trans-cyclobutane motif by a Wolff rearrangement with in situ catalytic, asymmetric trapping of the ketene. An investigation of the substrate scope of this method to prepare enantioenriched 8-aminoquinolinamides is disclosed. Three routes toward (+)-psiguadial B were evaluated that featured the following key steps: (1) an ortho-quinone methide hetero-Diels-Alder cycloaddition to prepare the chroman framework, (2) a Prins cyclization to form the bridging bicyclo[4.3.1]decane system, and (3) a modified Norrish-Yang cyclization to generate the chroman. Ultimately, the successful strategy employed a ring-closing metathesis to form the seven-membered ring and an intramolecular O-arylation reaction to complete the polycyclic framework of the natural product.


Assuntos
Produtos Biológicos/síntese química , Terpenos/síntese química , Catálise , Cromanos/síntese química , Ciclização , Reação de Cicloadição , Ciclobutanos/química , Indolquinonas/química , Estrutura Molecular , Floroglucinol/química , Estereoisomerismo
18.
Bioorg Med Chem Lett ; 28(11): 2061-2067, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29716780

RESUMO

A set of (-)-isopulegol derived octahydro-2H-chromen-4-ols was synthesized and evaluated in vitro for antiviral activity against panel of reference influenza virus strains differing in subtype, origin (human or avian) and drug resistance. Compound (4R)-11a produced via one-pot synthesis by interaction between (-)-isopulegol and acetone was found to exhibit an outstanding activity against a number of H1N1 and H2N2 influenza virus strains with selectivity index more than 1500. (4R)-11a was shown to be most potent at early stages of viral cycle. Good correlation between anti-viral activity and calculated binding energy to hemagglutinin TBHQ active site was demonstrated.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Terpenos/farmacologia , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Terpenos/síntese química , Terpenos/química
19.
J Am Chem Soc ; 140(20): 6483-6492, 2018 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-29694031

RESUMO

The akuammiline alkaloids are a structurally diverse class of bioactive natural products isolated from plants found in various parts of the world. A particularly challenging subset of akuammiline alkaloids are those that contain a methanoquinolizidine core. We describe a synthetic approach to these compounds that has enabled the first total syntheses of (+)-strictamine, (-)-2( S)-cathafoline, (+)-akuammiline, and (-)-Ψ-akuammigine. Our strategy relies on the development of the reductive interrupted Fischer indolization reaction to construct a common pentacyclic intermediate bearing five contiguous stereocenters, in addition to late-stage formation of the methanoquinolizidine framework using a deprotection-cyclization cascade. The total syntheses of (-)-Ψ-akuammigine and (+)-akuammiline mark the first preparations of akuammiline alkaloids containing both a methanoquinolizidine core and vicinal quaternary centers. Lastly, we describe the bioinspired reductive rearrangements of (+)-strictamine and (+)-akuammiline to ultimately provide (-)-10-demethoxyvincorine and a new analogue thereof.


Assuntos
Alcaloides/síntese química , Produtos Biológicos/síntese química , Quinolizidinas/síntese química , Alcaloides de Triptamina e Secologanina/síntese química , Terpenos/síntese química , Alcaloides/química , Produtos Biológicos/química , Técnicas de Química Sintética , Ciclização , Modelos Moleculares , Plantas/química , Quinolizidinas/química , Alcaloides de Triptamina e Secologanina/química , Estereoisomerismo , Terpenos/química
20.
J Med Chem ; 61(8): 3609-3625, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29634260

RESUMO

It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor (( R, E)-5-(4-( tert-butyl)phenyl)-3-(4,8-dimethylnona-3,7-dien-1-yl)furan-2(5 H)-one, 7d) with improved chemical stability and long-term safety was obtained. Compound 7d showed multiple and strong in vivo efficacies in reducing weight gain, lowering HbAlc level, and improving insulin resistance and lipid dysfunction in both ob/ob and diet-induced obesity (DIO) mice models. Compound 7d was also found to reduce hepatic steatosis in ob/ob model. 16S rRNA gene sequencing, SCFA, and intestinal mucosal barrier function analysis indicated that gut microbiota plays a central and causative role in mediating the multiple efficacies of 7d. Our results demonstrate that 7d is a promising drug candidate for metabolic syndrome.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Terpenos/uso terapêutico , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/toxicidade , Estabilidade de Medicamentos , Fígado Gorduroso/tratamento farmacológico , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacocinética , Inibidores de Glicosídeo Hidrolases/toxicidade , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Lactonas/síntese química , Lactonas/farmacocinética , Lactonas/uso terapêutico , Lactonas/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Ratos Sprague-Dawley , Suínos , Terpenos/síntese química , Terpenos/farmacocinética , Terpenos/toxicidade , alfa-Glucosidases/metabolismo
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