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1.
Molecules ; 26(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804175

RESUMO

The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as well as their potential activation of p53. Twelve aminocarbazole alkaloids were semi-synthesized from heptaphylline (1), 7-methoxy heptaphylline (2), and 7-methoxymukonal (3), isolated from Clausena harmandiana, using a reductive amination protocol. Naturally-occurring carbazoles 1-3 and their amino derivatives were evaluated for their potential effect on wild-type and mutant p53 activity using a yeast screening assay and on human tumor cell lines. Naturally-occurring carbazoles 1-3 showed the most potent growth inhibitory effects on wild-type p53-expressing cells, being heptaphylline (1) the most promising in all the investigated cell lines. However, compound 1 also showed growth inhibition against non-tumor cells. Conversely, semi-synthetic aminocarbazole 1d showed an interesting growth inhibitory activity in tumor cells expressing both wild-type and mutant p53, exhibiting low growth inhibition on non-tumor cells. The yeast assay showed a potential reactivation of mutant p53 by heptaphylline derivatives, including compound 1d. The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carbazóis/síntese química , Carbazóis/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Alcaloides/síntese química , Alcaloides/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Clausena/química , Células HCT116 , Células HT29 , Humanos , Mutação/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
2.
Eur J Med Chem ; 213: 113165, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33454546

RESUMO

Inflammation is an adaptive response of the immune system to tissue malfunction or homeostatic imbalance. Corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently applied to treat varieties of inflammatory diseases but are associated with gastrointestinal, cardiovascular, and kidney side effects. Developing more effective and less toxic agents remain a challenge for pharmaceutical chemist due to the complexity of the different inflammatory processes. Alkaloids are widely distributed in plants with diverse anti-inflammatory activities, providing various potential lead compounds or candidates for the design and discovery of new anti-inflammatory drug candidates. Therefore, re-examining the anti-inflammatory alkaloid natural products is advisable, bringing more opportunities. In this review, we summarized and described the recent advances of natural alkaloids with anti-inflammatory activities and possible mechanisms in the period from 2009 to 2020. It is hoped that this review of anti-inflammatory alkaloids can provide new ideas for researchers engaged in the related fields and potential lead compounds for the discovery of anti-inflammatory drugs.


Assuntos
Alcaloides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Produtos Biológicos/uso terapêutico , Descoberta de Drogas , Inflamação/tratamento farmacológico , Alcaloides/síntese química , Alcaloides/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Humanos , Estrutura Molecular
3.
Molecules ; 26(2)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467493

RESUMO

A synthetic route for the enantioselective construction of the tetracyclic spiro[indolizidine-1,3'-oxindole] framework present in a large number of oxindole alkaloids, with a cis H-3/H-15 stereochemistry, a functionalized two-carbon substituent at C-15, and an E-ethylidene substituent at C-20, is reported. The key steps of the synthesis are the generation of the tetracyclic spirooxindole ring system by stereoselective spirocyclization from a tryptophanol-derived oxazolopiperidone lactam, the removal of the hydroxymethyl group, and the stereoselective introduction of the E-ethylidene substituent by acetylation at the α-position of the lactam carbonyl, followed by hydride reduction and elimination. Following this route, the 21-oxo derivative of the enantiomer of the alkaloid 7(S)-geissoschizol oxindole has been prepared.


Assuntos
Alcaloides/síntese química , Oxindóis/síntese química , Compostos de Espiro/síntese química , Alcaloides/química , Ciclização , Modelos Moleculares , Estrutura Molecular , Oxindóis/química , Compostos de Espiro/química , Estereoisomerismo
4.
Eur J Med Chem ; 210: 113048, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33316690

RESUMO

Invasive candidiasis, such as intra-abdominal candidiasis (IAC), is a significant cause of morbidity and mortality worldwide. IAC is still poorly understood, and its treatment represents a challenge for public health. In this study, we showed the in vitro anti-Candida activity of four alkaloid synthetic derivatives and their antifungal potential in a murine model of IAC. The biological effects of alkaloids were evaluated against Candida spp. through the determination of the minimum inhibitory concentration (MIC). For the alkaloids that showed antifungal activity, the fungicidal concentration, time-kill curve, synergism with azoles and polyenes, phenotypic effects, and the effect against virulence factors were also determined. The most active alkaloids were selected for in vivo assays. The compounds 6a and 6b were active against C. albicans, C. glabrata, and C. tropicalis (MIC 7.8 µg/mL) and showed promising antifungal activity against C. krusei (MIC 3.9 µg/mL). The compound 6a presented a potent fungicidal effect in vitro, eliminating the yeast C. albicans after 8 h of incubation at MIC. An important in vitro synergistic effect with ketoconazole was observed for these two alkaloids. They also induced the lysis of fungal cells by binding to the ergosterol of the membrane. Besides that, 6a and 6b were able to reduce yeast-to-hyphal transition in C. albicans, as well as inhibit the biofilm formation of this pathogen. In the in vivo assay, the compound 6a did not show acute toxicity and was mainly absorbed by the liver, spleen, and lung after a parenteral administration. Also, this analogue significantly reduced the fungal load of C. albicans on the kidney and spleen of animals with IAC. Therefore, these results showed that the compound 6a is a potent anti-Candida agent in vitro and in vivo.


Assuntos
Alcaloides/farmacologia , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Desenho de Fármacos , Fungicidas Industriais/farmacologia , Alcaloides/síntese química , Alcaloides/química , Antifúngicos/síntese química , Antifúngicos/química , Relação Dose-Resposta a Droga , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 210: 113092, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333398

RESUMO

Marine natural products are known for their diverse chemical structures and extensive bioactivities. Renieramycins, the member of tetrahydroisoquinoline family of marine natural products, arouse interests because of their strong antitumor activities and similar structures to the first marine antitumor agent ecteinascidin-743, approved by the European Union. According to the literatures, researches on the pharmacological activities of renieramycins mainly focus on their antitumor activities. In addition, by structural modification, derivatives of renieramycins show stronger antiproliferative activity and less accidental necrosis activity on cells. Nevertheless, the difficulties in extraction and separation hinder their further development. Hence, the synthetic chemistry work of renieramycins plays a key role in their further development. In this review, currently reported researches on the synthetic chemistry, pharmacological activities and structural modification of renieramycins are summarized, which will benefit future drug development and innovation.


Assuntos
Alcaloides/farmacologia , Anti-Infecciosos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Produtos Biológicos/farmacologia , Neoplasias/tratamento farmacológico , Tetra-Hidroisoquinolinas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Estrutura Molecular , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química
6.
Nat Commun ; 11(1): 5314, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082332

RESUMO

The powerful insecticidal and multi-drug-resistance-reversing activities displayed by the stemofoline group of alkaloids render them promising lead structures for further development as commercial agents in agriculture and medicine. However, concise, enantioselective total syntheses of stemofoline alkaloids remain a formidable challenge due to their structural complexity. We disclose herein the enantioselective total syntheses of four stemofoline alkaloids, including (+)-stemofoline, (+)-isostemofoline, (+)-stemoburkilline, and (+)-(11S,12R)-dihydrostemofoline, in just 19 steps. Our strategy relies on a biogenetic hypothesis, which postulates that stemoburkilline and dihydrostemofolines are biogenetic precursors of stemofoline and isostemofoline. Other highlights of our approach are the use of Horner-Wadsworth-Emmons reaction to connect the two segments of the molecule, an improved protocol allowing gram-scale access to the tetracyclic cage-type core, and a Cu-catalyzed direct and versatile nucleophilic alkylation reaction on an anti-Bredt iminium ion. The synthetic techniques that we developed could also be extended to the preparation of other Stemona alkaloids.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Inseticidas/síntese química , Stemonaceae/química , Alcaloides/síntese química , Alcaloides/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Inseticidas/química , Estrutura Molecular , Extratos Vegetais/síntese química , Extratos Vegetais/química , Estereoisomerismo
7.
Nat Commun ; 11(1): 3538, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669587

RESUMO

Ever since Hirata's report of yuzurimine in 1966, nearly fifty yuzurimine-type alkaloids have been isolated, which formed the largest subfamily of the Daphniphyllum alkaloids. Despite extensive synthetic studies towards this synthetically challenging and biologically intriguing family, no total synthesis of any yuzurimine-type alkaloids has been achieved to date. Here, the first enantioselective total synthesis of (+)-caldaphnidine J, a highly complex yuzurimine-type Daphniphyllum alkaloid, is described. Key transformations of this approach include a highly regioselective Pd-catalyzed hydroformylation, a samarium(II)-mediated pinacol coupling, and a one-pot Swern oxidation/ketene dithioacetal Prins reaction. Our approach paves the way for the synthesis of other yuzurimine-type alkaloids and related natural products.


Assuntos
Alcaloides/síntese química , Daphniphyllum/química , Produtos Biológicos , Catálise , Desenho de Fármacos , Etilenos/química , Cetonas/química , Espectroscopia de Ressonância Magnética , Modelos Químicos , Estrutura Molecular , Oxirredução , Oxigênio/química , Samário/química , Estereoisomerismo
8.
J Chromatogr A ; 1625: 461286, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32709336

RESUMO

In the past two decades, supercritical fluid chromatography has evolved from a niche application to a comprehensive technology and a fully-fledged alternative to conventional high-performance liquid chromatography. In this study, we have focused on chiral separation of synthetic cathinones in gradient supercritical fluid chromatography coupled to mass spectrometry using an inverse gradient of a make-up solvent. Synthetic cathinones possess an amphetamine-like effect and, therefore, are frequently being offered on the Internet as a replacement for illicit drugs. Cathinones are chiral compounds, however, they are usually marketed and used as racemic mixtures. Since the effect of individual enantiomers can significantly vary, there is a need for the development of enantioseparation methods enabling to study the biological effects of individual enantiomers. Since cathinones are basic molecules, they are easily protonated (positively charged) under weakly acidic mobile phase conditions, which is a typical feature of supercritical mobile phases with an alcohol as an organic modifier. The positively charged species represent ideal analytes for ion exchangers, such as chiral zwitterion ion exchangers Chiralpak ZWIX (+) and Chiralpak ZWIX (-), which possess a positively and negatively charged unit in the molecular structure of the selectors. The presence of the positive charge in the selector's structure, functioning as a counter-ion for the positively charged analytes, significantly reduces the required amount of a buffer, which is plausible for hyphenation of such a separation system with mass spectrometry. For mass spectrometry hyphenated to supercritical fluid chromatography, the use of a make-up solvent is required to avoid analyte precipitation when using a low concentration of an organic co-solvent (modifier) in the super-/subcritical mobile phase. Hereby, we introduce a unique approach, which is based on the gradient introduction of the make-up to the post-column effluent. Using this approach, it is possible to keep constant the overall amount of the organic solvent (modifier and make-up) introduced into the mass spectrometer when using a gradient of the organic modifier. We show that the developed gradient elution method facilitates the chiral separation of all employed analytes, while the mobile-phase gradient compensation by the inverse make-up gradient enables their detection with high signal intensities.


Assuntos
Alcaloides/química , Alcaloides/isolamento & purificação , Cromatografia com Fluido Supercrítico/métodos , Espectrometria de Massas/métodos , Reologia , Solventes/química , Alcaloides/síntese química , Cromatografia Líquida de Alta Pressão , Pressão , Estereoisomerismo , Temperatura
9.
Org Biomol Chem ; 18(13): 2432-2446, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32163085

RESUMO

This work reports the construction of key building blocks towards the synthesis of cortistatins; a family of steroidal alkaloids. Cortistatin A, being a primary target due to its superior biological properties over other congeners, has been prepared by two different synthetic routes. Synthesis of the precursor to the heavily substituted A-ring starting from d-glucose and construction of the DE-ring junction employing a Hajos-Parrish ketone as a chiral pool have been demonstrated. Efforts are underway to assemble these key fragments and build towards the total synthesis of cortistatin A.


Assuntos
Alcaloides/síntese química , Homosteroides/síntese química , Ciclização , Estereoisomerismo
10.
Eur J Med Chem ; 194: 112253, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32222678

RESUMO

The prevention and control of plant diseases and insect pests is the most crucial issue facing crop protection. To discover novel pesticide candidates with diverse chemical structures from natural products, a series of luotonin A analogues were designed, synthesized and evaluated for their antifungal and insecticidal activities. Most of these compounds exhibited potent activity against Botrytis cinerea, Magnaporthe oryzae and Aphis craccivora. Among them, the antifungal activity of compound 10s against B. cinerea was comparable to azoxystrobin (EC50 = 0.09 mM) and against M. oryzae (EC50 = 0.19 mM) was slightly weaker than that of azoxystrobin (EC50 = 0.17 mM). Compounds 10k and 10o are the most active compounds against A. craccivora having identical mortality value of 42.05% at 50 µg/mL, respectively, which were slightly lower than pymetrozine (51.14%) at the same concentration. Revealed morphological changes of the fungal cell surface by scanning electron microscopy indicated that luotonin A analogues might exert their antifungal activity by destroying fungal cell membrane and cell wall. Furthermore, the results of the in vivo protective and curative activities of the compound 10s against S. sclerotiorum and B. cinerea showed that the curative effect was stronger than its protective effect and the curative effects reached 67.17% and 73.82% at 80 µg/mL respectively. The above results further demonstrated the potential of luotonin A analogues as novel fungicides and insecticides.


Assuntos
Alcaloides/farmacologia , Produtos Biológicos/farmacologia , Descoberta de Drogas , Fungicidas Industriais/farmacologia , Inseticidas/farmacologia , Pirróis/farmacologia , Quinonas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Animais , Afídeos/efeitos dos fármacos , Produtos Biológicos/síntese química , Produtos Biológicos/química , Botrytis/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Inseticidas/síntese química , Inseticidas/química , Magnaporthe/efeitos dos fármacos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Quinonas/síntese química , Quinonas/química , Relação Estrutura-Atividade
11.
Alkaloids Chem Biol ; 83: 1-112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32098648

RESUMO

Lamellarins are marine alkaloids containing fused 14-phenyl-6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinoline or non-fused 3,4-diarylpyrrole-2-carboxylate ring systems. To date, more than 50 lamellarins have been isolated from a variety of marine organisms, such as mollusks, tunicates, and sponges. Many of them, especially fused type I lamellarins, exhibit impressive biological activity, such as potent cytotoxicity, topoisomerase I inhibition, protein kinases inhibition, and anti-HIV-1 activity. Due to their useful biological activity and limited availability from natural sources, a number of synthetic methods have been developed. In this chapter, we present an updated and comprehensive review on lamellarin alkaloids summarizing their isolation, synthesis, and biological activity.


Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/isolamento & purificação , Pirróis/farmacologia , Inibidores da Topoisomerase I/farmacologia , Alcaloides/síntese química , Alcaloides/química , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Pirróis/síntese química , Pirróis/química , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/isolamento & purificação
12.
Molecules ; 25(4)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059504

RESUMO

The synthesis of an unreported 2-aminopyrrolidine-1-carboxamidine unit is here described for the first time. This unusual and promising structure was attained through the oxidative decarboxylation of amino acids using the pair of reagents, silver(I)/peroxydisulfate (Ag(I)/S2O82-) followed by intermolecular (in the case of l-proline derivative) and intramolecular trapping (in the case of acyl l-arginine) by N-nucleophiles. The l-proline approach has a broader scope for the synthesis of 2-aminopyrrolidine-1-carboxamidine derivatives, whereas the intramolecular cyclization afforded by the l-acylarginines, when applied, results in higher yields. The former allowed the first synthesis of cernumidine, a natural alkaloid isolated in 2011 from Solanum cernuum Vell, as its racemic form.


Assuntos
Guanina/síntese química , Estrutura Molecular , Pirrolidinas/síntese química , Alcaloides/síntese química , Alcaloides/química , Aminas/química , Ciclização , Descarboxilação , Guanina/química , Oxirredução , Pirrolidinas/química , Prata/química
13.
Top Curr Chem (Cham) ; 378(2): 22, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32030596

RESUMO

Heterocyclic compounds having a nitrogen atom in the ring exhibit very interesting biological activities. Indole is the core structure of many bioactive compounds owing to its high affinity to bind with most biological targets. Indole is an electron-rich compound and generally prefers electrophilic rather than nucleophilic substitution. Hence, many important indole derivatives are difficult to synthesize through the conventional reactivity of indole. This limitation can be avoided by using the umpolung, from the German word meaning polarity inversion. In umpolung, the indole molecule, especially the C2 and C3 positions, behave as an electrophile. As C2-functionalized indoles have substantial importance in synthetic and pharmaceutical chemistry, this review focuses on the C2 umpolung of indoles via the indirect approach which is less explored. Unlike direct approaches of indole umpolung, indirect methods have several advantages and therefore a number of research articles have been published in this field. But no review is available up till now. This is the first review on this topic and we believe that it will surely motivate the readers to work in this area further.


Assuntos
Carbono/química , Indóis/química , Alcaloides/síntese química , Alcaloides/química , Catálise , Ciclização , Iodo/química , Quinolinas/síntese química , Quinolinas/química , Ácidos Sulfínicos/química
14.
Chem Pharm Bull (Tokyo) ; 68(2): 103-116, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009077

RESUMO

The merits of biogenetic considerations in the chemical syntheses of natural products have been emphasized by describing the total syntheses of Lycopodium alkaloids; lycodine, flabellidine, lycopodine, and flabelliformine, as well as monoterpenoid indole alkaloids; C-mavacurine, kopsiyunnanine K, koumine, and 11-methoxy-19R-hydroxygelselegine.


Assuntos
Alcaloides/síntese química , Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos , Lycopodium/química , Alcaloides de Triptamina e Secologanina/síntese química , Alcaloides/química , Produtos Biológicos/química , Alcaloides de Triptamina e Secologanina/química
15.
Org Lett ; 22(2): 666-669, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31909622

RESUMO

A catalytic conjunctive cross-coupling reaction is developed that allows the construction of chiral organoboronic esters from alkylboron ate complexes and alkyl iodide electrophiles. The process occurs most efficiently with a Ni/Pybox-comprised catalyst and with an acenapthoquinone-derived boron ligand. Because of the broad functional group tolerance of this reaction, it can be a versatile tool for organic synthesis. Applications to the construction of (R)-coniine and (-)-indolizidine 209D are described.


Assuntos
Alcaloides/síntese química , Ácidos Borônicos/síntese química , Ésteres/síntese química , Indolizinas/síntese química , Níquel/química , Piperidinas/síntese química , Alcaloides/química , Ácidos Borônicos/química , Catálise , Ésteres/química , Indolizinas/química , Estrutura Molecular , Piperidinas/química
16.
Org Biomol Chem ; 18(6): 1046-1056, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31971201

RESUMO

The fascinating structure of Strychnos alkaloids has evoked immense synthetic interest from the chemical community since the landmark synthesis of strychnine by Woodward. After that, the pursuit of the total synthesis of Strychnos alkaloids has never stopped. In this context, the synthesis of strychnine has become a benchmark for the evaluation of new synthetic strategies. Furthermore, the characteristic structure of these alkaloids has also served as an inspiration for the development of novel synthetic methodologies, which provide new synthetic strategies for the synthesis of Strychnos alkaloids. In this article, the recent progress in the total synthesis of Strychnos alkaloids since 2011 is reviewed, including successful total syntheses and synthetic efforts toward Strychnos alkaloids. According to the key feature employed in the synthesis, the content was categorized into novel synthetic methodologies and innovative strategies based on well-documented methodologies.


Assuntos
Alcaloides/síntese química , Strychnos/química , Alcaloides/química , Conformação Molecular
17.
Molecules ; 25(3)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973223

RESUMO

The synthesis of the alkaloid (-)-monophyllidin is described. The molecule is a hybrid of xanthoxyline and (S)-proline, accessible in one-step through a Mannich reaction. In the solid-state, defined structural arrangements with different physical properties are formed. Single crystal X-ray diffraction revealed structures of six distinct polymorphs. In the crystalline state, the alkaloid can host small polar molecules (preferably water), while the (S)-proline moiety is present in the zwitterionic state. Combined with the chelate, which is already present in the xanthoxyline substructure, an ideal disposition for multiple hydrogen bond networks evolve. Therefore, highly water-soluble polymorphs of monophyllidin can form. This structural flexibility explains the many faces of the molecule in terms of structure as well as analytical data. Furthermore, speculations about the biological role of the molecule, with regard to the manifold interactions with water, are presented.


Assuntos
Alcaloides/química , Acetonitrilas/química , Alcaloides/síntese química , Cristalografia por Raios X , Ésteres/síntese química , Ésteres/química , Etanol/química , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Oxigênio/química , Solventes/química , Água/química
18.
Molecules ; 25(2)2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31963860

RESUMO

The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-ß-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011-2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations.


Assuntos
Modelos Moleculares , Alcaloides/síntese química , Alcaloides/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Ciclização , Rutênio/química
19.
Org Biomol Chem ; 18(7): 1232-1278, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31930246

RESUMO

The natural occurrence of enantiomers and diastereomers is often encountered. In addition, the synthesis of these stereoisomers is important for structure determination and for the study of structure-activity relationships. Stereodivergent routes simplify the access to these molecules starting from a common material. This review is focused on the synthesis of carbohydrates, amino acids, alkaloids and terpenes using this efficient strategy. In the case of carbohydrates, such as monosaccharides, carbasugars, aminosugars and azasugars, carbohydrates are usually employed as common starting materials. As a very common strategy, configurations of hydroxy groups are inverted by SN2 methods playing with protection and deprotection processes. For the synthesis of acyclic α-AAs, diastereoselective methods using mainly Garner's aldehyde have been described. Diastereodivergent routes allowed the synthesis of ß-hydroxy- and ß-amino-α-amino acids, as well as of ß- and γ-amino acids. Heterocyclic and cyclic amino phosphonic acids were synthesized using diastereodivergent routes. Alkaloids containing five- and six-membered saturated azaheterocycles needed multistep stereodivergent routes and other alkaloids, such as enantiomers of balanol, vincamine, anatoxin and codeine, and diastereomeric isochaetominines C and galanthamines. In the terpene field, sesquiterpenes ß-santalene, α-curcumene and α-cuparenone and the diterpene scopadulcic acid A have been synthesized using enantiodivergent routes.


Assuntos
Alcaloides/síntese química , Aminoácidos/síntese química , Carboidratos/síntese química , Terpenos/síntese química , Alcaloides/química , Aminoácidos/química , Carboidratos/química , Estrutura Molecular , Estereoisomerismo , Terpenos/química
20.
J Neuroimmunol ; 339: 577115, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31778849

RESUMO

Multiple sclerosis (MS) is an autoimmune disease that remains in need of effective therapies. Plant-derived medicines have appealing properties for the treatment of autoimmune diseases. MYMD-1 is a synthetic plant alkaloid that has been shown to ameliorate the course of autoimmune thyroiditis. The goal of the present study was to determine whether MYMD-1 would produce similar beneficial effects in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin oligodendrocyte glycoprotein. MYMD-1 improved the course of EAE and suppressed activation of effector T cells without causing global immunosuppression or toxicity. These results suggest that MYMD-1 may be of interest for evaluating for the treatment of autoimmune diseases.


Assuntos
Alcaloides/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Alcaloides/síntese química , Alcaloides/farmacologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
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