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1.
Yakugaku Zasshi ; 140(10): 1213-1224, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999200

RESUMO

In basic pharmaceutical sciences to achieve drug development, research on the efficient chemical synthesis of small molecules having cyclic skeletons is important. We have been engaged in the development of artificial catalysts for asymmetric ring formation reactions that exclusively synthesize right-handed or left-handed cyclic compounds and have achieved the construction of optically active cyclic skeletons using our original catalysts. The synthesis of biologically active compounds was facilitated through six-membered ring construction by Diels-Alder reaction of Danishefsky diene; however, no asymmetric variant of the reaction has been achieved. We approached this unresolved issue using multi-coordinated lanthanide metals. A new chiral lanthanide catalyst was developed, and the catalytic asymmetric Diels-Alder reaction of Danishefsky diene was realized for the first time. By modifying the chemical structure of Danishefsky diene, we applied the lanthanide catalyst to the syntheses of polycyclic compounds and biologically active compounds. We achieved the asymmetric synthesis of natural products, antibacterial and antimalarial compounds, and an anti-obesity drug lead compound. Moreover, the novel catalyst exhibited higher performance than the previously reported ones. The latest generation of the catalyst can be handled stably in air at room temperature. Furthermore, we succeeded in the development of new catalysts by focusing on the properties of its metal precursors, such as nickel and indium, and achieved the construction of polycyclic skeletons by using these catalysts.


Assuntos
Compostos Heterocíclicos/síntese química , Compostos Policíclicos/síntese química , Alcenos/química , Antibacterianos/síntese química , Fármacos Antiobesidade/síntese química , Antimaláricos/síntese química , Produtos Biológicos/síntese química , Catálise , Reação de Cicloadição , Desenvolvimento de Medicamentos , Índio , Elementos da Série dos Lantanídeos/química , Níquel , Estereoisomerismo
2.
Nature ; 584(7819): 75-81, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760044

RESUMO

Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates3-6. The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C-H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists7, enables a predetermined and site-selective carbon-nitrogen (C-N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C-N coupling protocol by preparing commercial medicines and by the late-stage amination-aromatization of natural products, steroids and terpene feedstocks.


Assuntos
Compostos de Anilina/síntese química , Hidrogênio/química , Processos Fotoquímicos , Aminação , Aminas/química , Compostos de Anilina/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise/efeitos da radiação , Cicloexanonas/química , Oxirredução/efeitos da radiação , Processos Fotoquímicos/efeitos da radiação , Esteroides/síntese química , Esteroides/química , Terpenos/síntese química , Terpenos/química
4.
Science ; 368(6494): 1007-1011, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32467391

RESUMO

Bryostatins are a family of 21 complex marine natural products with a wide range of potent biological activities. Among all the 21 bryostatins, bryostatin 3 is structurally the most complex. Whereas nine total syntheses of bryostatins have been achieved to date, bryostatin 3 has only been targeted once and required the highest number of steps to synthesize (43 steps in the longest linear sequence and 88 total steps). Here, we report a concise total synthesis of bryostatin 3 using 22 steps in the longest linear sequence and 31 total steps through a highly convergent synthetic plan by the use of highly atom-economical and chemoselective transformations in which alkynes played a major role in reducing step count.


Assuntos
Produtos Biológicos/síntese química , Briostatinas/síntese química , Macrolídeos/síntese química , Alquinos/química , Produtos Biológicos/química , Briostatinas/química , Técnicas de Química Sintética , Macrolídeos/química
5.
Yakugaku Zasshi ; 140(4): 455-470, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32238625

RESUMO

Natural products are useful sources in the search for biochemical probes and drug leads because of their unique biological activities. However, synthetic studies or functional analyses of polycyclic complex natural products or conjugated lipids (e.g., glycolipids) are often hampered because of their synthesis and handling are challenging. On the basis of rational designs, synthetic studies, and chemical modifications, natural products need to be optimized to more potent compounds with improved activities, selectivities and/or physical properties. We have been synthesizing natural products and their derivatives for the elucidation of their biological mechanisms and discovery of drug leads. This review describes three topics for developing functional compounds derived from natural products for prospective involvement in pharmaceutical research: 1) direct construction of the ergot alkaloid scaffold by palladium catalyzed domino cyclization of amino allenes; 2) identification of novel sphingosine kinase inhibitors through a structure-activity relationship study of jaspine B; and 3) design, synthesis and biological evaluation of novel CD1d glycolipid ligands containing modified lipid moieties.


Assuntos
Produtos Biológicos/síntese química , Alcadienos/química , Antígenos CD1d , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Catálise , Fenômenos Químicos , Ciclização , Desenvolvimento de Medicamentos , Alcaloides de Claviceps/química , Glicolipídeos , Ligantes , Paládio/química , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Relação Estrutura-Atividade
6.
Org Biomol Chem ; 18(15): 2793-2812, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32239033

RESUMO

The current review summarizes the latest achievements in the synthesis of piperidine-2,4-dione-type azaheterocycles. Two main groups traditional (carbonyl compound transformations) and novel (anionic enolate rearrangements) of complementary methods for the simple and effective preparation of structurally diverse compounds in racemic and enantiopure forms have been reported. Due to the specific structure and appropriate reactivity profiles of dione-type molecules, they are a convenient modern platform for the construction of functionalized piperidine-type systems possessing high synthetic and medicinal potential. This potential is successfully realized by the creation of highly active pharmaceutically relevant compounds and the synthesis of natural products.


Assuntos
Compostos Aza/síntese química , Produtos Biológicos/síntese química , Desenvolvimento de Medicamentos , Compostos Heterocíclicos/síntese química , Piperidonas/síntese química , Compostos Aza/química , Produtos Biológicos/química , Compostos Heterocíclicos/química , Estrutura Molecular , Piperidonas/química
7.
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
8.
Nature ; 580(7805): 621-627, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32179876

RESUMO

Frequently referred to as the 'magic methyl effect', the installation of methyl groups-especially adjacent (α) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules1-3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/síntese química , Carbono/química , Técnicas de Química Sintética , Hidrogênio/química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/síntese química , Androstenos/síntese química , Androstenos/química , Catálise , Agonismo Inverso de Drogas , Elétrons , Flúor/química , Hidroxilação , Ácidos de Lewis/química , Manganês/química , Metilação , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Oxazolidinonas/síntese química , Oxazolidinonas/química , Oxirredução , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Tetrazóis/síntese química , Tetrazóis/química
9.
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
10.
Org Biomol Chem ; 18(7): 1279-1336, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32025682

RESUMO

Enantio- and diastereodivergent routes to marine-origin natural products with different sizes of cyclic ethers and lactones have been used in order to assign stereochemical features. Kainoid amino acids such as isodomoic acids have been synthesized using diastereodivergent routes. The bis(indole) alkaloid dragmacidin F has been prepared by enantiodivergent strategies as well as furanoterpenes and the tetracyclic agelastatin A. Natural products containing five-membered lactones like quercus lactones, muricatacins, goniofufuranones, methylenolactocins and frenolicin B have been synthesized using stereodivergent routes. Macrolides are very abundant lactones and have been mainly prepared from the corresponding seco-acids by lactonization, such as lasiodiplodin, zaeralanes, macrosphelides and haloprins, or by ring-closing metathesis, such as aspercyclides, microcarpalides, macrolides FD-891 and 892, and tetradic-5-en-9-olides. Other natural products including cyclic ethers (such as sesamin, asarinin, acetogenins, centrolobines and nabilones), alcohols (such as sulcatol), esters (such as methyl jasmonates), polycyclic precursors of fredericamycin, amino alcohols (such as ambroxol and sphingosines), isoprostanes, isofurans, polyketide precursors of anachelins, brevicomins, gummiferol, shikimic acid and the related compounds, and the pheromone disparlure have been synthesized stereodivergently. Heterocyclic systems such as epoxides, theobroxides and bromoxones, oxetan-3-ones, 5- to 8-membered cyclic ethers, azetidones, γ-lactams, oxazolidinones, bis(oxazolines), dihydropyridoisoindolines and octahydroisoquinolines have been prepared following stereodivergent routes. Stereodivergent routes to unnatural compounds such as alkenes, dienes, allenes, cyclopropanes, alcohols, aldols, amines, amino alcohols, ß-amino acids, carboxylic acids, lactones, nitriles and α-amino nitriles have been considered as well.


Assuntos
Produtos Biológicos/síntese química , Compostos Heterocíclicos/síntese química , Lactonas/síntese química , Álcoois/síntese química , Álcoois/química , Alcenos/síntese química , Alcenos/química , Aminas/síntese química , Aminas/química , Aminoácidos/síntese química , Aminoácidos/química , Produtos Biológicos/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Compostos Heterocíclicos/química , Lactonas/química , Estrutura Molecular , Nitrilos/síntese química , Nitrilos/química , Estereoisomerismo
11.
Molecules ; 25(4)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32075004

RESUMO

The total synthesis of (-)-antrocin and its enantiomer are presented. Antrocin (-)-1 is an important natural product which acts as an antiproliferative agent in a metastatic breast cancer cell line (IC50: 0.6 µM). The key features of this synthesis are: (a) selective anti-addition of trimethylsilyl cyanide (TMSCN) to α,ß-unsaturated ketone; (b) resolution of (±)-7 using chiral auxiliary L-dimethyl tartrate through formation of cyclic ketal diastereomers followed by simple column chromatography separation and acid hydrolysis; (c) substrate-controlled stereoselective aldol condensation of (+)-12 with monomeric formaldehyde and pyridinium chlorochromate (PCC) oxidation for synthesis of essential lactone core in (-)-14; and (d) non-basic Lombardo olefination of the carbonyl at the final step to yield (-)-antrocin. In addition, (+)-9 cyclic ketal diastereomer was converted to (+)-antrocin with similar reaction sequences.


Assuntos
Produtos Biológicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Lactonas/síntese química , Sesquiterpenos/síntese química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cianetos/síntese química , Cianetos/química , Feminino , Humanos , Lactonas/química , Lactonas/farmacologia , Metástase Neoplásica , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Estereoisomerismo , Tartaratos/síntese química , Tartaratos/química , Compostos de Trimetilsilil/síntese química , Compostos de Trimetilsilil/química
12.
Nature ; 580(7802): 220-226, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32066140

RESUMO

Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences1. Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements2. These structures are often generated from [1.1.1]propellane via opening of the internal C-C bond through the addition of either radicals or metal-based nucleophiles3-13. The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, α-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.


Assuntos
Técnicas de Química Sintética , Cobre/química , Pentanos/química , Pentanos/síntese química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Ciclização , Preparações Farmacêuticas/metabolismo
13.
Org Lett ; 22(2): 584-588, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31904969

RESUMO

We describe herein the first asymmetric total synthesis and biological evaluation of the natural PDE4 inhibitor toddacoumalone and its stereoisomers. The key step of the total synthesis is a formal asymmetric [4 + 2] cycloaddition reaction catalyzed by chiral secondary amine catalysts. A variety of pyranoquinolinones and 3-methylcrotonaldehyde are well tolerated under the optimized reaction conditions, which paved the way for further SAR studies. Further biological evaluation showed 1a' with the best PDE4 inhibitory activity (IC50 = 0.18 µM).


Assuntos
Produtos Biológicos/farmacologia , Cumarínicos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/química , Cumarínicos/síntese química , Cumarínicos/química , Reação de Cicloadição , Humanos , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Estereoisomerismo
14.
Chem Pharm Bull (Tokyo) ; 68(1): 1-33, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902899

RESUMO

Novel reactions using hetero-heavy atoms (P, S, Si, Se, and Sn) were developed and applied to the synthesis of biofunctional molecules and some medicine-candidates, in which the following items are covered. 1) Development of introduction of C1-unit using cyanophosphates (CPs). 2) Carbene-generation under neutral condition from CPs and its application to organic synthesis. 3) [3,3]Sigmatropic rearrangement-ring expansion reactions of medium-sized cyclic thionocarbonates containing a sulfur atom and their application to natural product synthesis. 4) Stereoselective synthesis of novel ß-imidazole C-nucleosides via diazafulvene intermediates and their application to investigating ribozyme reaction mechanism. 5) Developments of novel histamine H3- and H4-receptor ligands using new synthetic methods involving Se or Sn atoms.


Assuntos
Produtos Biológicos/química , Metais/química , Animais , Produtos Biológicos/síntese química , Proliferação de Células/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Metano/análogos & derivados , Metano/química , Metano/metabolismo , Nitrilos/química , Nucleosídeos/síntese química , Nucleosídeos/química
15.
Org Biomol Chem ; 18(4): 687-693, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31903473

RESUMO

The first total synthesis of a marine natural product, exigurin, has been accomplished in 13 steps starting from (+)-menthone. The key intermediate (-)-10-epi-axisonitrile-3 was prepared by stereoselective intramolecular cyclopropanation followed by a cyclopropane ring opening reaction by the azide anion. The bioinspired Ugi reaction of (-)-10-epi-axisonitrile-3, formaldehyde, sarcosine and methanol successfully constructed the target exigurin in which its terpene and amino acid units were linked through an amide bond.


Assuntos
Produtos Biológicos/síntese química , Iminoácidos/síntese química , Sesquiterpenos/síntese química , Estereoisomerismo
16.
Nat Commun ; 11(1): 405, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964883

RESUMO

Both of O-glycosides and nucleosides are important biomolecules with crucial rules in numerous biological processes. Chemical synthesis is an efficient and scalable method to produce well-defined and pure carbohydrate-containing molecules for deciphering their functions and developing therapeutic agents. However, the development of glycosylation methods for efficient synthesis of both O-glycosides and nucleosides is one of the long-standing challenges in chemistry. Here, we report a highly efficient and versatile glycosylation method for efficient synthesis of both O-glycosides and nucleosides, which uses glycosyl ortho-(1-phenylvinyl)benzoates as donors. This glycosylation protocol enjoys the various features, including readily prepared and stable donors, cheap and readily available promoters, mild reaction conditions, good to excellent yields, and broad substrate scopes. In particular, the applications of the current glycosylation protocol are demonstrated by one-pot synthesis of several bioactive oligosaccharides and highly efficient synthesis of nucleosides drugs capecitabine, galocitabine and doxifluridine.


Assuntos
Benzoatos/química , Técnicas de Química Sintética/métodos , Química Farmacêutica/métodos , Glicosídeos/síntese química , Nucleosídeos/síntese química , Produtos Biológicos/síntese química , Capecitabina/síntese química , Floxuridina/síntese química , Glicosilação , Estrutura Molecular
17.
Molecules ; 25(2)2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31963275

RESUMO

It has been found that both eugenol and isoeugenol derivatives reacted with 2-pyridinesulfenyl and 2-pyridineselenenyl halides in a regioselective mode affording products with opposite regiochemistry. Synthesis of new families of 2H,3H-[1,3]thia- and -selenazolo[3,2-a]pyridin-4-ium heterocycles has been developed by annulation reactions of 2-pyridinechalcogenyl halides with natural compounds (eugenol, isoeugenol, methyl eugenol, methyl isoeugenol, acetyl eugenol, trans-anethole) and their structural analogs. The influence of the substrate structure and the nature of halogen on the product yields are studied. The 2-pyridinesulfenyl and 2-pyridineselenenyl chlorides are more efficient reagents compared to corresponding bromides. The obtained condensed heterocycles are novel water-soluble functionalized compounds with promising biological activity.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Piridinas/química , Piridinas/farmacologia , Produtos Biológicos/síntese química , Técnicas de Química Sintética , Estrutura Molecular , Piridinas/síntese química , Solubilidade , Análise Espectral , Relação Estrutura-Atividade
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.
Chem Commun (Camb) ; 56(15): 2280-2283, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31984987

RESUMO

Herein, we describe the natural product inspired synthesis of 38 complex small molecules based upon 20 unique frameworks suitable for fragment-based screening. Utilising an efficient strategy, two key building block diastereomers were harnessed to generate novel, three-dimensional fragments which each possess numerous synthetically accessible fragment growth positions.


Assuntos
Produtos Biológicos/química , Descoberta de Drogas , Bibliotecas de Moléculas Pequenas/química , Produtos Biológicos/síntese química , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química
20.
J Appl Microbiol ; 128(5): 1279-1288, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31618796

RESUMO

As bacteria aggregate and form biofilms on surfaces in the human body such as tissues, indwelling medical devices, dressings and implants, they can cause a significant health risk. Bacterial biofilms possess altered phenotypes: physical features that facilitate antibiotic resistance and evasion of the host immune response. Since metabolic and physical factors contribute to biofilm maturation and persistence, an objective in antibiofilm therapy is to target these factors to deliver innovative approaches for solving these important health problems. Currently, there is little research on the direct immunological effects resulting from the introduction of foreign components to the body pertaining to biofilm inhibition methods. Detailed research involving animal models is necessary to better understand the biological side effects of synthetic peptides, genetically modified bacteriophages and isolated proteins and any resistance that may develop from these approaches.


Assuntos
Antibacterianos/farmacologia , Infecções Bacterianas/prevenção & controle , Biofilmes/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/isolamento & purificação , Infecções Bacterianas/terapia , Biofilmes/crescimento & desenvolvimento , Produtos Biológicos/síntese química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Resistência Microbiana a Medicamentos , Humanos , Evasão da Resposta Imune
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