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1.
ACS Infect Dis ; 10(6): 1958-1969, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38841740

RESUMO

About 100,000 deaths are attributed annually to infections with methicillin-resistant Staphylococcus aureus (MRSA) despite concerted efforts toward vaccine development and clinical trials involving several preclinically efficacious drug candidates. This necessitates the development of alternative therapeutic options against this drug-resistant bacterial pathogen. Using the Masuda borylation-Suzuki coupling (MBSC) sequence, we previously synthesized and modified naturally occurring bisindole alkaloids, alocasin A, hyrtinadine A and scalaradine A, resulting in derivatives showing potent in vitro and in vivo antibacterial efficacy. Here, we report on a modified one-pot MBSC protocol for the synthesis of previously reported and several undescribed N-tosyl-protected bisindoles with anti-MRSA activities and moderate cytotoxicity against human monocytic and kidney cell lines. In continuation of the mode of action investigation of the previously synthesized membrane-permeabilizing hit compounds, mechanistic studies reveal that bisindoles impact the cytoplasmic membrane of Gram-positive bacteria by promiscuously interacting with lipid II and membrane phospholipids while rapidly dissipating membrane potential. The bactericidal and lipid II-interacting lead compounds 5c and 5f might be interesting starting points for drug development in the fight against MRSA.


Assuntos
Antibacterianos , Alcaloides Indólicos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Humanos , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/química , Alcaloides Indólicos/síntese química , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Linhagem Celular , Relação Estrutura-Atividade , Indóis/farmacologia , Indóis/química , Indóis/síntese química , Estrutura Molecular
2.
Molecules ; 29(12)2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38930871

RESUMO

Synthetic efforts toward complex natural product (NP) scaffolds are useful ones, particularly those aimed at expanding their bioactive chemical space. Here, we utilised an orthogonal cheminformatics-based approach to predict the potential biological activities for a series of synthetic bis-indole alkaloids inspired by elusive sponge-derived NPs, echinosulfone A (1) and echinosulfonic acids A-D (2-5). Our work includes the first synthesis of desulfato-echinosulfonic acid C, an α-hydroxy bis(3'-indolyl) alkaloid (17), and its full NMR characterisation. This synthesis provides corroborating evidence for the structure revision of echinosulfonic acids A-C. Additionally, we demonstrate a robust synthetic strategy toward a diverse range of α-methine bis(3'-indolyl) acids and acetates (11-16) without the need for silica-based purification in either one or two steps. By integrating our synthetic library of bis-indoles with bioactivity data for 2048 marine indole alkaloids (reported up to the end of 2021), we analyzed their overlap with marine natural product chemical diversity. Notably, the C-6 dibrominated α-hydroxy bis(3'-indolyl) and α-methine bis(3'-indolyl) analogues (11, 14, and 17) were found to contain significant overlap with antibacterial C-6 dibrominated marine bis-indoles, guiding our biological evaluation. Validating the results of our cheminformatics analyses, the dibrominated α-methine bis(3'-indolyl) alkaloids (11, 12, 14, and 15) were found to exhibit antibacterial activities against methicillin-sensitive and -resistant Staphylococcus aureus. Further, while investigating other synthetic approaches toward bis-indole alkaloids, 16 incorrectly assigned synthetic α-hydroxy bis(3'-indolyl) alkaloids were identified. After careful analysis of their reported NMR data, and comparison with those obtained for the synthetic bis-indoles reported herein, all of the structures have been revised to α-methine bis(3'-indolyl) alkaloids.


Assuntos
Antibacterianos , Quimioinformática , Alcaloides Indólicos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/síntese química , Quimioinformática/métodos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/síntese química
3.
Bioorg Med Chem ; 109: 117799, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38897138

RESUMO

Natural products as starting templates have shown historically major contribution to development of drugs. Inspired by the structure-function of an anticancer natural alkaloid Rutaecarpine, the Scaffold-hopped Acyclic Analogues of Rutaecarpine (SAAR) with 'N'-atom switch (1°-hop) and ring-opening (2°-hop) were investigated. A new synthetic route was developed for an effective access to the analogues, i.e. 2-indolyl-pyrido[1,2-a]pyrimidinones, which involved preparation of N-Boc-N'-phthaloyltryptamine/mexamine-bromides and pyridopyrmidinon-2-yl triflate, a nickel/palladium-catalysed Ullmann cross-coupling of these bromides and triflate, deprotection of phthalimide followed by N-aroylation, and Boc-deprotection. Fourteen novel SAAR-compounds were prepared, and they showed characteristic antiproliferative activity against various cancer cells. Three most active compounds (11a, 11b, and 11c) exhibited good antiproliferative activity, IC50 7.7-15.8 µM against human breast adenocarcinoma cells (MCF-7), lung cancer cells (A549), and colon cancer cells (HCT-116). The antiproliferative property was also observed in the colony formation assay. The SAAR compound 11b was found to have superior potency than original natural product Rutaecarpine and an anticancer drug 5-FU in antiproliferative activities with relatively lower cytotoxicity towards normal breast epithelial cells (MCF10A) and significantly higher inhibitory effect on cancer cells' migration. The compound 11b was found to possess favourable in silico physicochemical characteristics (lipophilicity-MLOGP, TPSA, and water solubility-ESOL, and others), bioavailability score, and pharmacokinetic properties (GI absorption, BBB non-permeant, P-gp, and CYP2D6). Interestingly, the compound 11b did not show any medicinal chemistry structural alert of PAINS and Brenk filter. The study represents for the first time the successful discovery of new potent anticancer chemotypes using Rutaecarpine natural alkaloid as starting template and reaffirms the significance of natural product-inspired scaffold-hopping technique in drug discovery research.


Assuntos
Antineoplásicos , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Alcaloides Indólicos , Quinazolinas , Humanos , Quinazolinas/química , Quinazolinas/farmacologia , Quinazolinas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Linhagem Celular Tumoral , Pirimidinonas/química , Pirimidinonas/farmacologia , Pirimidinonas/síntese química , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Relação Dose-Resposta a Droga , Quinazolinonas
4.
J Nat Prod ; 87(6): 1556-1562, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38758599

RESUMO

Bis-indole alkaloids from marine sponges are an intriguing class of natural products with a variety of activities. However, only a preliminary biological study of tulongicin A (5), a related previously isolated marine tris-indole alkaloid, has been conducted. In this study, we accomplished the first asymmetric total synthesis of 5 via the construction of an imidazoline-linked bis-indolylmethane skeleton using a Friedel-Crafts-type reaction. Our synthesis enabled a detailed study of the antibacterial profile of 5. Compound 5 displayed bactericidal activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains.


Assuntos
Antibacterianos , Alcaloides Indólicos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Staphylococcus aureus , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Estrutura Molecular , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Animais , Staphylococcus aureus/efeitos dos fármacos , Poríferos/química , Biologia Marinha
5.
Chem Biodivers ; 21(6): e202400416, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38587971

RESUMO

Goniomitine is of the aspidosperma alkaloid family, with an angularly fused tetracyclic skeleton housing an all-carbon quaternary carbon chiral center alongside an aminal functional group. This natural product has garnered attention as a synthetic target due to its intriguing molecular architecture and anti-proliferative activity in recent years. Following the first synthesis of (-)-goniomitine by Takano in 1991, synthetic chemists have developed various methods. This review provides an overview of the methodologies used in the synthesis of goniomitine in racemic and enantiopure forms via divergent construction indole framework, indole functionalization, and the integrated oxidation/reduction/cyclization (iORC) sequence from 1991 to 2023.


Assuntos
Aspidosperma , Alcaloides Indólicos , Aspidosperma/química , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Estereoisomerismo , Ciclização , Estrutura Molecular , Oxirredução
6.
Nat Chem ; 16(6): 1003-1014, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38374457

RESUMO

A compound's overall contour impacts its ability to elicit biological response, rendering access to distinctly shaped molecules desirable. A natural product's framework can be modified, but only if it is abundant and contains suitably modifiable functional groups. Here we introduce a programmable strategy for concise synthesis of precisely altered scaffolds of scarce bridged polycyclic alkaloids. Central to our approach is a scalable catalytic multi-component process that delivers diastereo- and enantiomerically enriched tertiary homoallylic alcohols bearing differentiable alkenyl moieties. We used one product to launch progressively divergent syntheses of a naturally occurring alkaloid and its precisely expanded, contracted and/or distorted framework analogues (average number of steps/scaffold of seven). In vitro testing showed that a skeleton expanded by one methylene in two regions is cytotoxic against four types of cancer cell line. Mechanistic and computational studies offer an account for several unanticipated selectivity trends.


Assuntos
Alcaloides Indólicos , Catálise , Alcaloides Indólicos/química , Alcaloides Indólicos/síntese química , Humanos , Linhagem Celular Tumoral , Estereoisomerismo , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais
7.
Nat Prod Rep ; 41(5): 784-812, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38275179

RESUMO

Covering 1963 to 2023Monoterpene indole alkaloids are the main sub-family of indole alkaloids with fascinating structures, stereochemistry, and diverse bioactivities (e.g., anticancer, anti-malarial and anti-arrhythmic etc.). Vallesamidine alkaloids and structurally more complex schizozygane alkaloids are small groups of rearranged monoterpene indole alkaloids with a unique 2,2,3-trialkylated indoline scaffold, while schizozygane alkaloids can generate a further rearranged skeleton, isoschizozygane, possessing a tetra-substituted, bridged tetrahydroquinoline core. In this review, the origin and structural features of vallesamidine and schizozygane alkaloids are introduced, and a discussion on the relationship of these alkaloids with aspidosperma alkaloids and a structural rearrangement hypothesis based on published studies is followed. Moreover, uncommon skeletons and potential bioactivities, such as anti-malarial and anti-tumour activities, make such alkaloids important synthetic targets, attracting research groups globally to accomplish total synthesis, resulting in impressive works on novel total synthesis, formal synthesis, and construction of key intermediates. These synthetic endeavours are systematically reviewed and highlighted with key strategies and efficiencies, providing different viewpoints on molecular structures and promoting the extension of chemical space and mining of new active scaffolds.


Assuntos
Alcaloides Indólicos , Antimaláricos/farmacologia , Antimaláricos/química , Antimaláricos/síntese química , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/síntese química , Estrutura Molecular , Monoterpenos/química , Monoterpenos/farmacologia , Monoterpenos/síntese química
8.
Methods Mol Biol ; 2505: 101-112, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35732940

RESUMO

Enzymatic biotransformation has become a widely used technique in synthetic chemistry to achieve difficult chemical transformations. Cytochrome P450 monooxygenase enzymes found in nature carry out a wide range of difficult chemical reactions, such as the oxidation of the monoterpene indole alkaloid (-)-tabersonine at the unreactive 16th position on the indoline benzene ring in the biosynthesis of biologically active natural products such as the bis-indole alkaloid (-)-melodinine K. Herein, we describe the first semisynthesis of (-)-melodinine K enabled by a biological gram scale route to the northern fragment, (-)-16-hydroxytabersonine, as well as a chemical route to the southern fragment, (-)-pachysiphine, both derived from (-)-tabersonine and subsequently coupled in only eight linear steps. (-)-16-Hydroxytabersonine is produced through an enzymatic biotransformation with a genetically modified Saccharomyces cerevisiae yeast strain expressing a tabersonine 16-hydroxylase enzyme to enable regioselective oxidation on multigram scale, and (-)-pachysiphine is produced through stereoselective and regioselective epoxidation of the disubstituted alkene.


Assuntos
Alcaloides Indólicos , Biotransformação , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Alcaloides Indólicos/síntese química , Oxirredução , Saccharomyces cerevisiae/metabolismo
9.
Nat Commun ; 13(1): 908, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35177620

RESUMO

Sarpagine-Ajmaline-Koumine type monoterpenoid indole alkaloids represent a fascinating class of natural products with polycyclic and cage-like structures, interesting biological activities, and related biosynthetic origins. Herein we report a unified approach towards the asymmetric synthesis of these three types of alkaloids, leading to a collective synthesis of 14 natural alkaloids. Among them, akuammidine, 19-Z-akuammidine, vincamedine, vincarine, quebrachidine, vincamajine, alstiphylianine J, and dihydrokoumine are accomplished for the first time. Features of our synthesis are a new Mannich-type cyclization to construct the key indole-fused azabicyclo[3.3.1]nonane common intermediate, a SmI2 mediated coupling to fuse the aza-bridged E-ring, stereoselective olefinations to install either the 19-E or 19-Z terminal alkenes presented in the natural alkaloids, and an efficient iodo-induced cyclization to establish the two vicinal all-carbon quaternary centers in the Koumine-type alkaloids.


Assuntos
Ajmalina/síntese química , Técnicas de Química Sintética/métodos , Alcaloides Indólicos/síntese química , Ciclização , Estrutura Molecular , Estereoisomerismo
10.
Eur J Med Chem ; 227: 113937, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34710744

RESUMO

Evodiamine and rutaecarpine are two alkaloids isolated from traditional Chinese herbal medicine Evodia rutaecarpa, which have been reported to have various biological activities in past decades. To explore the potential applications for evodiamine and rutaecarpine alkaloids and their derivatives, various kinds of evodiamine and rutaecarpine derivatives were designed and synthesized. Their antifungal profile against six phytopathogenic fungi Rhizoctonia solani, Botrytis cinerea, Fusarium graminearum, Fusarium oxysporum, Sclerotinia sclerotiorum, and Magnaporthe oryzae were evaluated for the first time. Furthermore, a series of modified imidazole derivatives of rutaecarpine were synthesized to investigate the structure-activity relationship. The results of antifungal activities in vitro showed that imidazole derivative of rutaecarpine A1 exhibited broad-spectrum inhibitory activities against R. solani, B. cinerea, F. oxysporum, S. sclerotiorum, M. oryzae and F. graminearum with EC50 values of 1.97, 5.97, 12.72, 2.87 and 16.58 µg/mL, respectively. Preliminary mechanistic studies showed that compound A1 might cause mycelial abnormalities of S. sclerotiorum, mitochondrial distortion and swelling, and inhibition of sclerotia formation and germination. Moreover, the curative effects of compound A1 were 94.7%, 81.5%, 80.8%, 65.0% at 400, 200, 100, 50 µg/mL in vivo experiments, which was far more effective than the positive control azoxystrobin. Significantly, no phytotoxicity of compound A1 on oilseed rape leaves was observed obviously even at a high concentration of 400 µg/mL. Therefore, compound A1 is expected to be a novel leading structure for the development of new antifungal agents.


Assuntos
Antifúngicos/farmacologia , Desenho de Fármacos , Alcaloides Indólicos/farmacologia , Quinazolinas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Ascomicetos/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fusarium/efeitos dos fármacos , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Rhizoctonia/efeitos dos fármacos , Relação Estrutura-Atividade
11.
Eur J Med Chem ; 227: 113904, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34662748

RESUMO

This study presents the design, synthesis, and characterization of bisindole molecules as anti-cancer agents against Tousled-like kinases (TLKs). We show that compound 2 composed of an indirubin-3'-oxime group linked with a (N-methylpiperidin-2-yl)ethyl moiety possessed inhibitory activity toward both TLK1 and TLK2 in vitro and diminished the phosphorylation level of the downstream substrate anti-silencing function 1 (ASF1) in replicating cells. The treatment of compound 2 impaired DNA replication, slowed S-phase progression, and triggered DNA damage response in replicating cells. Structure optimization further discovered six derivatives exhibiting potent TLK inhibitory activity and revealed the importance of the tertiary amine-containing moiety of the side chain. Moreover, the derivatives 6, 17, 19, and 20 strongly suppressed the growth of triple-negative breast cancer MDA-MB-231 cells, non-small cell lung cancer A549 cells, and colorectal cancer HCT-116 cells, while normal lung fibroblast MRC5 and IMR90 cells showed a lower response to these compounds. Taken together, this study identifies tertiary amine-linked indirubin-3'-oximes as potent anticancer agents that inhibit TLK activity.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Alcaloides Indólicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
J Am Chem Soc ; 143(43): 18280-18286, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34670085

RESUMO

trans-syn-Fused drimane meroterpenoids are unique natural products that arise from contra-thermodynamic polycyclizations of their polyene precursors. Herein we report the first total syntheses of four trans-syn-fused drimane meroterpenoids, namely polysin, N-acetyl-polyveoline, chrodrimanin C, and verruculide A, in 7-18 steps from sclareolide. The trans-syn-fused drimane unit is accessed through an efficient acid-mediated C9 epimerization of sclareolide. Subsequent applications of enzymatic C-H oxidation and contemporary annulation methodologies install the requisite C3 hydroxyl group and enable rapid generation of structural complexity to provide concise access to these natural products.


Assuntos
Alcaloides Indólicos/síntese química , Sesquiterpenos/síntese química , Ciclização , Sistema Enzimático do Citocromo P-450/química , Diterpenos/química , Hidroxilação , Oxirredução , Estereoisomerismo
13.
Sci Rep ; 11(1): 19915, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620892

RESUMO

The synthesis of tetracyclic indole alkaloid (±)-decursivine was accomplished using BINOL-phosphoric acid catalyzed tandem oxidative cyclization as a key step with (bis(trifluoroacetoxy)iodo)benzene (PIFA) as an oxidizing agent. This represents one of the shortest and highest yielding routes for the synthesis of (±)-decursivine from readily available starting materials.


Assuntos
Alcaloides Indólicos/síntese química , Naftóis/química , Oxirredução , Ácidos Fosfóricos/química , Catálise , Técnicas de Química Sintética , Ciclização , Alcaloides Indólicos/química , Estrutura Molecular
14.
Org Lett ; 23(17): 6836-6840, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34410141

RESUMO

The first asymmetric total synthesis of three picrinine-type akuammiline alkaloids, (-)-picrinine, (-)-scholarisine C, and (+)-5-ß-methoxyaspidophylline, has been accomplished. The synthesis features an efficient acid-promoted oxo-bridge ring-opening and further carbonyl O-cyclization to assemble the furoindoline scaffold, an unusual Dauben-Michno oxidation to construct the requisite α,ß-unsaturated aldehyde functionality, and a nickel-mediated reductive Heck reaction to forge the [3.3.1]-azabicyclic core.


Assuntos
Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Estrutura Molecular , Oxirredução , Estereoisomerismo
15.
Yakugaku Zasshi ; 141(8): 985-994, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34334550

RESUMO

On the occasion of receiving the Pharmaceutical Society of Japan Award 2020, I explained our research activities on the total syntheses of polycyclic alkaloids as an invited review. The structure of lundurine B, which has an unstable cyclopropane fused indoline skeleton, was proved firstly by the total synthesis. I also describe the total syntheses of optically active lundurine B and rapidilectine B utilizing asymmetric desymmetrization of the spiro intermediate. We developed an intramolecular bond formation reaction between the 2-position of the furan ring to the iminium cation (furane-iminium cation cyclization) to synthesize manzamine alkaloids. The reaction was applied to the total synthesis of the core skeleton of nakadomarin A and ircinal A. A ring-closing metathesis reaction effectively applied to the synthesis of medium and large heterocyclic rings containing the cis double bond found in the structures of nakadomarin A and ircinal A. The total synthesis of schizocommunin, a metabolite of Schizophyllum commune isolated from a patient with human allergenic bronchopulmonary mycosis, was accomplished. We could correct the error in the proposed structure by total synthesis of the natural product. A part of the mechanism of cytotoxicity expression was clarified using newly synthesized shizocommunin.


Assuntos
Alcaloides/síntese química , Produtos Biológicos/síntese química , Ciclopropanos/síntese química , Compostos Policíclicos/síntese química , Alcaloides/química , Produtos Biológicos/química , Carbolinas/síntese química , Carbolinas/química , Ciclização , Ciclopropanos/química , Humanos , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Indóis/síntese química , Indóis/química , Aspergilose Pulmonar Invasiva/metabolismo , Compostos Policíclicos/química
16.
J Am Chem Soc ; 143(31): 12412-12417, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34324817

RESUMO

A total synthesis of (-)-strempeliopine is disclosed that enlists a powerful SmI2-mediated and BF3·OEt2-initiated dearomative transannular radical cyclization onto an indole by an N-acyl α-aminoalkyl radical that is derived by single electron reduction of an in situ generated iminium ion for formation of a quaternary center and the strategic C19-C2 bond in its core structure.


Assuntos
Alcaloides Indólicos/síntese química , Ciclização , Alcaloides Indólicos/química , Conformação Molecular , Estereoisomerismo
17.
Org Lett ; 23(15): 5964-5968, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34270272

RESUMO

Melonine is a basic monoterpene indole alkaloid (MIA) skeleton from Melodinus philliraeoides that was reported in 1983. The scarcity of its spectroscopic data questioned the validity of its structure. This prompted us to reisolate this molecule and to revise its structure into an unprecedented MIA scaffold. DFT-validated biosynthetic paths to both this new core and the originally reported form are proposed. The pathway to the original structure of melonine seems to be thermodynamically feasible, and that compound may exist as a natural product.


Assuntos
Apocynaceae/química , Alcaloides Indólicos/química , Monoterpenos/química , Produtos Biológicos , Alcaloides Indólicos/síntese química , Estrutura Molecular , Monoterpenos/síntese química
18.
J Am Chem Soc ; 143(29): 10872-10875, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34279940

RESUMO

Reported herein is the total synthesis of (+)-ambiguine G, the first member of the chlorinated pentacyclic ambiguines to yield to chemical synthesis. The synthesis is accomplished through a convergent strategy that proceeds in 10 steps from (S)-carvone oxide. Pivotal to the concise route is the successful realization of a [4+3] cycloaddition that conjoins two easily synthesized components of the carbon framework of the natural product. Also featured in the synthesis is the efficient, diastereoselective construction of a key vinylated chloro ketone and the unprecedented, one-pot reduction-elimination-oxidation sequence that transforms an enone to an advanced hydroxylated-diene intermediate.


Assuntos
Alcaloides Indólicos/síntese química , Halogenação , Alcaloides Indólicos/química , Conformação Molecular , Estereoisomerismo
19.
Nat Commun ; 12(1): 4158, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230497

RESUMO

Prenylated indole alkaloids featuring spirooxindole rings possess a 3R or 3S carbon stereocenter, which determines the bioactivities of these compounds. Despite the stereoselective advantages of spirooxindole biosynthesis compared with those of organic synthesis, the biocatalytic mechanism for controlling the 3R or 3S-spirooxindole formation has been elusive. Here, we report an oxygenase/semipinacolase CtdE that specifies the 3S-spirooxindole construction in the biosynthesis of 21R-citrinadin A. High-resolution X-ray crystal structures of CtdE with the substrate and cofactor, together with site-directed mutagenesis and computational studies, illustrate the catalytic mechanisms for the possible ß-face epoxidation followed by a regioselective collapse of the epoxide intermediate, which triggers semipinacol rearrangement to form the 3S-spirooxindole. Comparing CtdE with PhqK, which catalyzes the formation of the 3R-spirooxindole, we reveal an evolutionary branch of CtdE in specific 3S spirocyclization. Our study provides deeper insights into the stereoselective catalytic machinery, which is important for the biocatalysis design to synthesize spirooxindole pharmaceuticals.


Assuntos
Cicloexenos/síntese química , Cicloexenos/metabolismo , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/metabolismo , Vias Biossintéticas/genética , Catálise , Técnicas de Química Sintética , Compostos de Epóxi , Fermentação , Proteínas Fúngicas/genética , Modelos Moleculares , Estrutura Molecular , Oxigenases , Penicillium/genética , Penicillium/metabolismo
20.
Org Lett ; 23(14): 5368-5372, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34170714

RESUMO

Nortopsentin D is part of a class of bis(indole) alkaloids known for their biological activity, including inhibitory activity in tumoral cells and antifungal activity. Herein we describe the first total synthesis of nortopsentin D, in which amidine and dione undergo a pivotal condensation and subsequent cyclization via a pinacol-like rearrangement. This synthesis represents a unique strategy for the formation of 5,5-disubstituted (4H)-imidazol-4-one containing natural products, many of which have yet to succumb to total synthesis.


Assuntos
Glicóis/química , Imidazóis/síntese química , Alcaloides Indólicos/síntese química , Indóis/síntese química , Produtos Biológicos/síntese química , Imidazóis/química , Alcaloides Indólicos/química , Indóis/química , Estrutura Molecular
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