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1.
Nat Commun ; 11(1): 6214, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277480

RESUMO

Radioprotectors for acute injuries caused by large doses of ionizing radiation are vital to national security, public health and future development of humankind. Here, we develop a strategy to explore safe and efficient radioprotectors by combining Hantzsch's reaction, high-throughput methods and polymer chemistry. A water-soluble polymer with low-cytotoxicity and an excellent anti-radiation capability has been achieved. In in vivo experiments, this polymer is even better than amifostine, which is the only approved radioprotector for clinical applications, in effectively protecting zebrafish embryos from fatally large doses of ionizing radiation (80 Gy X-ray). A mechanistic study also reveals that the radioprotective ability of this polymer originates from its ability to efficiently prevent DNA damage due to high doses of radiation. This is an initial attempt to explore polymer radioprotectors via a multi-component reaction. It allows exploiting functional polymers and provides the underlying insights to guide the design of radioprotective polymers.


Assuntos
Técnicas de Química Sintética/métodos , Embrião não Mamífero/efeitos da radiação , Fibroblastos/efeitos da radiação , Polímeros/síntese química , Protetores contra Radiação/síntese química , Raios X , Amifostina/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/embriologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Camundongos , Modelos Químicos , Estrutura Molecular , Polímeros/química , Polímeros/farmacologia , Protetores contra Radiação/química , Protetores contra Radiação/farmacologia , Peixe-Zebra/embriologia
2.
Nat Commun ; 11(1): 6308, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33298909

RESUMO

Despite the availability of numerous routes to substituted nicotinates based on the Bohlmann-Rahtz pyridine synthesis, the existing methods have several limitations, such as the inevitable ortho-substitutions and the inability to conjugate vitamin B3 to other pharmaceutical agents. Inspired by the biosynthesis of nicotinic acid (a form of vitamin B3) from tryptophan, we herein report the development of a strategy for the synthesis of meta-aminoaryl nicotinates from 3-formyl(aza)indoles. Our strategy is mechanistically different from the reported routes and involves the transformation of (aza)indole scaffolds into substituted meta-aminobiaryl scaffolds via Aldol-type addition and intramolecular cyclization followed by C-N bond cleavage and re-aromatization. Unlike previous synthetic routes, this biomimetic method utilizes propiolates as enamine precursors and thus allows access to ortho-unsubstituted nicotinates. In addition, the synthetic feasibility toward the halo-/boronic ester-substituted aminobiaryls clearly differentiates the present strategy from other cross-coupling strategies. Most importantly, our method enables the late-stage conjugation of bioactive (hetero)arylamines with nicotinates and nicotinamides and allows access to the previously unexplored chemical space for biomedical research.


Assuntos
Aminas/síntese química , Biomimética/métodos , Técnicas de Química Sintética/métodos , Niacina/síntese química , Niacinamida/síntese química , Compostos Aza/síntese química , Ciclização , Estudos de Viabilidade , Indóis/síntese química , Estrutura Molecular , Niacina/análogos & derivados , Niacinamida/análogos & derivados
3.
Nat Protoc ; 15(11): 3579-3594, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33028982

RESUMO

Efficient methods to functionalize proteins are essential for the development of many diagnostic and therapeutic compounds, such as fluorescent probes for immunohistochemistry, zirconium-89 radiolabeled mAbs (89Zr-mAbs) for positron emission tomography and antibody-drug conjugates (ADCs). This protocol describes a step-by-step procedure for the light-induced functionalization of proteins with compounds bearing the photochemically active aryl azide group. As an illustration of the potential utility of our approach, this protocol focuses on the synthesis of 89Zr-mAbs using photoactivatable derivatives of the metal ion binding chelate desferrioxamine B (DFO). The light-induced synthesis of 89Zr-mAbs is a unique, one-pot process involving simultaneous radiolabeling and protein conjugation. The photoradiochemical synthesis of purified 89Zr-mAbs, starting from unmodified proteins, [89Zr][Zr(C2O4)4]4- (89Zr-oxalate), and a photoactivatable DFO derivative, can be performed in <90 min. The method can be easily adapted to prepare other radiolabeled proteins, ADCs or fluorescently tagged proteins by using drug molecules or fluorophores functionalized with photoactive moieties.


Assuntos
Anticorpos Monoclonais/química , Imunoconjugados/química , Radioisótopos/química , Zircônio/química , Técnicas de Química Sintética/instrumentação , Técnicas de Química Sintética/métodos , Desenho de Equipamento , Luz , Modelos Moleculares
4.
Nat Commun ; 11(1): 5345, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093494

RESUMO

Due to its longevity and enormous information density, DNA is an attractive medium for archival storage. The current hamstring of DNA data storage systems-both in cost and speed-is synthesis. The key idea for breaking this bottleneck pursued in this work is to move beyond the low-error and expensive synthesis employed almost exclusively in today's systems, towards cheaper, potentially faster, but high-error synthesis technologies. Here, we demonstrate a DNA storage system that relies on massively parallel light-directed synthesis, which is considerably cheaper than conventional solid-phase synthesis. However, this technology has a high sequence error rate when optimized for speed. We demonstrate that even in this high-error regime, reliable storage of information is possible, by developing a pipeline of algorithms for encoding and reconstruction of the information. In our experiments, we store a file containing sheet music of Mozart, and show perfect data recovery from low synthesis fidelity DNA.


Assuntos
Técnicas de Química Sintética/métodos , DNA/síntese química , Armazenamento e Recuperação da Informação/métodos , Algoritmos , Sequência de Bases , DNA/química , DNA/genética , Biblioteca Gênica , Luz , Método de Monte Carlo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Processos Fotoquímicos , Análise de Sequência de DNA
5.
Nature ; 588(7836): 83-88, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33049755

RESUMO

Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years1-7. However, the field has progressed greatly since the development of early programs such as LHASA1,7, for which reaction choices at each step were made by human operators. Multiple software platforms6,8-14 are now capable of completely autonomous planning. But these programs 'think' only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary15,16 and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program's knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships17,18, allowing it to 'strategize' over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization.


Assuntos
Inteligência Artificial , Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos , Química Orgânica/métodos , Software , Inteligência Artificial/normas , Automação/métodos , Automação/normas , Benzilisoquinolinas/síntese química , Benzilisoquinolinas/química , Técnicas de Química Sintética/normas , Química Orgânica/normas , Indanos/síntese química , Indanos/química , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Bases de Conhecimento , Lactonas/síntese química , Lactonas/química , Macrolídeos/síntese química , Macrolídeos/química , Reprodutibilidade dos Testes , Sesquiterpenos/síntese química , Sesquiterpenos/química , Software/normas , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química
6.
Nat Commun ; 11(1): 5036, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028818

RESUMO

Alkyl carboxylic acids as well as primary amines are ubiquitous in all facets of biological science, pharmaceutical science, chemical science and materials science. By chemical conversion to redox-active esters (RAE) and Katritzky's N-alkylpyridinium salts, respectively, alkyl carboxylic acids and primary amines serve as ideal starting materials to forge new connections. In this work, a Mn-mediated reductive decarboxylative/deaminative functionalization of activated aliphatic acids and primary amines is disclosed. A series of C-X (X = S, Se, Te, H, P) and C-C bonds are efficiently constructed under simple and mild reaction conditions. The protocol is applicable to the late-stage modification of some structurally complex natural products or drugs. Preliminary mechanistic studies suggest the involvement of radicals in the reaction pathway.


Assuntos
Aminas/química , Técnicas de Química Sintética/métodos , Ácidos Graxos/química , Manganês/química , Catálise , Estudos de Viabilidade , Oxirredução
7.
Nat Commun ; 11(1): 4443, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895371

RESUMO

Aryl azole scaffolds are present in a wide range of pharmaceutically relevant molecules. Their ortho-selective metalation at the aryl ring is challenging, due to the competitive metalation of the more acidic heterocycle. Seeking a practical access to a key Active Pharmaceutical Ingredient (API) intermediate currently in development, we investigated the metalation of 1-aryl-1H-1,2,3-triazoles and other related heterocycles with sterically hindered metal-amide bases. We report here a room temperature and highly regioselective ortho-magnesiation of several aryl azoles using a tailored magnesium amide, TMPMgBu (TMP = 2,2,6,6-tetramethylpiperidyl) in hydrocarbon solvents followed by an efficient Pd-catalyzed arylation. This scalable and selective reaction allows variation of the initial substitution pattern of the aryl ring, the nature of the azole moiety, as well as the nature of the electrophile. This versatile method can be applied to the synthesis of bioactive azole derivatives and complements existing metal-mediated ortho-functionalizations.


Assuntos
Azóis/química , Técnicas de Química Sintética/métodos , Estereoisomerismo , Catálise , Estrutura Molecular , Triazóis/química
8.
Nat Commun ; 11(1): 4170, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820174

RESUMO

Sulfur-sulfur motifs widely occur in vital function and drug design, which yearns for polysulfide construction in an efficient manner. However, it is a great challenge to install desired functional groups on both sides of sulfur-sulfur bonds at liberty. Herein, we designed a mesocyclic bilateral disulfurating reagent for sequential assembly and modular installation of polysulfides. Based on S-O bond dissociation energy imparity (mesocyclic compared to linear imparity is at least 5.34 kcal mol-1 higher), diverse types of functional molecules can be bridged via sulfur-sulfur bonds distinctly. With these stable reagents, excellent reactivities with nucleophiles including C, N and S are comprehensively demonstrated, sequentially installing on both sides of sulfur-sulfur motif with various substituents to afford six species of unsymmetrical polysulfides including di-, tri- and even tetra-sulfides. Life-related molecules, natural products and pharmaceuticals can be successively cross-linked with sulfur-sulfur bond. Remarkably, the cyclization of tri- and tetra-peptides affords 15- and 18-membered cyclic disulfide peptides with this reagent, respectively.


Assuntos
Dissulfetos/química , Indicadores e Reagentes/química , Peptídeos/química , Sulfetos/química , Enxofre/química , Produtos Biológicos/química , Técnicas de Química Sintética/métodos , Ciclização , Indicadores e Reagentes/síntese química , Modelos Químicos , Estrutura Molecular , Oxirredução , Preparações Farmacêuticas/química
9.
J Oleo Sci ; 69(7): 693-701, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612019

RESUMO

Fatty acid sugar esters are non-ionic surfactant active agents with excellent performance and many uses. This work is devoted to the synthesis of sugar esters by the esterification reaction of sugar with mixed carboxylicpalmitic anhydrides using resin Amberlyst-15 as heterogeneous acid catalyst. These anhydrides should be stable and react as acylating agents. Influence of different reaction parameters, such as the molar ratio (sucrose/anhydride), the type of solvent and the reaction time on the yield of the esterification reaction were studied. The esterification reaction of sucrose with mixed palmitic benzoic anhydride leads to a mixture of sucrose esters of palmitic acid with a good percentage of conversion. The mixed anhydride was both reactive and selective for the preparation of fatty acid ester.


Assuntos
Benzoatos/química , Ácidos Carboxílicos/química , Técnicas de Química Sintética/métodos , Ésteres/síntese química , Ácidos Graxos/síntese química , Ácido Palmítico/química , Sacarose/síntese química , Acilação , Catálise , Esterificação , Solventes , Estirenos , Tensoativos/síntese química , Fatores de Tempo
10.
Chem Soc Rev ; 49(11): 3638-3687, 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32396593

RESUMO

Biomass is increasingly used as a source of fuels and chemicals as a renewable alternative to fossil feedstocks. Cellulose, hemicellulose and lignin are converted into platform chemicals from which a large range of compounds are derived with different structures. These biomass transformation processes require the use of efficient and durable catalysts that should drive the selectivity of the process. This review focuses on the use of metal-organic frameworks (MOFs) and derivatives as catalysts for biomass conversion. After an introduction setting up the importance of the field and the MOF features that justify their prevalence as heterogeneous catalysts for liquid phase reactions, the two main parts of the review are the description of MOF synthesis and adaptation and coverage of the catalytic reactions involving biomass substrates organized according to the type of MOF. The last section summarizes the current state of the art and our outlook for the future development of the field.


Assuntos
Materiais Biocompatíveis/química , Estruturas Metalorgânicas/química , Biocombustíveis , Biomassa , Catálise , Celulose/química , Técnicas de Química Sintética/métodos , Lignina/química , Conformação Molecular , Polímeros/química , Dióxido de Silício/química , Solventes/química , Propriedades de Superfície
11.
J Med Chem ; 63(16): 8791-8808, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32352286

RESUMO

Ring systems in pharmaceuticals, agrochemicals, and dyes are ubiquitous chemical motifs. While the synthesis of common ring systems is well described and novel ring systems can be readily and computationally enumerated, the synthetic accessibility of unprecedented ring systems remains a challenge. "Ring Breaker" uses a data-driven approach to enable the prediction of ring-forming reactions, for which we have demonstrated its utility on frequently found and unprecedented ring systems, in agreement with literature syntheses. We demonstrate the performance of the neural network on a range of ring fragments from the ZINC and DrugBank databases and highlight its potential for incorporation into computer aided synthesis planning tools. These approaches to ring formation and retrosynthetic disconnection offer opportunities for chemists to explore and select more efficient syntheses/synthetic routes.


Assuntos
Técnicas de Química Sintética/métodos , Compostos Heterocíclicos/síntese química , Hidrocarbonetos Cíclicos/síntese química , Redes Neurais de Computação , Bases de Dados de Compostos Químicos
12.
Sci Rep ; 10(1): 6492, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32300148

RESUMO

A novel and efficient protocol for the synthesis of thiazolo[4,5-c]pyridazine derivatives was developed. The approach utilizes a high pressure Q-Tube reactor to promote cyclocondensation reactions between 3-oxo-2-arylhydrazonopropanals and 4-thiazolidinones. The process has a significantly high atom economy and a broad substrate scope, as well as being applicable to gram scale syntheses. The in vitro cytotoxic activities of the synthesized thiazolo[4,5-c]pyridazine derivatives were examined utilizing a MTT colorimetric assay with doxorubicin as a reference anti-cancer drug and three human cancer cell lines including HCT-116 (colon), MCF-7 (breast) and A549 (lung). The results show that thiazolopyridazines 7c, h, k and p have high cytotoxic activity against the MCF-7 cell line with respective IC50 values of 14.34, 10.39, 15.43 and 13.60 µM. Moreover, the thiazolopyridazine derivative 7s also show promising cytotoxic activity against the HCT-116 cell line with IC50 = 6.90 µM . Observations made in this effort serve as a basis for further investigations into the design and preparation of new anti-cancer drugs.


Assuntos
Antineoplásicos/síntese química , Técnicas de Química Sintética/métodos , Piridazinas/farmacologia , Tiazóis/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Química Farmacêutica/métodos , Ciclização , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Pressão , Piridazinas/síntese química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazolidinas/química
13.
Nat Protoc ; 15(5): 1707-1741, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32269381

RESUMO

Here, we provide a protocol to generate synthetic nanobodies, known as sybodies, against any purified protein or protein complex within a 3-week period. Unlike methods that require animals for antibody generation, sybody selections are carried out entirely in vitro under controlled experimental conditions. This is particularly relevant for the generation of conformation-specific binders against labile membrane proteins or protein complexes and allows selections in the presence of non-covalent ligands. Sybodies are especially suited for cases where binder generation via immune libraries fails due to high sequence conservation, toxicity or insufficient stability of the target protein. The procedure entails a single round of ribosome display using the sybody libraries encoded by mRNA, followed by two rounds of phage display and binder identification by ELISA. The protocol is optimized to avoid undesired reduction in binder diversity and enrichment of non-specific binders to ensure the best possible selection outcome. Using the efficient fragment exchange (FX) cloning method, the sybody sequences are transferred from the phagemid to different expression vectors without the need to amplify them by PCR, which avoids unintentional shuffling of complementary determining regions. Using quantitative PCR (qPCR), the efficiency of each selection round is monitored to provide immediate feedback and guide troubleshooting. Our protocol can be carried out by any trained biochemist or molecular biologist using commercially available reagents and typically gives rise to 10-30 unique sybodies exhibiting binding affinities in the range of 500 pM-500 nM.


Assuntos
Técnicas de Química Sintética/métodos , Anticorpos de Domínio Único/química , Bacteriófagos/química , Ribossomos/química
14.
Nat Protoc ; 15(5): 1760-1774, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32296151

RESUMO

The direct cleavage of otherwise inert C-H bonds has emerged as a sustainable approach for organic synthesis; in contrast to other approaches, these reactions result in the formation of fewer undesired by-products and do not require pre-functionalization steps. In recent years, oxidative C-H/N-H alkyne annulations and C-H oxygenations were realized by 3d metals. Unfortunately, most of these reactions require stoichiometric amounts of often toxic chemical oxidants. This protocol provides a general method for cobaltaelectro-catalyzed C-H activations of benzamides. Here, anodic oxidation obviates the need for a chemical oxidant and uses 10-20% of a more environmentally benign, inexpensive catalyst. We outline a detailed and precise description of the designed electrolytic cell for metallaelectrocatalysis, including readily available electrode materials and electrode holders. The custom-made device is further compared with the commercially available and standardized ElectraSyn 2.0 electrochemistry kit. As example applications of this approach, we describe cobaltaelectro-catalyzed C-H activation protocols for the direct C-H oxygenation of benzamides and resource-economical synthesis of isoquinolones. The cobaltaelectrocatalysis setup and reaction take about 17 h, while an additional 5 h have to be anticipated for workup and chromatographic purification. The methods described herein feature broad functional group tolerance, operational simplicity, low waste-product formation and an overall exceptional level of resource economy.


Assuntos
Benzamidas/química , Técnicas de Química Sintética/métodos , Cobalto/química , Técnicas Eletroquímicas/métodos , Catálise , Oxirredução
15.
Nature ; 581(7809): 415-420, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32268340

RESUMO

The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and small-molecule biological probes1,2 has stimulated efforts towards their streamlined synthesis3-9. Arguably the most robust method for the synthesis of tertiary alkylamines is carbonyl reductive amination3, which comprises two elementary steps: the condensation of a secondary alkylamine with an aliphatic aldehyde to form an all-alkyl-iminium ion, which is subsequently reduced by a hydride reagent. Direct strategies have been sought for a 'higher order' variant of this reaction via the coupling of an alkyl fragment with an alkyl-iminium ion that is generated in situ10-14. However, despite extensive efforts, the successful realization of a 'carbonyl alkylative amination' has not yet been achieved. Here we present a practical and general synthesis of tertiary alkylamines through the addition of alkyl radicals to all-alkyl-iminium ions. The process is facilitated by visible light and a silane reducing agent, which trigger a distinct radical initiation step to establish a chain process. This operationally straightforward, metal-free and modular transformation forms tertiary amines, without structural constraint, via the coupling of aldehydes and secondary amines with alkyl halides. The structural and functional diversity of these readily available precursors provides a versatile and flexible strategy for the streamlined synthesis of complex tertiary amines.


Assuntos
Aminas/química , Aminas/síntese química , Técnicas de Química Sintética/métodos , Aldeídos/química , Alquilação , Aminação , Loratadina/análogos & derivados , Loratadina/síntese química , Loratadina/química
16.
J Med Chem ; 63(16): 8667-8682, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32243158

RESUMO

Artificial intelligence and machine learning have demonstrated their potential role in predictive chemistry and synthetic planning of small molecules; there are at least a few reports of companies employing in silico synthetic planning into their overall approach to accessing target molecules. A data-driven synthesis planning program is one component being developed and evaluated by the Machine Learning for Pharmaceutical Discovery and Synthesis (MLPDS) consortium, comprising MIT and 13 chemical and pharmaceutical company members. Together, we wrote this perspective to share how we think predictive models can be integrated into medicinal chemistry synthesis workflows, how they are currently used within MLPDS member companies, and the outlook for this field.


Assuntos
Técnicas de Química Sintética/métodos , Química Farmacêutica/métodos , Aprendizado de Máquina , Indústria Química/métodos , Descoberta de Drogas/métodos , Modelos Químicos , Pesquisa Farmacêutica/métodos
17.
Nat Protoc ; 15(5): 1742-1759, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32269382

RESUMO

[18F]6-fluoro-L-DOPA ([18F]FDOPA) is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that is used to image Parkinson's disease, brain tumors, and focal hyperinsulinism of infancy. Despite these important applications, [18F]FDOPA PET remains underutilized because of synthetic challenges associated with accessing the radiotracer for clinical use; these stem from the need to radiofluorinate a highly electron-rich catechol ring in the presence of an amino acid. To address this longstanding challenge in the PET radiochemistry community, we have developed a one-pot, two-step synthesis of high-molar-activity [18F]FDOPA by Cu-mediated fluorination of a pinacol boronate (BPin) precursor. The method is fully automated, has been validated to work well at two separate sites (an academic facility with a cyclotron on site and an industry lab purchasing [18F]fluoride from an outside vendor), and provides [18F]FDOPA in reasonable radiochemical yield (2.44 ± 0.70 GBq, 66 ± 19 mCi, 5 ± 1%), excellent radiochemical purity (>98%) and high molar activity (76 ± 30 TBq/mmol, 2,050 ± 804 Ci/mmol), n = 26. Herein we report a detailed protocol for the synthesis of [18F]FDOPA that has been successfully implemented at two sites and validated for production of the radiotracer for human use.


Assuntos
Ácidos Borônicos/química , Técnicas de Química Sintética/métodos , Cobre/química , Di-Hidroxifenilalanina/análogos & derivados , Glicóis/química , Di-Hidroxifenilalanina/síntese química , Radioisótopos de Flúor , Halogenação
18.
Nat Chem ; 12(7): 615-619, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32284576

RESUMO

The fungal-derived bicyclo[2.2.2]diazaoctane alkaloids are of interest to the scientific community for their potent and varied biological activities. Within this large and diverse family of natural products, the insecticidal metabolite (+)-brevianamide A is particularly noteworthy for its synthetic intractability and inexplicable biogenesis. Despite five decades of research, this alkaloid has remained an elusive target for chemical synthesis due to insurmountable issues of reactivity and selectivity associated with all previously explored strategies. We herein report the chemical synthesis of (+)-brevianamide A (seven steps, 7.2% overall yield, 750 mg scale), which involves a bioinspired cascade transformation of the linearly fused (-)-dehydrobrevianamide E into the topologically complex bridged-spiro-fused structure of (+)-brevianamide A.


Assuntos
Alcaloides/síntese química , Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos , Piperazinas/síntese química , Alcaloides/biossíntese , Alcaloides/química , Produtos Biológicos/química , Ciclização , Estrutura Molecular , Penicillium/metabolismo , Piperazinas/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Estereoisomerismo
19.
PLoS One ; 15(4): e0231147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287324

RESUMO

This paper reports the synthesis, characterization, anticancer screening and quantum chemical calculation of a tetradentate Schiff base 2,2'-((1E,1'E)-((2,2-dimethylpropane-1,3-diyl)bis- (azanylylidene))bis(methanylylidene))bis(4-fluorophenol) (L2F) and its Pd (II) complex (PdL2F). The compounds were characterized via UV-Visible, NMR, IR spectroscopy and single crystal x-ray diffraction. Density Functional Theory (DFT) and time-dependent DFT calculations in gas and solvent phases were carried out using B3LYP, B3P86, CAM-B3LYP and PBE0 hybrid functionals combined with LanL2DZ basis set. Complexation of L2F to form PdL2F was observed to cause a bathochromic shift of the maximum absorption bands of n-π* from 327 to 410 nm; an upfield shift for δ (HC = N) from 8.30 to 7.96 ppm and a decreased wavenumber for ν(C = N) from 1637 to 1616 cm-1. Overall, the UV-Vis, NMR and IR spectral data are relatively well reproduced through DFT and TD-DFT methods. L2F and PdL2F showed IC50 of 90.00 and 4.10 µg/mL, respectively, against human colorectal carcinoma (HCT116) cell lines, signifying increased anticancer activity upon complexation with Pd (II).


Assuntos
Complexos de Coordenação/farmacologia , Paládio/farmacologia , Bases de Schiff/farmacologia , Técnicas de Química Sintética/métodos , Complexos de Coordenação/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Concentração Inibidora 50 , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Paládio/química , Bases de Schiff/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier
20.
Top Curr Chem (Cham) ; 378(2): 34, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32206929

RESUMO

In past decades, interdisciplinary research has been of great interest for scholars. Thiazolidine motifs behave as a bridge between organic synthesis and medicinal chemistry and compel researchers to explore new drug candidates. Thiazolidine motifs are very intriguing heterocyclic five-membered moieties present in diverse natural and bioactive compounds having sulfur at the first position and nitrogen at the third position. The presence of sulfur enhances their pharmacological properties, and, therefore, they are used as vehicles in the synthesis of valuable organic combinations. They show varied biological properties viz. anticancer, anticonvulsant, antimicrobial, anti-inflammatory, neuroprotective, antioxidant activity and so on. This diversity in the biological response makes it a highly prized moiety. Based on literature studies, various synthetic approaches like multicomponent reaction, click reaction, nano-catalysis and green chemistry have been employed to improve their selectivity, purity, product yield and pharmacokinetic activity. In this review article, we have summarized systematic approaches for the synthesis of thiazolidine and its derivatives, along with their pharmacological activity, including advantages of green synthesis, atom economy, cleaner reaction profile and catalyst recovery which will help scientists to probe and stimulate the study of these scaffolds.


Assuntos
Técnicas de Química Sintética/métodos , Tiazolidinas/química , Estrutura Molecular
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