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1.
J Am Chem Soc ; 145(19): 10533-10541, 2023 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-37146260

RESUMO

Amino acids and their derivatives were probably instrumental in the transition of prebiotic chemistry to early biology. Accordingly, amino acid formation under prebiotic conditions has been intensively investigated. Unsurprisingly, most of these studies have taken place with water as the solvent. Herein, we describe an investigation into the formation and subsequent reactions of aminonitriles and their formylated derivatives in formamide. We find that N-formylaminonitriles form readily from aldehydes and cyanide in formamide, even in the absence of added ammonia, suggesting a potentially prebiotic source of amino acid derivatives. Alkaline processing of N-formylaminonitriles proceeds with hydration at the nitrile group faster than deformylation, protecting aminonitrile derivatives from reversion of the Strecker condensation equilibrium during hydration/hydrolysis and furnishing mixtures of N-formylated and unformylated amino acid derivatives. Furthermore, the facile synthesis of N-formyldehydroalanine nitrile is observed in formamide from glycolaldehyde and cyanide without intervention. Dehydroalanine derivatives have been proposed as important compounds for prebiotic peptide synthesis, and we demonstrate both a synthesis suggesting that they are potentially plausible components of a prebiotic inventory, and reactions showing their utility as abiotic precursors to a range of compounds of prebiological interest.


Assuntos
Aminoácidos , Formamidas , Formamidas/química , Nitrilas , Cianetos
3.
Chem Sci ; 13(5): 1313-1322, 2022 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-35222915

RESUMO

The bicyclo[2.2.2]diazaoctane alkaloids are a vast group of natural products which have been the focus of attention from the scientific community for several decades. This interest stems from their broad range of biological activities, their diverse biosynthetic origins, and their topologically complex structures, which combined make them enticing targets for chemical synthesis. In this article, full details of our synthetic studies into the chemical feasibility of a proposed network of biosynthetic pathways towards the brevianamide family of bicyclo[2.2.2]diazaoctane alkaloids are disclosed. Insights into issues of reactivity and selectivity in the biosynthesis of these structures have aided the development of a unified biomimetic synthetic strategy, which has resulted in the total synthesis of all known bicyclo[2.2.2]diazaoctane brevianamides and the anticipation of an as-yet-undiscovered congener.

4.
J Am Chem Soc ; 143(36): 14482-14486, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34469129

RESUMO

The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent finding that two RNA subunits (cytidine, C, and uridine, U) and two DNA subunits (deoxyadenosine, dA, and deoxyinosine, dI) can be coproduced in the same reaction network, compatible with a consistent geological scenario, supports this theory. However, a prebiotically plausible synthesis of the missing units (purine ribonucleosides and pyrimidine deoxyribonucleosides) in a unified reaction network remains elusive. Herein, we disclose a strictly stereoselective and furanosyl-selective synthesis of purine ribonucleosides (adenosine, A, and inosine, I) and purine deoxynucleosides (dA and dI), alongside one another, via a key photochemical reaction of thioanhydroadenosine with sulfite in alkaline solution (pH 8-10). Mechanistic studies suggest an unexpected recombination of sulfite and nucleoside alkyl radicals underpins the formation of the ribo C2'-O bond. The coproduction of A, I, dA, and dI from a common intermediate, and under conditions likely to have prevailed in at least some primordial locales, is suggestive of the potential coexistence of RNA and DNA building blocks at the dawn of life.


Assuntos
Desoxirribonucleosídeos/síntese química , Nucleosídeos de Purina/síntese química , Ribonucleosídeos/síntese química , Adenosina/análogos & derivados , Adenosina/efeitos da radiação , Evolução Química , Concentração de Íons de Hidrogênio , Modelos Químicos , Sulfitos/química , Sulfitos/efeitos da radiação , Raios Ultravioleta
5.
Astrobiology ; 21(9): 1099-1120, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34152196

RESUMO

Ultraviolet (UV) light has long been invoked as a source of energy for prebiotic chemical synthesis, but experimental support does not involve sources of UV light that look like the young Sun. Here we experimentally investigate whether the UV flux available on the surface of early Earth, given a favorable atmosphere, can facilitate a variety of prebiotic chemical syntheses. We construct a solar simulator for the UV light of the faint young Sun on the surface of early Earth, called StarLab. We then attempt a series of reactions testing different aspects of a prebiotic chemical scenario involving hydrogen cyanide (HCN), sulfites, and sulfides under the UV light of StarLab, including hypophosphite oxidation by UV light and hydrogen sulfide, photoreduction of HCN with bisulfite, the photoanomerization of α-thiocytidine, the production of a chemical precursor of a potentially prebiotic activating agent (nitroprusside), the photoreduction of thioanhydrouridine and thioanhydroadenosine, and the oxidation of ethanol (EtOH) by photochemically generated hydroxyl radicals. We compare the output of StarLab to the light of the faint young Sun to constrain the timescales over which these reactions would occur on the surface of early Earth. We predict that hypophosphite oxidation, HCN reduction, and photoproduction of nitroprusside would all operate on the surface of early Earth in a matter of days to weeks. The photoanomerization of α-thiocytidine would take months to complete, and the production of oxidation products from hydroxyl radicals would take years. The photoreduction of thioanhydrouridine with hydrogen sulfide did not succeed even after a long period of irradiation, providing a lower limit on the timescale of several years. The photoreduction of thioanhydroadenosine with bisulfite produced 2'-deoxyriboadenosine (dA) on the timescale of days. This suggests the plausibility of the photoproduction of purine deoxyribonucleotides, such as the photoproduction of simple sugars, proceeds more efficiently in the presence of bisulfite.


Assuntos
Planeta Terra , Atmosfera , Fotoquímica , Raios Ultravioleta
6.
Nat Commun ; 12(1): 3018, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021158

RESUMO

High-yielding and selective prebiotic syntheses of RNA and DNA nucleotides involve UV irradiation to promote the key reaction steps and eradicate biologically irrelevant isomers. While these syntheses were likely enabled by UV-rich prebiotic environment, UV-induced formation of photodamages in polymeric nucleic acids, such as cyclobutane pyrimidine dimers (CPDs), remains the key unresolved issue for the origins of RNA and DNA on Earth. Here, we demonstrate that substitution of adenine with 2,6-diaminopurine enables repair of CPDs with yields reaching 92%. This substantial self-repairing activity originates from excellent electron donating properties of 2,6-diaminopurine in nucleic acid strands. We also show that the deoxyribonucleosides of 2,6-diaminopurine and adenine can be formed under the same prebiotic conditions. Considering that 2,6-diaminopurine was previously shown to increase the rate of nonenzymatic RNA replication, this nucleobase could have played critical roles in the formation of functional and photostable RNA/DNA oligomers in UV-rich prebiotic environments.


Assuntos
2-Aminopurina/análogos & derivados , 2-Aminopurina/farmacologia , Reparo do DNA/efeitos dos fármacos , DNA/efeitos dos fármacos , Adenina , DNA/efeitos da radiação , Simulação de Dinâmica Molecular , Ácidos Nucleicos , Nucleotídeos , Dímeros de Pirimidina , RNA/química , Raios Ultravioleta/efeitos adversos
7.
J Am Chem Soc ; 143(19): 7219-7236, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33880920

RESUMO

Solar radiation is the principal source of energy available to Earth and has unmatched potential for the synthesis of organic material from primordial molecular building blocks. As well as providing the energy for photochemical synthesis of (proto)biomolecules of interest in origins of life-related research, light has also been found to often provide remarkable selectivity in these processes, for molecules that function in extant biology and against those that do not. As such, light is heavily implicated as an environmental input on the nascent Earth that was important for the emergence of complex yet selective chemical systems underpinning life. Reactivity and selectivity in photochemical prebiotic synthesis are discussed, as are their implications for origins of life scenarios and their plausibility, and the future directions of this research.


Assuntos
Nitrilas/síntese química , Origem da Vida , Raios Ultravioleta , Planeta Terra , Nitrilas/química , Processos Fotoquímicos , Energia Solar
8.
Nature ; 582(7810): 60-66, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32494078

RESUMO

The nature of the first genetic polymer is the subject of major debate1. Although the 'RNA world' theory suggests that RNA was the first replicable information carrier of the prebiotic era-that is, prior to the dawn of life2,3-other evidence implies that life may have started with a heterogeneous nucleic acid genetic system that included both RNA and DNA4. Such a theory streamlines the eventual 'genetic takeover' of homogeneous DNA from RNA as the principal information-storage molecule, but requires a selective abiotic synthesis of both RNA and DNA building blocks in the same local primordial geochemical scenario. Here we demonstrate a high-yielding, completely stereo-, regio- and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides: deoxyadenosine and deoxyinosine. Our synthesis uses key intermediates in the prebiotic synthesis of the canonical pyrimidine ribonucleosides (cytidine and uridine), and we show that, once generated, the pyrimidines persist throughout the synthesis of the purine deoxyribonucleosides, leading to a mixture of deoxyadenosine, deoxyinosine, cytidine and uridine. These results support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have coexisted before the emergence of life5.


Assuntos
DNA/química , Evolução Química , Origem da Vida , Nucleosídeos de Purina/síntese química , Nucleosídeos de Pirimidina/síntese química , RNA/química , Adenosina/análogos & derivados , Adenosina/química , Citidina/química , DNA/genética , Oxirredução/efeitos da radiação , Nucleosídeos de Purina/química , Nucleosídeos de Purina/genética , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/genética , RNA/genética , Uridina/química
9.
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
10.
Chem Sci ; 11(39): 10688-10697, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34094321

RESUMO

The complexity of the simplest conceivable cell suggests that the chemistry of prebiotic mixtures needs to be explored to understand the intricate network of prebiotic reactions that led to the emergence of life. Early cells probably relied upon compatible and interconnected chemistries to link RNA, peptides and membranes. Here we show that several types of vesicles, composed of prebiotically plausible mixtures of amphiphiles, spontaneously form and sustain the methyl isocyanide-mediated activation of amino acids, peptides and nucleotides. Activation chemistry also drives the advantageous conversion of reactive monoacylglycerol phosphates into inert cyclophospholipids, thus supporting their potential role as major constituents of protocells. Moreover, activation of prebiotic building blocks within fatty acid-based vesicles yields lipidated species capable of localising to and functionalising primitive membranes. Our findings describe a potentially prebiotic scenario in which the components of primitive cells undergo activation and provide new species that might have enabled an increase in the functionality of protocells.

11.
Nat Chem ; 11(5): 457-462, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936523

RESUMO

Breakthroughs in the study of the origin of life have demonstrated how some of the building blocks essential to biology could have been formed under various primordial scenarios, and could therefore have contributed to the chemical evolution of life. Missing building blocks are then sometimes inferred to be products of primitive biosynthesis, which can stretch the limits of plausibility. Here, we demonstrate the synthesis of 2'-deoxy-2-thiouridine, and subsequently 2'-deoxyadenosine and 2-deoxyribose, under prebiotic conditions. 2'-Deoxy-2-thiouridine is produced by photoreduction of 2,2'-anhydro-2-thiouridine, which is in turn formed by phosphorylation of 2-thiouridine-an intermediate of prebiotic RNA synthesis. 2'-Deoxy-2-thiouridine is an effective deoxyribosylating agent and may have functioned as such in either abiotic or proto-enzyme-catalysed pathways to DNA, as demonstrated by its conversion to 2'-deoxyadenosine by reaction with adenine, and 2-deoxyribose by hydrolysis. An alternative prebiotic phosphorylation of 2-thiouridine leads to the formation of its 5'-phosphate, showing that hypotheses in which 2-thiouridine was a key component of early RNA sequences are within the bounds of synthetic credibility.


Assuntos
Evolução Química , Tiouridina/análogos & derivados , Desoxiadenosinas/síntese química , Modelos Químicos , Oxirredução , Fosforilação , Tiouridina/síntese química , Tiouridina/química , Tiouridina/efeitos da radiação , Raios Ultravioleta
12.
Angew Chem Int Ed Engl ; 57(21): 6198-6202, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29637681

RESUMO

A bio-inspired, pyrrolidine-mediated, dimerization of para-quinols has been developed. It represents one of the most complex, yet general, dimerization reactions ever disclosed, selectively forming four new bonds, four new rings, and eight new contiguous stereogenic centres. The para-quinol starting materials are easily handled, bench-stable compounds, accessed in just one step from aromatic feedstocks. The reaction can be scaled up to give grams of polycyclic material, primed for further elaboration.

13.
Phys Chem Chem Phys ; 20(4): 2872-2879, 2018 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-29327022

RESUMO

This study investigates the problem of diffusion kinetics in a three-body system, motivated by the theory of radiation chemical kinetics. The backward diffusion equation for the joint density of the distances is formulated, and an explicit formula for the infinitesimal covariance of two diffusing distances is derived. The Clifford-Green theorem is used to show how the infinitesimal covariance of two distances is linked to the covariance of the corresponding two squared distances as time evolves. In addition, computer simulations for the problem are presented, which indicate that hitting probabilities are also correlated. While the results indicate that more work is needed before a usable correction to the independence approximation is possible, clear progress has been made.

14.
Phys Chem Chem Phys ; 19(30): 20016-20028, 2017 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-28722734

RESUMO

This work describes stochastic models developed to study the competition between radical scavenging and recombination for simple model systems typical of radiation chemistry, where the reactive particles are tightly clustered and reactions are assumed fully diffusion limited. Three models are developed: a Monte Carlo random flights model with a periodic boundary condition for scavengers, Monte Carlo simulations in which the scavenging rate is calculated from the Smoluchowski theory for diffusion-limited reactions and a modification of the independent reaction times method where the scavengers close to the spur are explicitly included and the scavengers further away are treated as a continuum. The results indicate that the Smoluchowski theory makes a systematic overestimate of the scavenging rate when such competition is present. A correction for the Smoluchowski rate constant is suggested, an analytical justification is presented and it is tested against the simulations, and shown to be a substantial improvement.

15.
Org Biomol Chem ; 15(15): 3105-3129, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28327756

RESUMO

The Diels-Alder reaction that involves a nitrogen atom in the diene or dienophile is termed the aza-Diels-Alder reaction. As well as the powerful all-carbon Diels-Alder reaction, the aza-Diels-Alder reaction has also played an important role in the total synthesis of natural products. Herein, we review various natural products using an aza-Diels-Alder reaction as a key step to their total synthesis, and divide the syntheses into inter- and intra-molecular aza-Diels-Alder reactions and a retro-aza-Diels-Alder reaction. Inter- and intra-molecular aza-Diels-Alder reactions involve an imine as an electron deficient dienophile and an imine as an electron deficient azadiene. The significance of the aza-Diels-Alder reaction for the construction of a six-membered ring containing nitrogen is tremendous, but the development of asymmetric, in particular catalytic enantioselective intramolecular aza-Diels-Alder reaction in the total synthesis of natural products remains highly challenging, and will no doubt see enormous advances in the future.


Assuntos
Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos , Produtos Biológicos/química , Iminas/química
16.
Angew Chem Int Ed Engl ; 55(32): 9244-8, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27375221

RESUMO

[Pd(PPh3 )4 ] catalyzes a Suzuki-Miyaura-like twofold cross-coupling sequence between underivatized propargylic diols and either aryl or alkenyl boronic acids to furnish highly substituted 1,3-dienes. Thus, 2,3-diaryl-1,3-butadienes and their dialkenic congeners ([4]dendralenes) are delivered in a (pseudo)halogen-free, single-step synthesis which supersedes existing methods. Allenols are also readily formed. Treatment of these single- and twofold cross-coupled products with acid leads to remarkably short syntheses of highly-substituted benzofulvenes and aryl indenes, respectively.

17.
Health Expect ; 17(2): 186-96, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22390825

RESUMO

BACKGROUND AND CONTEXT: Most people with urinary incontinence are given limited choice when provided with absorbent products through the British National Health Service (NHS), even though the available range is large. OBJECTIVE: To investigate users' preferences for four disposable designs (inserts, all-in-ones, belted/T-shaped and pull-ups) and towelling washable/reusable products, day and night. DESIGN: Shopping experiment. SETTING AND PARTICIPANTS: Community-dwelling women and men in England with moderate-to-heavy urinary incontinence recruited to a larger trial. INTERVENTION: Participants tested each design and selected products they would prefer with a range of different budgets. MAIN OUTCOME MEASURES: Design preferences (rankings); 'purchasing' decisions from designated budgets. Results Eighty-five participants (49 men) tested products, 75 completed the shopping experiment. Inserts, most frequently supplied by the NHS, were ranked second to pull-ups by women and lowest by men. When faced with budget constraints, up to 40% of participants opted to 'mix-and-match' designs. Over 15 different combinations of products were selected by participants in the shopping experiment. Most (91%) stated a willingness to 'top-up' assigned budgets from income to secure preferred designs. DISCUSSION: Participants displayed diverse preferences. Enabling user choice of absorbent product design through individual budgets could improve satisfaction of consumers and efficiency of allocation of limited NHS resources. CONCLUSION: Recent policy for the NHS seeks to provide consumers with more control in their care. Extension of the concept of individual budgets to continence supplies could be feasible and beneficial for patients and provide better value-for-money within the NHS. Further research is warranted.


Assuntos
Tampões Absorventes para a Incontinência Urinária/classificação , Tampões Absorventes para a Incontinência Urinária/economia , Preferência do Paciente , Medicina Estatal/estatística & dados numéricos , Incontinência Urinária/economia , Adulto , Inglaterra , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Socioeconômicos
19.
FEBS Lett ; 584(2): 318-24, 2010 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-19932103

RESUMO

The T box mechanism is widely used in Gram-positive bacteria to regulate expression of aminoacyl-tRNA synthetase genes and genes involved in amino acid biosynthesis and uptake. Binding of a specific uncharged tRNA to a riboswitch element in the nascent transcript causes a structural change in the transcript that promotes expression of the downstream coding sequence. In most cases, this occurs by stabilization of an antiterminator element that competes with formation of a terminator helix. Specific tRNA recognition by the nascent transcript results in increased expression of genes important for tRNA aminoacylation in response to decreased pools of charged tRNA.


Assuntos
Aminoacil-tRNA Sintetases/genética , Bacillus subtilis/enzimologia , Regulação Bacteriana da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , RNA de Transferência/metabolismo , Bacillus subtilis/genética , RNA de Transferência/química , RNA de Transferência/genética , Transcrição Gênica
20.
J R Soc Interface ; 7 Suppl 2: S257-64, 2010 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-20007172

RESUMO

A critical requirement in the proposed chemical model of the avian magnetic compass is that the molecules that play host to the magnetically sensitive radical pair intermediates must be immobilized and rotationally ordered within receptor cells. Rotational disorder would cause the anisotropic responses of differently oriented radical pairs within the same cell to interfere destructively, while rapid molecular rotation would tend to average the crucial anisotropic magnetic interactions and induce electron spin relaxation, reducing the sensitivity to the direction of the geomagnetic field. So far, experimental studies have been able to shed little light on the required degree of ordering and immobilization. To address this question, computer simulations have been performed on a collection of radical pairs undergoing restricted rigid-body rotation, coherent anisotropic spin evolution, electron spin relaxation and spin-selective recombination reactions. It is shown that the ordering and motional constraints necessary for efficient magnetoreception can be simultaneously satisfied if the radical pairs are uniaxially ordered with a moderate order parameter and if their motional correlation time is longer than about a quarter of their lifetime.


Assuntos
Biopolímeros/química , Biopolímeros/efeitos da radiação , Modelos Químicos , Simulação por Computador , Relação Dose-Resposta à Radiação , Campos Eletromagnéticos , Estresse Mecânico
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