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1.
Oncol Rep ; 41(6): 3517-3526, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002359

RESUMO

Resveratrol, a plant­derived stilbene compound, has exhibited anticancerous properties, including breast cancer. Stilbenes have a molecular structure highly similar to estrogen and have the ability to bind estrogen receptors and regulate activity. Numerous studies have demonstrated the effectiveness of resveratrol in estrogen receptor­positive (ER­positive) subtypes of breast cancer, yet the effects in ER­negative subtypes, including triple­negative breast cancer (TNBC), have been limited. In the present study, resveratrol and 28 analogues were tested on a panel of ER­positive and TNBC cell lines to determine effects on cell viability. Several compounds exhibited significant impacts on cell viability and suggested changes in cell morphology, with high potency of select compounds compared to resveratrol observed in a dose­dependent manner. Due to the lack of estrogen receptors in TNBC and the estrogenic nature of stilbenes, regulation of breast cancer­associated cellular pathways was assessed for five analogues shown to significantly inhibit cell viability. Top regulated pathways included apoptosis (confirmed by caspase assay) and DNA damage repair. Overall, our results indicated several resveratrol analogues to be active in ER­negative phenotypes, acting through an ER receptor­independent manner, supporting further investigation into their mechanism of action and use as potential chemotherapeutics in higher­risk breast cancer cases.


Assuntos
Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Resveratrol/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Feminino , Humanos , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
2.
J Org Chem ; 83(11): 5954-5968, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29717607

RESUMO

A general protocol is described for inducing enantioselective halolactonizations of unsaturated carboxylic acids using novel bifunctional organic catalysts derived from a chiral binaphthalene scaffold. Bromo- and iodolactonization reactions of diversely substituted, unsaturated carboxylic acids proceed with high degrees of enantioselectivity, regioselectivity, and diastereoselectivity. Notably, these BINOL-derived catalysts are the first to induce the bromo- and iodolactonizations of 5-alkyl-4( Z)-olefinic acids via 5- exo mode cyclizations to give lactones in which new carbon-halogen bonds are created at a stereogenic center with high diastereo- and enantioselectivities. Iodolactonizations of 6-substituted-5( Z)-olefinic acids also occur via 6- exo cyclizations to provide δ-lactones with excellent enantioselectivities. Several notable applications of this halolactonization methodology were developed for desymmetrization, kinetic resolution, and epoxidation of Z-alkenes. The utility of these reactions is demonstrated by their application to a synthesis of precursors of the F-ring subunit of kibdelone C and to the shortest catalytic, enantioselective synthesis of (+)-disparlure reported to date.


Assuntos
Lactonas/química , Naftóis/química , Alcanos/síntese química , Bromo/química , Catálise , Ciclização , Iodo/química , Estrutura Molecular , Estereoisomerismo , Xantonas/síntese química
3.
Tetrahedron ; 69(36): 7592-7607, 2013 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-24072939

RESUMO

A formal synthesis of didehydrostemofoline and isodidehydrostemofoline has been accomplished by preparing an intermediate in the Overman synthesis of these alkaloids from commercially available 2-deoxy-D-ribose. The work presented in this account chronicles the evolution of our explorations to identify the optimal steric and electronic control elements necessary to generate the tricyclic core structure of these alkaloids in a single operation from an acyclic precursor. The key step in the synthesis is a novel dipolar cycloaddition cascade sequence that is initiated by cyclization of a rhodium-derived carbene onto the nitrogen atom of a proximal imine group to generate an azomethine ylide that then undergoes spontaneous cyclization via dipolar cycloaddition. The synthesis features several other interesting reactions, including a Boord elimination to prepare a chiral allylic alcohol, a highly diastereoselective Hirama-Itô cyclization, and a useful modification of the Barton decarboxylation protocol.

5.
Org Lett ; 14(24): 6290-3, 2012 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-23199100

RESUMO

The enantioselective iodolactonizations of a series of diversely substituted olefinic carboxylic acids are promoted by a BINOL-derived, bifunctional catalyst. Reactions involving 5-alkyl- and 5-aryl-4(Z)-pentenoic acids and 6-alkyl- and 6-aryl-5(Z)-hexenoic acids provide the corresponding γ- and δ-lactones having stereogenic C-I bonds in excellent yields and >97:3 er. Significantly, this represents the first organocatalyst that promotes both bromo- and iodolactonization with high enantioselectivities. The potential of this catalyst to induce kinetic resolutions of racemic unsaturated acids is also demonstrated.


Assuntos
Alcenos/química , Ácidos Carboxílicos/química , Hidrocarbonetos Iodados/química , Lactonas/química , Catálise , Ciclização , Hidrocarbonetos Bromados/química , Estrutura Molecular , Naftóis/química , Estereoisomerismo
6.
Angew Chem Int Ed Engl ; 51(42): 10596-9, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22987285

RESUMO

Sweet to the core: Enantioselective formal total syntheses of the title compounds were accomplished in 24 steps from 2-deoxy-D-ribose. The synthesis features a novel cascade of reactions culminating in an intramolecular dipolar cycloaddition to form the tricyclic core of the stemofoline alkaloids from an acyclic diazo imine intermediate.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Catálise , Reação de Cicloadição , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura Molecular , Estereoisomerismo
7.
J Am Chem Soc ; 134(27): 11128-31, 2012 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-22726214

RESUMO

A novel bifunctional catalyst derived from BINOL has been developed that promotes the highly enantioselective bromolactonizations of a number of structurally distinct unsaturated acids. Like some known catalysts, this catalyst promotes highly enantioselective bromolactonizations of 4- and 5-aryl-4-pentenoic acids, but it also catalyzes the highly enantioselective bromolactonizations of 5-alkyl-4(Z)-pentenoic acids. These reactions represent the first catalytic bromolactonizations of alkyl-substituted olefinic acids that proceed via 5-exo mode cyclizations to give lactones in which new carbon-bromine bonds are formed at a stereogenic center with high enantioselectivity. We also disclose the first catalytic desymmetrization of a prochiral dienoic acid by enantioselective bromolactonization.


Assuntos
Alcenos/química , Bromo/química , Ácidos Carboxílicos/química , Lactonas/química , Catálise , Halogenação , Naftóis/química , Estereoisomerismo
8.
J Am Chem Soc ; 133(19): 7536-46, 2011 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-21513338

RESUMO

We report in full detail our studies on the catalytic, asymmetric α-fluorination of acid chlorides, a practical method that produces an array of α-fluorocarboxylic acid derivatives in which improved yield and virtually complete enantioselectivity are controlled through electrophilic fluorination of a ketene enolate intermediate. We discovered, for the first time, that a third catalyst, a Lewis acidic lithium salt, could be introduced into a dually activated system to amplify yields of aliphatic products, primarily through activation of the fluorinating agent. Through our mechanistic studies (based on kinetic data, isotopic labeling, spectroscopic measurements, and theoretical calculations) we were able to utilize our understanding of this "trifunctional" reaction to optimize the conditions and obtain new products in good yield and excellent enantioselectivity.


Assuntos
Ácidos Carboxílicos/química , Cloretos/química , Halogenação , Ácidos de Lewis/química , Elementos de Transição/química , Catálise , Metais Alcalinos/química , Estereoisomerismo
9.
Tetrahedron ; 65(34): 3771-6803, 2009 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-21494417
10.
Synlett ; 10: 1651-1654, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20442797

RESUMO

A catalytic, highly diastereoselective process for the synthesis of trans-beta-lactams is reported. This system is based on a phosphonium fluoride precatalyst that both activates the nucleophile and directs the reaction process for high yield and diastereoselectivity.

11.
J Am Chem Soc ; 130(51): 17260-1, 2008 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-19049284

RESUMO

In this Communication, we disclose a catalytic, highly enantioselective (up to >99% ee) alpha-fluorination of acid chlorides to produce a variety of optically active carboxylic acid derivatives from readily accessible and commercially available starting materials. The reaction depends on dually activated ketene enolates generated from two discrete catalysts--a chiral nucleophile and an achiral transition metal complex working in tandem. The active, putative alpha-fluorobis(sulfonimide) intermediates readily transacylate in situ under mild conditions upon addition of a wide variety of nucleophiles, including complex natural products. As a consequence, the power of this method is witnessed by the broad range of alpha-fluorinated products that can be accessed efficiently depending on the work up conditions.


Assuntos
Ácidos/química , Química Orgânica/métodos , Cloretos/química , Etilenos/química , Flúor/química , Cetonas/química , Metais/química , Ácidos Carboxílicos/química , Catálise , Modelos Químicos , Sulfonamidas/química
12.
J Am Chem Soc ; 130(50): 17085-94, 2008 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-19053448

RESUMO

We report a detailed synthetic and mechanistic study of an unusual bifunctional, sequential hetero-Diels-Alder/ring-opening reaction in which chiral, metal complexed ketene enolates react with o-quinones to afford highly enantioenriched, alpha-hydroxylated carbonyl derivatives in excellent yield. A number of Lewis acids were screened in tandem with cinchona alkaloid derivatives; surprisingly, trans-(Ph(3)P)(2)PdCl(2) was found to afford the most dramatic increase in yield and rate of reaction. A series of Lewis acid binding motifs were explored through molecular modeling, as well as IR, UV, and NMR spectroscopy. Our observations document a fundamental mechanistic "switch", namely the formation of a tandem Lewis base/Lewis acid activated metal enolate in preference to a metal-coordinated quinone species (as observed in other reactions of o-quinone derivatives). This new method was applied to the syntheses of several pharmaceutical targets, each of which was obtained in high yield and enantioselectivity.


Assuntos
Ácidos/química , Hidroxiácidos/química , Catálise , Cloranila/química , Modelos Anatômicos , Estrutura Molecular , Paládio/química , Fosfitos/química , Espectrofotometria , Estereoisomerismo
13.
Acc Chem Res ; 41(5): 655-63, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18402470

RESUMO

In the field of catalytic, asymmetric synthesis, there is a growing emphasis on multifunctional systems, in which multiple parts of a catalyst or multiple catalysts work together to promote a specific reaction. These efforts, in part, are result-driven, and they are also part of a movement toward emulating the efficiency and selectivity of nature's catalysts, enzymes. In this Account, we illustrate the importance of bifunctional catalytic methods, focusing on the cooperative action of Lewis acidic and Lewis basic catalysts by the simultaneous activation of both electrophilic and nucleophilic reaction partners. For our part, we have contributed three separate bifunctional methods that combine achiral Lewis acids with chiral cinchona alkaloid nucleophiles, for example, benzoylquinine (BQ), to catalyze highly enantioselective cycloaddition reactions between ketene enolates and various electrophiles. Each method requires a distinct Lewis acid to coordinate and activate the electrophile, which in turn increases the reaction rates and yields, without any detectable influence on the outstanding enantioselectivities inherent to these reactions. To place our results in perspective, many important contributions to this emerging field are highlighted and our own reports are chronicled.


Assuntos
beta-Lactamas/síntese química , Alumínio/química , Catálise , Ciclização , Etilenos/química , Iminas/química , Cetonas/química , Estrutura Molecular , Naftóis/química , Fosfinas/química , Estereoisomerismo , beta-Lactamas/química
14.
J Org Chem ; 72(14): 5380-2, 2007 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-17555354

RESUMO

A catalytic, asymmetric process for the synthesis of 1,4-benzoxazinones from o-benzoquinone imides and ketene enolates is reported. Addition of Lewis acids (Zn(OTf)2, In(OTf)3, and in particular Sc(OTf)3) creates a bifunctional catalytic system that dramatically increases the reaction rate and the yield of these non-natural amino acid precursors while preserving the remarkable enantioselectivity inherent to the reaction. Cocatalyst Sc(OTf)3 increases the yield by up to 42% while producing products in >99% ee.


Assuntos
Aminoácidos/química , Aminoácidos/síntese química , Produtos Biológicos/química , Catálise , Metais/química , Estrutura Molecular , Estereoisomerismo
15.
J Am Chem Soc ; 128(41): 13370-1, 2006 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-17031945

RESUMO

In this Communication, we report a system in which an achiral Lewis acid (activating the diene) works in concert with a chiral nucleophile (dienophile) to effect the first highly enantio- and regioselective catalytic inverse electron demand Diels-Alder [4 + 2] cycloaddition reaction to form biologically active quinoxalinones from ketene enolates and o-benzoquinone diimides in good to excellent yields with >99% ee.


Assuntos
Álcoois/química , Alcadienos/química , Benzoquinonas/química , Elétrons , Etilenos/química , Imidas/química , Cetonas/química , Catálise , Modelos Químicos , Estereoisomerismo
16.
Environ Sci Technol ; 39(6): 1420-6, 2005 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-15819193

RESUMO

Triclocarban (TCC) and triclosan (TCS) are antimicrobial additives in personal care products. Whereas TCS has been studied extensively, the environmental fate of TCC remains largely unknown. To address this data gap, we performed quantitative structure-activity relationship (QSAR) analyses that suggested a propensity of TCC to persist in various environmental compartments with predicted half-lives ranging from 0.75 days in air to 540 days in sediment. Moreover, concentrations of both antimicrobials were measured in 42 environmental samples from the Greater Baltimore region using a combination of solid-phase extraction, liquid chromatography/mass spectrometry, and isotope dilution. The co-occurrence of TCC and TCS was observed, owing to similar properties, usage, disposal, and environmental half-lives. A linear empirical correlation (R2 = 0.9882) fit the log-log-transformed data from diverse aquatic media and spanned 5 orders of magnitude in concentration. Occurrences of TCC predicted for 85 U.S. streams were statistically indistinguishable from experimental regional data (alpha < or = 0.05). Annual loading of antimicrobials to water resources probably is dominated by activated sludge treatment plants (39-67%), followed by trickling filters (31-54%) and combined and sanitary sewer overflows (2-7% and <0.2%, respectively). Study results suggest that TCC is a previously unrecognized contaminant of U.S. water resources nationwide, likely ranking in the top 10 in occurrence rate and in the top 20 in maximum concentration among 96 organic pollutants considered. The magnitude and frequency of TCC contamination (regional, 6750 ng/L, 68%; predicted nationwide for 1999--2000, 1150 ng/L, 60%) were markedly higher than non-peer-reviewed numbers (240 ng/L, 30%, U.S.) currently used by the U.S. Environmental Protection Agency for evaluating TCC's ecological and human health risks.


Assuntos
Anti-Infecciosos Locais/análise , Carbanilidas/análise , Triclosan/análise , Poluentes Químicos da Água/análise , Animais , Anti-Infecciosos Locais/efeitos adversos , Anti-Infecciosos Locais/farmacocinética , Disponibilidade Biológica , Carbanilidas/efeitos adversos , Carbanilidas/farmacocinética , Monitoramento Ambiental , Meia-Vida , Humanos , Relação Quantitativa Estrutura-Atividade , Medição de Risco , Poluentes Químicos da Água/efeitos adversos , Poluentes Químicos da Água/farmacocinética
17.
Environ Sci Technol ; 38(18): 4849-55, 2004 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-15487795

RESUMO

Triclocarban, N-(4-chlorophenyl)-N'-(3,4-dichlorophenyl)urea, is a polychlorinated phenyl urea pesticide, marketed under the trademark TCC and used primarily as an antibacterial additive in personal care products. Despite its extensive use over several decades, environmental occurrence data on TCC are scarce. This is due in part to a lack of analytical techniques offering the desired sensitivity, selectivity, affordability, and ease of use. This need is addressed here by introducing a liquid chromatography electrospray ionization mass spectrometry (LC/ESI/MS) method allowing for the determination of TCC concentrations in aquatic environments at the ng/L level. TCC was concentrated from aqueous samples by solid-phase extraction, separated from interferences on a C18 column by either isocratic or gradient elution, and detected and identified in negative ESI mode by selectively monitoring the (M - H)- base peak (m/z 313) and its 37Cl-containing isotopes (m/z 315, 317) that served as reference ions. Particulates contained in aquatic samples were extracted and analyzed separately. Accurate quantification was achieved using stable isotopes of TCC and triclosan as internal standards. Addition of 10 mM acetic acid to the mobile phase yielded acetic acid adducts ([M - H + 60]-) that were successfully exploited to boost method sensitivity and selectivity, especially when analyzing challenging environmental matrixes. Method detection limits were matrix dependent, ranging from 3 to 50 ng/L. In 36 grab samples obtained from the Greater Baltimore area, TCC was detected in river water and wastewater at concentrations of up to 5600 and 6750 ng/L, respectively. Raw and finished drinking water did not contain detectable quantities of the pesticide (<3 ng/L). In conclusion, the new LC/ESI/MS method was applied successfully to collect environmental occurrence data on TCC in U.S. water resources. Study results suggest that the bacteriostat and pesticide is a frequent but currently underreported contaminant whose environmental fate and behavior deserve further scrutiny.


Assuntos
Antibacterianos/análise , Carbanilidas/análise , Cromatografia Líquida/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Poluentes Químicos da Água/análise , Monitoramento Ambiental/métodos , Maryland , Rios/química , Esgotos/análise , Abastecimento de Água/análise
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