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1.
Bioorg Med Chem Lett ; 40: 127963, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33741464

RESUMO

Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) are rate-limiting enzymes in the kynurenine pathway (KP) of l-tryptophan (l-Trp) metabolism and are becoming key drug targets in the combination therapy of checkpoint inhibitors in immunoncology. To discover a selective and potent IDO1 inhibitor, a structure-activity relationship (SAR) study of N-hydroxybenzofuran-5-carboximidamide as a novel scaffold was investigated in a systematic manner. Among the synthesized compounds, the N-3-bromophenyl derivative 19 showed the most potent inhibition, with an IC50 value of 0.44 µM for the enzyme and 1.1 µM in HeLa cells. The molecular modeling of 19 with the X-ray crystal structure of IDO1 indicated that dipole-ionic interactions with heme iron, halogen bonding with Cys129 and the two hydrophobic interactions were important for the high potency of 19.


Assuntos
Amidinas/farmacologia , Benzofuranos/farmacologia , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Oximas/farmacologia , Amidinas/síntese química , Amidinas/metabolismo , Benzofuranos/síntese química , Benzofuranos/metabolismo , Domínio Catalítico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indolamina-Pirrol 2,3,-Dioxigenase/química , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Oximas/síntese química , Oximas/metabolismo , Ligação Proteica , Eletricidade Estática , Relação Estrutura-Atividade
2.
J Org Chem ; 84(9): 4971-4991, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30977652

RESUMO

Despite numerous advances in spectroscopic methods through the latter part of the 20th century, the unequivocal structure determination of natural products can remain challenging, and inevitably, incorrect structures appear in the literature. Computational methods that allow the accurate prediction of NMR chemical shifts have emerged as a powerful addition to the toolbox of methods available for the structure determination of small organic molecules. Herein, we report the structure determination of a small, stereochemically rich natural product from Laurencia majuscula using the powerful combination of computational methods and total synthesis, along with the structure confirmation of notoryne, using the same approach. Additionally, we synthesized three further diastereomers of the L. majuscula enyne and have demonstrated that computations are able to distinguish each of the four synthetic diastereomers from the 32 possible diastereomers of the natural product. Key to the success of this work is to analyze the computational data to provide the greatest distinction between each diastereomer, by identifying chemical shifts that are most sensitive to changes in relative stereochemistry. The success of the computational methods in the structure determination of stereochemically rich, flexible organic molecules will allow all involved in structure determination to use these methods with confidence.


Assuntos
Alquil e Aril Transferases/química , Alquil e Aril Transferases/síntese química , Alcinos/química , Laurencia/química , Alquil e Aril Transferases/isolamento & purificação , Técnicas de Química Sintética , Modelos Moleculares , Conformação Molecular , Estereoisomerismo
3.
Chem Sci ; 9(6): 1473-1480, 2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29629170

RESUMO

The systematic investigation of chiral bidentate auxiliaries has resulted in the discovery of a chiral 2,2-dimethyl-1-(pyridin-2-yl)propan-1-amine-derived directing group that enables stereoselective palladium(ii)-catalyzed intramolecular C(sp3)-O bond formation. This new chiral directing group exhibited high reactivity in the activation of methylene C(sp3)-H bonds with excellent levels of stereoselectivity (a diastereomeric ratio of up to 39 : 1), which allowed the construction of a wide range of oxaspirocycles. Mechanistic investigations were also conducted to elucidate the reaction mechanism and understand the origin of the diastereoselectivity. DFT calculations suggest that only modest levels of diastereoselectivity are accomplished at the rate-determining C-H metalation-deprotonation step and the d.r. is further enriched at the reductive elimination step.

4.
Chemistry ; 24(11): 2634-2642, 2018 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-29222867

RESUMO

Substrate-controlled asymmetric total syntheses and structure confirmation of (+)-(3E)- and (-)-(3Z)-chlorofucin [(E)-1 a and (Z)-1 a], and (+)-(3E)- and (-)-(3Z)-bromofucin [(E)-1 b and (Z)-1 b] were accomplished. Our syntheses feature as key steps haloetherification (either 'conventional' or 'one-pot organoselenium-mediated') of α,α'-trans-γ,δ-unsaturated oxocene alcohol 9 and our (E)- and (Z)-selective cross-metathesis (CM) protocols. More importantly, a rationale is provided for the strikingly different pathways followed by α,α'-trans-γ,δ-unsaturated oxocene alcohol 9 and its α,α'-cis isomer 9' in the presence of different electrophiles during the intramolecular electrophilic addition reactions.

5.
Org Lett ; 19(22): 6252-6255, 2017 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-29112433

RESUMO

A highly efficient and stereoselective route to potential synthetic intermediates for ocellenyne and related C15 acetogenin natural products with 6,10-syn- and 6,10-anti-2,5-dioxabicyclo[2.2.1]heptane core structures has been developed by means of an iterative biogenesis-inspired oxonium ion formation/fragmentation sequence. In accordance with chemical transformations, the most likely stereostructure for (E)-ocellenyne on the basis of GIAO 13C NMR calculations possesses a 6,10-anti-2,5-dioxabicyclo[2.2.1]heptane core, as predicted from a plausible biosynthetic pathway, instead of the spectroscopically proposed 6,10-syn-2,5-dioxabicyclo[2.2.1]heptane skeleton.

6.
Chemistry ; 21(45): 15988-97, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26376617

RESUMO

Substrate-controlled asymmetric total syntheses of (+)-microcladallenes A, B, and C have been accomplished based on the proposed structures. The syntheses of microcladallenes A and B confirmed the structures and absolute configurations of both natural products. However, the synthesis of microcladallene C, which includes seven stereogenic centers and an (R)-bromoallene in its compact C15 framework, brought the realization that its proposed structure must be revised. The introduction of C12-bromine into these natural products with retention of configuration relied on TiBr4 -mediated nucleophile-assisting leaving group brominations, the stereochemical outcome of which could be attributed, at least in part, to an oxonium or halonium ion formation-fragmentation sequence through intricate neighboring group participation. In addition, the pivotal ß-oriented vicinal cis-dichloride function in microcladallene C was elaborated through a novel tandem Cl2 -induced electrophilic cyclization/imidate chlorination process. The positive rotations of these natural products with an (R)-bromoallene constitute exceptions to Lowe's rule for reasons yet to be determined.


Assuntos
Produtos Biológicos/síntese química , Sesquiterpenos/química , Sesquiterpenos/síntese química , Produtos Biológicos/química , Conformação Molecular , Estrutura Molecular
7.
J Am Chem Soc ; 137(27): 8716-9, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26133230

RESUMO

The total synthesis of the rare but extremely potent antitumor agent shishijimicin A has been achieved via a convergent strategy involving carboline disaccharide 3 and hydroxy enediyne thioacetate 4.


Assuntos
Antineoplásicos/síntese química , Produtos Biológicos/síntese química , Carbolinas/síntese química , Dissacarídeos/síntese química , Enedi-Inos/síntese química , Compostos de Sulfidrila/química , Antineoplásicos/química , Produtos Biológicos/química , Carbolinas/química , Dissacarídeos/química , Enedi-Inos/química , Compostos de Sulfidrila/síntese química
8.
Angew Chem Int Ed Engl ; 53(1): 272-6, 2014 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-24227662

RESUMO

A substrate-controlled asymmetric total synthesis of (+)-bermudenynol, a compact and synthetically challenging C15 Laurencia metabolite that contains several halogen atoms, is reported. The oxocene core, which contains a vinyl chloride, was constructed by an efficient and highly stereoselective intramolecular amide enolate alkylation (IAEA). This result showcases the broad utility of the IAEA methodology as a useful alternative for cases in which the ring-closing metathesis is inefficient.


Assuntos
Amidas/química , Oxocinas/síntese química , Alquilação , Oxocinas/química , Estereoisomerismo
9.
J Am Chem Soc ; 134(49): 20178-88, 2012 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-23194584

RESUMO

We report a completely substrate-controlled approach to the asymmetric total synthesis of representative dioxabicyclic bromoallene marine natural products with either a 2,10-dioxabicyclo[7.3.0]dodecene or 2,9-dioxabicyclo[6.3.0]undecene skeleton from commercially available glycidol as a common starting material. The former include (-)-isolaurallene (1), the enantiomeric form of natural (+)-neolaurallene (2), and (+)-itomanallene A (3c), and the latter are (+)-laurallene (4) and (+)-pannosallene (5a). In addition, our first syntheses of 3c and 5a established the structure and absolute stereochemistry of both natural products. Our general approach to establish the α,α'-relative stereochemistry of the medium-ring (oxonene or oxocene) and tetrahydrofuran, respectively, involved the judicious pairing of our protecting-group-dependent intermolecular amide enolate alkylation (either chemoselective chelation-controlled or dianion alkylation) with either our intramolecular amide enolate or nitrile anion alkylation. Remarkable selectivity was achieved through the use of the appropriate alkylation steps, and this approach offered us optional access to any of these dioxabicyclic bromoallene marine natural products. In addition, a computational analysis was performed to investigate conformational effects on the rate of oxonene formation via RCM, a key step in these approaches. The results suggested an alternative rationale for reactivity based on the avoidance of eclipsing torstional interactions in the AS2-type ring conformation.


Assuntos
Produtos Biológicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Produtos Biológicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Cristalografia por Raios X , Modelos Moleculares , Conformação Molecular , Teoria Quântica
10.
J Am Chem Soc ; 134(28): 11781-90, 2012 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-22758928

RESUMO

Elatenyne is a small dibrominated natural product first isolated from Laurencia elata. The structure of elatenyne was originally assigned as a pyrano[3,2-b]pyran on the basis of NMR methods. Total synthesis of the originally proposed pyrano[3,2-b]pyran structure of elatenyne led to the gross structure of the natural product being reassigned as a 2,2'-bifuranyl. The full stereostructure of this highly flexible small molecule was subsequently predicted by Boltzmann-weighted DFT calculations of (13)C NMR chemical shifts for all 32 potential diastereomers, with the predicted structure being in accord with the proposed biogenesis outlined below. Herein we report two complementary total syntheses of elatenyne, which confirm the computer-predicted stereostructure. Additionally, the total syntheses of (E)-elatenyne and a related 2,2'-bifuranyl, laurendecumenyne B, are reported. This work has not only allowed the full structure determination of all of these natural products but also provides excellent supporting evidence for their proposed biogenesis. The total synthesis of elatenyne demonstrates that DFT calculations of (13)C NMR chemical shifts coupled with biosynthetic postulates, comprise a very useful method for distinguishing among large numbers of highly flexible, closely related molecules.


Assuntos
Alcinos/síntese química , Furanos/síntese química , Espectroscopia de Ressonância Magnética/métodos , Alcinos/química , Isótopos de Carbono , Furanos/química , Estereoisomerismo
11.
J Am Chem Soc ; 132(35): 12226-7, 2010 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-20701317

RESUMO

An asymmetric total synthesis of trilobacin (1), an annonaceous acetogenin with potent anticancer activities, was accomplished wherein the construction of its erythro-bis(2,2')-tetrahydrofuran core 2 featured a novel organoselenium-mediated oxonium ion formation/SiO(2)-promoted fragmentation of alpha,alpha'-cis-oxocene 3.


Assuntos
Furanos/síntese química , Compostos Organosselênicos/química , Oxocinas/química , Dióxido de Silício/química , Ciclização , Furanos/química , Íons/química , Conformação Molecular , Estereoisomerismo
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