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1.
Chemistry ; 26(58): 13163-13169, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32359179

RESUMO

A cobalt-catalyzed cross-coupling of α-bromo α-fluoro ß-lactams with diarylzinc or diallylzinc reagents is herein disclosed. The protocol proved to be general, chemoselective and operationally simple allowing the C4 functionalization of ß-lactams. The substrate scope was expanded to α-bromo lactams and amides, α-bromo lactones and esters as well as N- and O-containing heterocycles.

2.
Chemistry ; 26(52): 12019-12026, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32485071

RESUMO

Viral infections cause life-threatening diseases in millions of people worldwide every year and there is an urgent need for new, effective antiviral drugs. Hybridization of two chemically diverse compounds into a new bioactive effector product is a successful concept to improve the properties of a hybrid drug relative to the parent compounds. In this study, (iso)quinoline-artemisinin hybrids, obtained through copper-catalyzed azide-alkyne cycloaddition or metal-free click reactions (in organic solvents or in the presence of water), were analyzed in vitro, for the first time, for their inhibitory activity against human cytomegalovirus (HCMV), relative to their parent compounds and the reference drug ganciclovir. EC50 (HCMV) values were obtained in a range 0.22-1.20 µm, which indicated highly potent antiviral properties in the absence of cytotoxic effects on normal cells (CC50 >100 µm). The most active hybrid, 1 (EC50 =0.22 µm), is 25 times more potent than its parent compound artesunic acid (EC50 =5.41 µm) and 12 times more efficient than the standard drug ganciclovir (EC50 =2.6 µm). Interestingly, hybrid 1 also shows inhibitory activity against hepatitis B virus in vitro (EC50 (HBeAg)=2.57 µm).


Assuntos
Vírus , Antivirais/farmacologia , Artemisininas/farmacologia , Química Click , Citomegalovirus , Humanos , Quinolinas/farmacologia
3.
Int J Mol Sci ; 21(15)2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32759737

RESUMO

Human cytomegalovirus (HCMV) is a major human pathogen associated with severe pathology. Current options of antiviral therapy only partly satisfy the needs of a well-tolerated long-term treatment/prophylaxis free from drug-induced viral resistance. Recently, we reported the strong antiviral properties in vitro and in vivo of the broad-spectrum anti-infective drug artesunate and its optimized derivatives. NF-κB signaling was described as a targeting mechanism and additional target proteins have recently been identified. Here, we analyzed the autofluorescent hybrid compound BG95, which could be utilized for intracellular visualization by confocal imaging and a tracking analysis in virus-infected primary human fibroblasts. As an important finding, BG95 accumulated in mitochondria visualized by anti-prohibitin and MitoTracker staining, and induced statistically significant changes of mitochondrial morphology, distinct from those induced by HCMV infection. Notably, mitochondrial membrane potential was found substantially reduced by BG95, an effect apparently counteracting efficient HCMV replication, which requires active mitochondria and upregulated energy levels. This finding was consistent with binding properties of artesunate-like compounds to mitochondrial proteins and thereby suggested a new mechanistic aspect. Combined, the present study underlines an important role of mitochondria in the multifaceted, host-directed antiviral mechanism of this drug class, postulating a new mitochondria-specific mode of protein targeting.


Assuntos
Antivirais/farmacologia , Artemisininas/farmacologia , Infecções por Citomegalovirus/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Antivirais/química , Artemisininas/química , Artesunato/análogos & derivados , Artesunato/farmacologia , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/virologia , Farmacorresistência Viral/efeitos dos fármacos , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Mitocôndrias/genética , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/genética , Replicação Viral/efeitos dos fármacos
4.
Angew Chem Int Ed Engl ; 58(6): 1684-1688, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30499607

RESUMO

Bioorthogonal late-stage diversification of structurally complex peptides has enormous potential for drug discovery and molecular imaging. In recent years, transition-metal-catalyzed C-H activation has emerged as an increasingly viable tool for peptide modification. Despite major accomplishments, these strategies largely rely on expensive palladium catalysts. We herein report an unprecedented cobalt(III)-catalyzed peptide C-H activation, which enables the direct C-H functionalization of structurally complex peptides, and sets the stage for a multicatalytic C-H activation/alkene metathesis/hydrogenation strategy for the assembly of novel cyclic peptides.


Assuntos
Cobalto/química , Compostos Organometálicos/química , Peptídeos/síntese química , Catálise , Estrutura Molecular , Peptídeos/química , Estereoisomerismo
5.
Angew Chem Int Ed Engl ; 58(37): 13066-13079, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31290221

RESUMO

A substantial challenge worldwide is emergent drug resistance in malaria parasites against approved drugs, such as chloroquine (CQ). To address these unsolved CQ resistance issues, only rare examples of artemisinin (ART)-based hybrids have been reported. Moreover, protein targets of such hybrids have not been identified yet, and the reason for the superior efficacy of these hybrids is still not known. Herein, we report the synthesis of novel ART-isoquinoline and ART-quinoline hybrids showing highly improved potencies against CQ-resistant and multidrug-resistant P. falciparum strains (EC50 (Dd2) down to 1.0 nm; EC50 (K1) down to 0.78 nm) compared to CQ (EC50 (Dd2)=165.3 nm; EC50 (K1)=302.8 nm) and strongly suppressing parasitemia in experimental malaria. These new compounds are easily accessible by step-economic C-H activation and copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reactions. Through chemical proteomics, putatively hybrid-binding protein targets of the ART-quinolines were successfully identified in addition to known targets of quinoline and artemisinin alone, suggesting that the hybrids act through multiple modes of action to overcome resistance.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Isoquinolinas/farmacologia , Malária/tratamento farmacológico , Plasmodium/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/uso terapêutico , Artemisininas/síntese química , Artemisininas/química , Artemisininas/uso terapêutico , Química Click , Resistência a Múltiplos Medicamentos , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Isoquinolinas/uso terapêutico , Camundongos
6.
Chem Soc Rev ; 46(23): 7399-7420, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29051927

RESUMO

Fully complementary bimetallic catalysis has been identified as an increasingly powerful tool for molecular transformations, which was largely inspired by early examples of sequential catalytic transformations. Thus, energy-efficient one-pot reactions involving different metal catalysts orchestrated in concert constitute an attractive alternative to multi-step protocols, with major recent progress through the elegant ligand design in heterobimetallic catalysis as well as sustainable photo-induced C-H transformations, among others. This review provides a critical assessment of the state of the art in heterobimetallic catalysis for sustainable organic syntheses (SOS), highlighting key advances and representative examples until summer 2017.

7.
Angew Chem Int Ed Engl ; 57(1): 203-207, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29135064

RESUMO

Secondary C(sp3 )-H arylations were accomplished by palladium catalysis with triazoles as peptide bond isosteres. The unique power of this approach is highlighted by the possibility of achieving secondary C(sp3 )-H functionalizations on terminal peptides as well as the unprecedented positional-selective C(sp3 )-H functionalization of internal peptide positions, setting the stage for modular peptide late-stage diversification.

8.
Angew Chem Int Ed Engl ; 57(33): 10554-10558, 2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-29883018

RESUMO

Late-stage BODIPY diversification of structurally complex amino acids and peptides was accomplished by racemization-free palladium-catalyzed C(sp3 )-H activation. Transformative fluorescence modification proved viable by triazole-assisted C(sp3 )-H arylation in a chemo- and site-selective fashion, providing modular access to novel BODIPY peptide sensors.


Assuntos
Compostos de Boro/química , Peptídeos/química , Aminoácidos/química , Carbono/química , Catálise , Hidrogênio/química , Paládio/química , Teoria Quântica , Triazóis/química
9.
Angew Chem Int Ed Engl ; 57(45): 14700-14717, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-29969532

RESUMO

The late-stage modification of structurally complex peptides bears great potential for drug discovery, crop protection, and the pharmaceutical industry, among others. Whereas traditional approaches largely rely on prefunctionalizations, C-H activation catalysis has in recent years emerged as an increasingly powerful tool for post-translational peptide modifications in a step-economic manner. Herein, we summarize recent progress in organometallic C-H activation on peptides until June 2018, including position- and chemoselective palladium-, ruthenium-, and manganese-catalyzed processes.


Assuntos
Aminoácidos/química , Peptídeos/química , Aminoácidos/síntese química , Carbono/química , Catálise , Ouro/química , Hidrogênio/química , Manganês/química , Paládio/química , Peptídeos/síntese química , Rutênio/química
10.
Angew Chem Int Ed Engl ; 56(22): 6339-6342, 2017 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-28474796

RESUMO

The decarboxylative C-H/C-O functionalization was accomplished by air- and water-tolerant manganese(I) catalysis. The versatile C-H allylation occurred by facile organometallic C-H metalation on indoles, arenes, amino acids and synthetically meaningful aryl ketimines with ample substrate scope and high levels of chemo-, site- and regio-selectivity.


Assuntos
Ar , Manganês/química , Água/química , Ácidos Carboxílicos/química , Catálise
11.
Angew Chem Int Ed Engl ; 55(35): 10386-90, 2016 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-27440498

RESUMO

Strongly coordinating nitrogen heterocycles, including pyrimidines, oxazolines, pyrazoles, and pyridines, were fully tolerated in cobalt-catalyzed C-H amidations by imidate assistance. Structurally complex quinazolines are thus accessible in a step-economic manner. Our findings also establish the relative powers of directing groups in cobalt(III)-catalyzed C-H functionalization for the first time.

12.
Chemistry ; 20(6): 1539-46, 2014 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-24403244

RESUMO

Pd(II)-catalyzed alkene aminopalladation and allylic C-H activation are two competing reaction sequences sharing the same reaction conditions. This study aimed at understanding the factors that bias one or the other path in the intramolecular oxidative cyclization of two types of N-tosyl amidoalkenes. The results obtained are in accord with the initial generation of a high-energy cyclic (5- or 6-membered) aminopalladated intermediate. However, this latter species can evolve only if the following specific conditions are met: the availability of distocyclic ß-H elimination pathway, the presence of a strong terminal oxidant, or the availability of a carbopalladation pathway. Conversely, the cyclic alkylpalladium complex is only a latent species in equilibrium with the initial substrate and cannot evolve. Such a reactivity hurdle leaves the way open for alternative reactivities such as allylic C-H activation of the olefinic substrate to generate a η(3)-allyl complex followed by its interception by the nitrogen nucleophile, [3,3]-sigmatropic rearrangement, or decomposition. This study proposes a unifying mechanistic picture that connects these competing mechanisms.

13.
Chemistry ; 19(38): 12607-12, 2013 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-23983072

RESUMO

Handy POMs: Several palladium-catalyzed coupling reactions have been applied to polyoxometalate post-functionalization. The feasibility of each reaction with one model substrate was investigated and each set of synthetic conditions was optimized to obtain full conversions and high purity hybrid compounds.

14.
J Am Chem Soc ; 132(41): 14412-4, 2010 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-20873750

RESUMO

An umpolung direct arylation process is described. The reaction requires only a catalytic amount of Pd(OAc)(2) and a substoichiometric amount of silver salts, without any external base or ligand to proceed. The directed oxidative insertion of the transition metal followed by the coupling into the C-H bond of an unactivated arene has surprisingly not yet been reported, despite the clear advantages in the ease of starting material synthesis. The reaction is regioselective with regards to the arene partner, and the role of the acetate and carbonate groups has been elucidated. This methodology adds to the very few examples of benzene coupling without the inclusion of electron-withdrawing groups to increase acidity.


Assuntos
Paládio/química , Prata/química , Catálise , Oxirredução
15.
Org Lett ; 21(16): 6241-6244, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31390216

RESUMO

The treatment of 3-bromo ß-lactams by an aryl Grignard, in the presence of CoCl2 (2 mol %) and TMEDA (2 mol %) in THF, produces 3-aryl ß-lactams in good yields and excellent diastereoselectivity.

16.
Org Lett ; 18(5): 1020-3, 2016 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-26902777

RESUMO

A new aerobic intramolecular palladium(II)-based catalytic system that triggers aminopalladation/dehydropalladation of N-sulfonylalkenylamides to give the corresponding methylidene γ-lactams has been identified. Use of triphenylphosphine and chloride anion as ligands is mandatory for optimal yields, and molecular oxygen can be used as the sole terminal oxidant. Scope and limitations of the methods are described. A mechanism is proposed on the basis of experimental results as well as density functional theory calculations.


Assuntos
Lactamas/síntese química , Paládio/química , Catálise , Lactamas/química , Estrutura Molecular , Oxidantes/química , Oxigênio/química , Estereoisomerismo
17.
Org Lett ; 15(12): 3050-3, 2013 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-23734985

RESUMO

An efficient palladium-catalyzed synthesis of 1,2-dihydroquinolines has been developed via the reaction between anilines and Morita-Baylis-Hillman adducts derived from o-bromobenzaldehyde. This new Pd(0)-catalyzed pseudo-domino type I sequence involves a Buchwald-Hartwig arylic amination and an allylic amination. When starting from an o-bromo allylic alcohol, the chronology is arylic amination/allylic arylation. However, the sequence reverses when the reaction is performed on the corresponding o-bromo allylic acetate.

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