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1.
Chem Rec ; 22(3): e202100286, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34894063

RESUMO

The compounds containing chiral centers and different functional groups serve as magnificent building blocks for the preparation of various natural products that are having immense biological activity. "Dimethyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-ol" is one of the wonderful synthons to construct multiple stereo centers at a time during the asymmetric synthesis. In this account, we discuss our research efforts toward the synthesis of various simple and complex natural products from the past three decades (1995-2020) by using dimethyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-ol as a synthon. Moreover, the synthetic utility of this starting material was investigated and well demonstrated. Further, we executed the desymmetrization of dimethyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-ol by hydroboration to get different chiral centers. After obtaining the stereocenters, we could manage either the fragment, formal or total synthesis of natural products, by simple protection and deprotection sequence followed by C-C bond formation steps.


Assuntos
Produtos Biológicos , Estereoisomerismo
2.
Angew Chem Int Ed Engl ; 58(44): 15904-15909, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31398275

RESUMO

Superior to linear peptides in biological activities, cyclic peptides are considered to have great potential as therapeutic agents. To identify cyclic-peptide ligands for therapeutic targets, phage-displayed peptide libraries in which cyclization is achieved by the covalent conjugation of cysteines have been widely used. To resolve drawbacks related to cysteine conjugation, we have invented a phage-display technique in which its displayed peptides are cyclized through a proximity-driven Michael addition reaction between a cysteine and an amber-codon-encoded Nϵ -acryloyl-lysine (AcrK). Using a randomized 6-mer library in which peptides were cyclized at two ends through a cysteine-AcrK linker, we demonstrated the successful selection of potent ligands for TEV protease and HDAC8. All selected cyclic peptide ligands showed 4- to 6-fold stronger affinity to their protein targets than their linear counterparts. We believe this approach will find broad applications in drug discovery.


Assuntos
Código Genético/genética , Biblioteca de Peptídeos , Peptídeos Cíclicos/genética , Ciclização , Cisteína/química , Cisteína/genética , Humanos , Ligantes , Lisina/química , Lisina/genética , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química
3.
J Org Chem ; 77(24): 11109-18, 2012 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-23140482

RESUMO

FD-891, a structurally unique 16-membered macrolide having anticancer activity, was synthesized according to a strategy employing asymmetric allylation, Prins cyclization, cross-metathesis reaction, Yamaguchi lactonization, and Julia-Kocienski olefination.


Assuntos
Macrolídeos/química , Macrolídeos/síntese química , Técnicas de Química Sintética , Estereoisomerismo , Especificidade por Substrato
4.
Protein Sci ; 31(12): e4512, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36382882

RESUMO

Phage-assisted, active site-directed ligand evolution (PADLE) is a recently developed technique that uses an amber codon-encoded noncanonical amino acid (ncAA) as an anchor to direct phage-displayed peptides to a target for an enhanced ligand identification process. 2-Amino-8-oxodecanoic acid (Aoda) is a ketone-containing ncAA residue in the macrocyclic peptide natural product apicidin that is a pan-inhibitor of Zn2+ -dependent histone deacetylases (HDACs). Its ketone serves as an anchoring point to coordinate the catalytic zinc ion in HDACs. Using a previously evolved N𝜀 -acetyl-lysyl-tRNA synthetase in combination with tRNAPyl , we showed that Aoda was efficiently incorporated into proteins in Escherichia coli by amber suppression. By propagating an amber codon-obligate phagemid library in E. coli encoding Aoda, we generated an Aoda-containing phage-displayed peptide library. Using this library to conduct PADLE against HDAC8 revealed a 7-mer peptide GH8P01F1 with Aoda-flanking amino acid residues that matched existing peptide sequences in identified HDAC8 substrates. Switching Aoda in GH8P01F1 to a more Zn2+ -chelating ncAA S-2-amino-8-hydroxyamino-8-oxooctanoic acid (Asuha) led to an extremely potent compound GH8HA01, which has an HDAC8-inhibition Ki value of 0.67 nM. GH8HA01 and its 5-mer truncation analogue Ac-GH8HA01Δ1Δ7 that has an HDAC8-inhibition Ki value of 0.31 nM are two of the most potent HDAC8 inhibitors that have been developed. Furthermore, both are highly selective against HDAC8 compared with other HDACs tested, demonstrating the great potential of using PADLE to identify highly potent and selective ligands for targets with conserved active sites among homologues.


Assuntos
Bacteriófagos , Inibidores de Histona Desacetilases , Aminoácidos/genética , Bacteriófagos/genética , Bacteriófagos/metabolismo , Domínio Catalítico , Códon de Terminação , Escherichia coli/genética , Escherichia coli/metabolismo , Histona Desacetilases/química , Cetonas , Ligantes , Peptídeos/química
5.
J Med Chem ; 64(15): 10997-11013, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34279931

RESUMO

Eleven-nineteen leukemia (ENL) protein is a histone acetylation reader essential for disease maintenance in acute leukemias, in particular, the mixed-lineage leukemia (MLL)-rearranged leukemia. In this study, we carried out high-throughput screening of a small-molecule library to identify inhibitors for the ENL YEATS domain. Structure-activity relationship studies of the hits and structure-based inhibitor design led to two compounds, 11 and 24, with IC50 values below 100 nM in inhibiting the ENL-acetyl-H3 interaction. Both compounds, and their precursor compound 7, displayed strong selectivity toward the ENL YEATS domain over all other human YEATS domains. Moreover, 7 exhibited on-target inhibition of ENL in cultured cells and a synergistic effect with the bromodomain and extraterminal domain inhibitor JQ1 in killing leukemia cells. Together, we have developed selective chemical probes for the ENL YEATS domain, providing the basis for further medicinal chemistry-based optimization to advance both basic and translational research of ENL.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Leucemia Mieloide Aguda/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Elongação da Transcrição/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ensaios de Triagem em Larga Escala , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Estrutura Molecular , Domínios Proteicos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Fatores de Elongação da Transcrição/metabolismo
6.
Beilstein J Org Chem ; 6: 8, 2010 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-20485590

RESUMO

The total synthesis of (3R,5R)-harzialactone A (1) and its (3R,5S)-isomer (2) is described. Epoxide opening with thioacetal and diastereoselective reductions are used as key reactions.

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