RESUMO
The formation of N-heterocycles with multiple substituents is important in organic synthesis. Herein, we report a novel method for the construction of functionalized dihydropyridinone rings through the annulation of an amide α-carbon with a tethered alkyne moiety. The reaction of the amide with the alkyne was achieved via O-silyl N,O-ketene acetal formation and silver-mediated addition. Furthermore, the developed method was applied for the total synthesis of phenanthroindolizidine and phenanthroquinolizidine alkaloids. By varying the coupling partners, a concise and collective total synthesis of these alkaloids was achieved.
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-AtividadeRESUMO
Asymmetric synthesis of α-substituted proline derivatives has been accomplished by an efficient chirality-transfer method. High diastereoselectivity of the N-alkylation of the proline ester (CâN chirality transfer) was achieved when a 2,3-disubstituted benzyl group was used as the N-substituent. DFT calculations provided a mechanistic rationale for the high degree of stereoselectivity. The generated N-chirality of the quaternary ammonium salt was transferred back to the α-carbon through a stereoselective [2,3]-Stevens rearrangement (NâC chirality transfer) to give α-substituted proline ester.
RESUMO
An efficient strategy for the asymmetric synthesis of Cα-tetrasubstituted proline derivatives from proline has been established. A nitrogen-fused bicyclic system was devised to control the stereodynamics of proline. Through N-quaternizations with allylic electrophiles followed by [2,3]-rearrangements, the bicyclic proline system delivered enantioenriched Cα-tetrasubstituted prolines. This strategy was applied to the concise total synthesis of (-)-amathaspiramide F.