RESUMO
Among my recent work on the syntheses of complex natural products based on the development of a novel synthetic method for the heteroaromatic skeleton, this article primarily deals with the total syntheses of (+)-CC-1065, isobatzeline A/B, and batzeline A. These syntheses were accomplished via a novel indole synthesis utilizing a ring expansion reaction of benzocyclobutenone oxime sulfonate as the key step. The 1,2-dihydro-3H-pyrrolo[3,2-e]indole segments of (+)-CC-1065 were rapidly constructed via a two-directional double-ring expansion strategy. Highly substituted pyrrolidine-fused common 5-chloro-2-methylthioindoles of isobatzeline A/B and batzeline A were constructed using a ring expansion reaction of benzocyclobutenone oxime sulfonate with NaSMe and a benzyne-mediated cyclization/functionalization reaction.
Assuntos
Produtos Biológicos , Química Orgânica , Duocarmicinas , Indóis , Pirroliminoquinonas , Quinolonas , Produtos Biológicos/síntese química , Química Orgânica/métodos , Ciclização , Duocarmicinas/síntese química , Indóis/síntese química , Oximas/química , Pirroliminoquinonas/síntese química , Quinolonas/síntese químicaRESUMO
Indoleamine 2,3-dioxygenase (IDO1) and tryptophane 2,3-dioxygenase (TDO) are two heme-containing enzymes which catalyze the conversion of tryptophan to N-formylkynurenine. Both enzymes are well establish therapeutic targets as important factors in the tumor immune evasion mechanism. A number of analogues of the marine pyrroloquinoline alkaloids tsitsikammamines or wakayin have been synthesized, two of them were synthesized using an original method to build the bispyrroloquinone framework. All the derivatives were evaluated in a cellular assay for their capacity to inhibit the enzymes. Six compounds have shown a significant potency on HEK 293-EBNA cell lines expressing hIDO1 or hTDO.
Assuntos
Alcaloides/síntese química , Inibidores Enzimáticos/síntese química , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Pirroliminoquinonas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Triptofano Oxigenase/antagonistas & inibidores , Alcaloides/metabolismo , Organismos Aquáticos/química , Inibidores Enzimáticos/metabolismo , Células HEK293 , Humanos , Alcaloides Indólicos/química , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Pirróis/química , Pirroliminoquinonas/metabolismo , Quinolinas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Relação Estrutura-AtividadeRESUMO
Recent reports on the synthetic studies of marine pyrroloiminoquinone alakloids and their analogs are reviewed.
Assuntos
Alcaloides/síntese química , Organismos Aquáticos/química , Modelos Químicos , Pirróis/síntese química , Pirroliminoquinonas/síntese química , Quinolinas/síntese química , Quinolonas/síntese química , Quinonas/síntese química , Tiazepinas/síntese química , Animais , Organismos Aquáticos/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Estrutura Molecular , Poríferos/química , Poríferos/metabolismoRESUMO
Many natural products with biologically interesting structures have been isolated from marine animals and plants such as sponges, corals, worms, etc. Some of them are discorhabdin alkaloids. The discorhabdin alkaloids (discorhabdin A-X), isolated from marine sponges, have a unique structure with azacarbocyclic spirocyclohexanone and pyrroloiminoquinone units. Due to their prominent potent antitumor activity, discorhabdins have attracted considerable attention. Many studies have been reported toward the synthesis of discorhabdins. We have accomplished the first total synthesis of discorhabdin A (1), having the strongest activity in vitro among discorhabdins in 2003. In 2009, we have also accomplished the first total synthesis of prianosin B (2), having the 16,17-dehydropyrroloiminoquinone moiety, by a novel dehydrogenation reaction with a catalytic amount of NaN(3). These synthetic studies, as well as syntheses of the discorhabdins by various chemists to-date, are reviewed here.
Assuntos
Alcaloides/síntese química , Produtos Biológicos/síntese química , Pirroliminoquinonas/síntese química , Alcaloides/isolamento & purificação , Animais , Antineoplásicos/síntese química , Antineoplásicos/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Humanos , Poríferos/química , Pirroliminoquinonas/isolamento & purificaçãoRESUMO
The structural assignment of bispyrroloquinone and bispyrroloiminoquinone regioisomers was achieved using (13)C NMR spectral data. In the case of bispyrroloiminoquinones, the carbonyl group in the regioisomer possessing a nitrogen atom in both alpha-positions was systematically less deshielded than the carbonyl group in the other regioisomer. In the case of bispyrroloquinones, the most deshielded carbonyl group in the regioisomer with a nitrogen atom in both alpha-positions was more deshielded than the same carbonyl group in the other regioisomer.
Assuntos
Pirroliminoquinonas/química , Isótopos de Carbono , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pirroliminoquinonas/síntese química , EstereoisomerismoRESUMO
An approach to the synthesis of the tetrahydropyrroloiminoquinone alkaloids has been developed and applied to the preparation of N-1-beta-D-ribofuranosyltetrahydropyrroloiminoquinones. The strategy utilizes oxidative cyclization of aryl-methoxyamides by hypervalent iodine to construct the quinoline framework shared by members of this alkaloid family. The hypervalent iodine oxidant is generated in situ by anodic oxidation of iodobenzene.
Assuntos
Alcaloides/química , Alcaloides/síntese química , Monossacarídeos/síntese química , Pirróis/síntese química , Pirroliminoquinonas/síntese química , Alcaloides/farmacologia , Animais , Catálise , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Iodobenzenos/química , Células KB , Biologia Marinha , Camundongos , Estrutura Molecular , Monossacarídeos/química , Monossacarídeos/farmacologia , Oxirredução , Pirróis/química , Pirróis/farmacologia , Pirroliminoquinonas/química , Pirroliminoquinonas/farmacologia , Estereoisomerismo , Inibidores da Topoisomerase IIRESUMO
Synthesis of 10 pyrroloiminoquinone derivatives is presented. The strategy is based around the elaboration of a common intermediate by reaction with primary amines. All the compounds obtained have been subjected to antiproliferative activity with three different cell lines (NCI-H460, HeLa, and HL-60). The capacity of 4 selected compounds to affect the enzymatic activity of the nuclear enzyme DNA topoisomerase II and to form the typical DNA fragmentation which occurs in the apoptotic process is discussed here.