RESUMO
Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2-6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9.
Assuntos
Antifúngicos , Rim , Polienos , Esteróis , Animais , Humanos , Camundongos , Anfotericina B/análogos & derivados , Anfotericina B/química , Anfotericina B/toxicidade , Antifúngicos/química , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Antifúngicos/toxicidade , Células Cultivadas , Colesterol/química , Colesterol/metabolismo , Farmacorresistência Fúngica , Ergosterol/química , Ergosterol/metabolismo , Rim/efeitos dos fármacos , Cinética , Testes de Sensibilidade Microbiana , Micoses/tratamento farmacológico , Micoses/microbiologia , Polienos/química , Polienos/metabolismo , Polienos/farmacologia , Inoculações Seriadas , Esteróis/química , Esteróis/metabolismo , Fatores de TempoRESUMO
Taking advantage of the C2-symmetry of the antitumor naturally occurring disorazole B1 molecule, a symmetrical total synthesis was devised with a monomeric advanced intermediate as the key building block, whose three-step conversion to the natural product allowed for an expeditious entry to this family of compounds. Application of the developed synthetic strategies and methods provided a series of designed analogues of disorazole B1, whose biological evaluation led to the identification of a number of potent antitumor agents and the first structure-activity relationships (SARs) within this class of compounds. Specifically, the substitutions of the epoxide units and lactone moieties with cyclopropyl and lactam structural motifs, respectively, were found to be tolerable for biological activities and beneficial with regard to chemical stability.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Oxazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Oxazóis/síntese química , Oxazóis/química , Relação Estrutura-AtividadeRESUMO
Exploration of intermediates that enable chemoselective cycloaddition reactions and expeditious construction of fused- or bridged-ring systems is a continuous challenge for organic synthesis. As an intermediate of interest, the oxyallyl cation has been harnessed to synthesize architectures containing seven-membered rings via (4+3) cycloaddition. However, its potential to access five-membered skeletons is underdeveloped, largely due to the thermally forbidden (3+2) pathway. Here, the combination of a tailored precursor and a Pd(0) catalyst generates a Pd-oxyallyl intermediate that cyclizes with conjugated dienes to produce a diverse array of tetrahydrofuran skeletons. The cycloaddition overrides conventional (4+3) selectivity by proceeding through a stepwise pathway involving a Pd-allyl transfer and ring closure sequence. Subsequent treatment of the (3+2) adducts with a palladium catalyst converts the heterocycles to the carbocyclic cyclopentanones.
RESUMO
An intramolecular FeCl3-catalyzed Michael addition reaction of styrene, a poor nucleophile, onto α,ß-unsaturated ketones was developed for the synthesis of highly substituted indene derivatives. The method was further applied to the total synthesis of the sesquiterpene natural products (±)-jungianol and 1-epi-jungianol.
RESUMO
A novel FeCl3 mediated formal [2+2] cycloaddition/ring opening cascade of o-keto-cinnamates was developed for the synthesis of indenones. The reaction tolerates a broad range of functional groups, including bromide, chloride, amide, acid and ester groups.
RESUMO
Highly substituted indene derivatives were readily prepared in excellent yields with high regioselectivity under very mild reaction conditions by the FeCl3 mediated intramolecular olefin-cationic cyclization of cinnamates.
Assuntos
Alcenos/química , Cinamatos/química , Indenos/química , Cátions , Ciclização , Indenos/síntese química , Estrutura Molecular , EstereoisomerismoRESUMO
A novel approach was developed for the synthesis of highly substituted indene derivatives, using an FeCl(3) catalyzed Prins-type cyclization reaction which was further applied in the total synthesis of jungianol and epi-jungianol.