RESUMO
Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2-a]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28. It turned out that BAY 1165747 (BAY-747, 28) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 (28) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.
Assuntos
Guanilato Ciclase , Hipertensão , Humanos , Guanilil Ciclase Solúvel/metabolismo , Guanilato Ciclase/metabolismo , Hipertensão/tratamento farmacológico , Vasodilatadores , Piridinas/farmacologia , Piridinas/uso terapêutico , Óxido Nítrico/metabolismoRESUMO
A modular total synthesis of the potent V-ATPase inhibitors archazolid A and B is reported. The convergent preparation was accomplished by late-stage diversification of joint intermediates. Key synthetic steps involve asymmetric boron-mediated aldol reactions, two consecutive Still-Gennari olefinations to set the characteristic (Z,Z)-diene system, a Brown crotyboration, and a diastereoselective aldol condensation of highly elaborate intermediates. For macrocyclization, both an HWE reaction and a Heck coupling were successfully employed to close the 24-membered macrolactone. During the synthetic campaign, a generally useful protocol for an E-selective Heck reaction of nonactivated alkenes and a method for the direct nucleophilic displacement of the Abiko-Masamune auxiliary with sterically hindered nucleophiles were developed. The expedient and flexible strategy will enable further SAR studies of the archazolids and more detailed evaluations of target-inhibitor interactions.
Assuntos
Macrolídeos/síntese química , Tiazóis/síntese química , Macrolídeos/química , Conformação Molecular , Estereoisomerismo , Tiazóis/química , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidoresRESUMO
The novel macrocyclic polyketide, 10-hydroxymethyl-archazolid-7-O-beta-D-glucopyranoside (archazolid D), was obtained from the myxobacterium Cystobacter violaceus. The structure of this first hydroxylated archazolid was determined by spectroscopic analysis, in particular by HMBC, HMQC, and ROESY NMR investigations, and by degradation. This novel metabolite was evaluated for growth inhibition of murine connective tissue cells and V-ATPase inhibition in comparison to other known archazolids.
Assuntos
Inibidores Enzimáticos/farmacologia , Myxococcales/química , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/isolamento & purificação , Fermentação , Hidroxilação , Espectroscopia de Ressonância Magnética , Manduca/enzimologia , Camundongos , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
[reaction: see text] A novel, biomimetic concept for the direct reductive amination of ketones is described that relies on selective imine activation by hydrogen bond formation. The mild, acid- and metal-free process requires only catalytic amounts of thiourea as hydrogen bond donor and utilizes the Hantzsch ester for transfer hydrogenation. The method allows the efficient synthesis of structurally diverse amines.
RESUMO
[structure: see text] The relative and absolute stereochemistry of the structurally unique 24-membered myxobacterial macrolides archazolid A and B, highly potent vacuolar-type ATPase (V-ATPase) inhibitors in vitro and in vivo, was determined on the basis of a combination of extensive high-field NMR studies, including J-based configuration analysis, molecular modeling, and chemical methods.
Assuntos
Antimitóticos/química , Antimitóticos/farmacologia , Macrolídeos/química , Macrolídeos/farmacologia , Myxococcales/química , Tiazóis/química , Tiazóis/farmacologia , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , Estrutura Molecular , EstereoisomerismoRESUMO
For prostate cancer, prostate specific membrane antigen (PSMA) has been identified as a diagnostic and therapeutic target. Fluorinated derivatives of 2-(phosphonomethyl)pentanedioic acid were designed and synthesized to explore whether this fluorine-substituent is tolerated in the pentanedioic acid moiety that is common to almost all PSMA targeting small molecule inhibitors. The binding affinities of the racemic and individual stereoisomers of 2-fluoro-4-(phosphonomethyl)pentanedioic acid were determined and showed that the introduction of fluorine was well tolerated. The radiosynthesis of the analogous 2-[(18)F]fluoro-4-(phosphonomethyl)pentanedioic acid was developed and evaluated in vivo with the PSMA positive LNCaP human prostate cancer cell. The biological results demonstrated specific binding of the tracer to PSMA positive tumors in mice. These results warrant the further evaluation of this class of compounds as radiolabeled tracers for the detection and staging of prostate cancer.
Assuntos
Diagnóstico por Imagem , Glutamato Carboxipeptidase II/antagonistas & inibidores , Compostos Organofosforados/química , Neoplasias da Próstata/diagnóstico , Compostos Radiofarmacêuticos , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Químicos , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/metabolismo , Radioquímica , Estereoisomerismo , Distribuição Tecidual , Tomografia Computadorizada por Raios X , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tedanolide, which was isolated by Schmitz in 1984 from the marine sponge Tedania ignis, is a highly cytotoxic macrolide leading to strong growth inhibition of P338 tumor cells in bioassays. A unique structural feature of the known tedanolides is the primary hydroxyl group incorporated in the macrolactone. This unusual motif for macrolactones originated from PKS biosynthesis might arise through lactonizations others than those derived by the thioesterase reaction. First experimental data that support this hypothesis and reflect the inherent preference of PKS-induced macrolactonization were obtained during this synthesis. The inherent preference for the formation of a 14-membered macrocyclization is discussed together with the pivotal steps in the synthesis.
Assuntos
Macrolídeos/síntese química , Poríferos/química , Animais , Lactonas/síntese química , Lactonas/química , Macrolídeos/química , Conformação Molecular , EstereoisomerismoRESUMO
Novel analogues of the V-ATPase inhibitors archazolid A and B with modifications of the free hydroxyl groups and the side chain were designed by molecular modeling, synthesized by derivatization of the parent natural product and evaluated for V-ATPase inhibition and growth inhibition of murine connective tissue cells.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Macrolídeos/farmacologia , Tiazóis/farmacologia , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , Animais , Antimitóticos/síntese química , Antimitóticos/farmacologia , Linhagem Celular , Desenho de Fármacos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Conformação Molecular , Myxococcales/química , Relação Estrutura-AtividadeRESUMO
The first total synthesis of the (+)-tedanolide is described. Pivotal steps are the Felkin-selective aldol coupling between C12 and C13 and an efficient Mitsunobu macrolactonization. Selective protecting group transformations and subsequent oxidations generate the macrocyclic triketone. In the endgame of the synthesis, four TBS groups are removed in one reaction and a chemo- and stereoselective final step epoxidation generates (+)-tedanolide.
Assuntos
Lactonas/síntese química , Macrolídeos , EstereoisomerismoRESUMO
Among nature's ecosystems, the marine environment has been an extremely rich source of structurally complex and biologically active molecules. This review aims to cover the recent developments in the synthesis of marine natural products, also reflecting the trend of their increased use to address biological questions. The examples chosen should be viewed as representative of the different structural motifs on the one hand and the strategies and stimuli for their synthesis on the other.