RESUMO
Prostaglandin E2 (PGE2) plays a key role in various stages of cancer. PGE2 signals through the EP2 and the EP4 receptors, promoting tumorigenesis, metastasis, and/or immune suppression. Dual inhibition of both the EP2 and the EP4 receptors has the potential to counteract the effect of PGE2 and to result in antitumor efficacy. We herein disclose for the first time the structure of dual EP2/EP4 antagonists. By merging the scaffolds of EP2 selective and EP4 selective inhibitors, we generated a new chemical series of compounds blocking both receptors with comparable potency. In vitro and inâ vivo profiling suggests that the newly identified compounds are promising lead structures for further development into dual EP2/EP4 antagonists for use in cancer therapy.
Assuntos
Dinoprostona , Neoplasias , Humanos , Receptores de Prostaglandina E Subtipo EP2 , Receptores de Prostaglandina E Subtipo EP4RESUMO
Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.
Assuntos
Analgésicos/síntese química , Encéfalo/metabolismo , Hiperalgesia/tratamento farmacológico , Naftalenos/síntese química , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Administração Oral , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Cricetinae , Cricetulus , AMP Cíclico/biossíntese , Humanos , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Naftalenos/farmacocinética , Naftalenos/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Vanilloid receptor 1 (VR1, TRPV1) is a cation-selective ion channel that is expressed on primary afferent neurons and is upregulated following inflammation and nerve damage. Blockers of this channel may have utility in the treatment of chronic nociceptive and neuropathic pain. Here, we describe the optimization from a high throughput screening hit, of a series of 6-aryl-7-isopropylquinazolinones that are TRPV1 antagonists in vitro. We also demonstrate that one compound is active in vivo against capsaicin-induced hyperalgesia and in models of neuropathic and nociceptive pain in the rat.
Assuntos
Dor/tratamento farmacológico , Quinazolinas/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Barreira Hematoencefálica/metabolismo , Células CHO , Células CACO-2 , Permeabilidade da Membrana Celular , Doença Crônica , Cricetinae , Cricetulus , Modelos Animais de Doenças , Humanos , Técnicas In Vitro , Camundongos , Testes para Micronúcleos , Microssomos Hepáticos/metabolismo , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Canais de Cátion TRPV/genéticaRESUMO
[structure: see text] An improved, third-generation, total synthesis of (+)-discodermolide, a potent microtubule-stabilizing anticancer agent of marine sponge origin, is achieved in 11.1% yield over 21 steps. Key steps include a Still-Gennari HWE olefination, performed using NaH as the base, between C1-C8 beta-ketophosphonate 7 and C9-C24 aldehyde 8, introducing the (8Z)-alkene with 10:1 selectivity, and K-Selectride reduction of the derived enone 16, installing the (7S)-configuration.
Assuntos
Alcanos/síntese química , Alcenos/química , Carbamatos/síntese química , Cetonas/química , Lactonas/síntese química , Organofosfonatos/química , Pironas/síntese química , Aldeídos/química , Alcanos/química , Carbamatos/química , Lactonas/química , Conformação Molecular , Pironas/química , EstereoisomerismoRESUMO
By relying solely on substrate-based stereocontrol, a practical total synthesis of the microtubule-stabilizing anticancer agent (+)-discodermolide has been realized. This exploits a novel aldol bond construction with 1,6-stereoinduction from the boron enolate of (Z)-enone 3 in addition to aldehyde 2. The 1,3-diol 7 is employed as a common building block for the C(1)-C(5), C(9)-C(16), and C(17)-C(24) subunits. [reaction--see text]
Assuntos
Alcanos , Antineoplásicos/síntese química , Boro/química , Carbamatos , Lactonas/síntese química , Animais , Antineoplásicos/química , Lactonas/química , Estrutura Molecular , Poríferos , PironasAssuntos
Alcanos/química , Alcanos/metabolismo , Carbamatos/química , Carbamatos/metabolismo , Epotilonas/química , Lactonas/química , Lactonas/metabolismo , Pironas/química , Pironas/metabolismo , Tubulina (Proteína)/metabolismo , Epotilonas/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Soluções/química , Tubulina (Proteína)/químicaRESUMO
[structure: see text] A novel total synthesis of the complex polyketide discodermolide, a promising anticancer agent of marine sponge origin, has been completed in 11.1% overall yield over 21 linear steps. This third-generation approach features an unprecedented Still-Gennari-type HWE olefination reaction between advanced C1-C8 beta-ketophosphonate 61 and C9-C24 aldehyde 7, introducing the (8Z)-alkene with 10:1 selectivity. The stereotetrad found in the C1-C8 subunit 61 was established via a highly diastereoselective boron-mediated aldol reaction/in situ reduction between ketone (S)-8 and 3-benzyloxypropanal. The (7S)-configuration was installed by the reduction of enone 73 with K-Selectride.
Assuntos
Alcanos/síntese química , Antineoplásicos/síntese química , Carbamatos/síntese química , Lactonas/síntese química , Organofosfonatos/síntese química , Aldeídos/química , Boro/química , Cetonas/química , Modelos Químicos , Oxirredução , Pironas , EstereoisomerismoRESUMO
A novel total synthesis of the complex polyketide (+)-discodermolide, a promising anticancer agent of sponge origin, has been completed in 7.8% overall yield over 24 linear steps, with 35 steps altogether. This second-generation approach was designed to rely solely on substrate control for introduction of the required stereochemistry, eliminating the use of all chiral reagents or auxiliaries. The common 1,2-anti-2,3-syn stereotriad found in each of three subunits, aldehyde 9 (C(1)-C(5)), ester 40 (C(9)-C(16)), and aldehyde 13 (C(17)-C(24)), was established via a boron-mediated aldol reaction of ethyl ketone 15 and formaldehyde, followed by hydroxyl-directed reduction to give 1,3-diol 14. Alternatively, a surrogate aldehyde 22 was employed for formaldehyde in this aldol reaction, leading to the beta-hydroxy aldehyde 20 as a common building block, corresponding to the discodermolide stereotriad. Key fragment unions were achieved by a lithium-mediated anti aldol reaction of ester 40 and aldehyde 13 under Felkin-Anh control to provide (16S,17S)-adduct 51 and a boron-mediated aldol reaction between enone 10 and aldehyde 9, exploiting unprecedented remote 1,6-stereoinduction, to give the (5S)-adduct 57.