RESUMO
Selective CDK2 inhibitors have the potential to provide effective therapeutics for CDK2-dependent cancers and for combating drug resistance due to high cyclin E1 (CCNE1) expression intrinsically or CCNE1 amplification induced by treatment of CDK4/6 inhibitors. Generative models that take advantage of deep learning are being increasingly integrated into early drug discovery for hit identification and lead optimization. Here we report the discovery of a highly potent and selective macrocyclic CDK2 inhibitor QR-6401 (23) accelerated by the application of generative models and structure-based drug design (SBDD). QR-6401 (23) demonstrated robust antitumor efficacy in an OVCAR3 ovarian cancer xenograft model via oral administration.
RESUMO
A pentasaccharide, beta-D-Man-(1-->2)-[beta-D-GlcNAc-(1-->4)]-alpha-L-Rha-(1-->4)-alpha-L-Rha-(1-->4)-alpha-L-Rha-1-OC8H17, representing the repeating unit of latosillan, was convergently synthesized from the building blocks, ethyl 2,3-O-isopropylidene-1-thio-alpha-l-rhamnopyranoside, 2-O-acetyl-3,4,6-tri-O-benzyl-beta-d-glucopyranosyl trichloroacetimidate, and 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-beta-d-glucopyranosyl trichloroacetimidate under standard glycosylation conditions. The target pentasaccharide showed acceptable differentiation-inducing activity on HL-60 cell lines at the dosages of 10-50 microg/mL.
Assuntos
Oligossacarídeos/síntese química , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Glucose/análogos & derivados , Glucose/química , Células HL-60 , Humanos , Camundongos , Oligossacarídeos/farmacologia , Polissacarídeos/síntese química , Polissacarídeos/farmacologia , Ramnose/análogos & derivados , Ramnose/químicaRESUMO
[reaction: see text] A new class of glycosyl donors having unprotected 2- and 2,4-hydroxyl groups were investigated under the standard glycosylation conditions. This approach was shown to be generally effective for the synthesis of alkyl and steroidal glycosides. A natural saponin, containing 2,4-branched oligosaccharide, was prepared in 35% overall yield in four straightforward sequential reactions by taking advantage of these partially protected donors.
Assuntos
Saponinas/síntese química , Glicosilação , Oligossacarídeos/síntese química , EstereoisomerismoRESUMO
An efficient method for the regioselective 3-O-silylation of beta-thiofucopyranoside was disclosed. Based on this discovery, we described a high-yielding strategy for the synthesis of the natural core structure of L-fucan and its fully sulfated derivative. The bioassay suggested that octyl 2,3,4-tri-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-beta-L-fucopyranoside presented better antitumor activities than that of the free tetramer based on Sarcoma 180 cells and Lewis lung carcinoma model studies.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Glicosídeos/síntese química , Glicosídeos/farmacologia , Oligossacarídeos/síntese química , Oligossacarídeos/farmacologia , Ésteres do Ácido Sulfúrico/síntese química , Ésteres do Ácido Sulfúrico/farmacologia , Animais , Antineoplásicos/química , Sequência de Carboidratos , Linhagem Celular Tumoral , Glicosídeos/química , Camundongos , Dados de Sequência Molecular , Oligossacarídeos/química , Ésteres do Ácido Sulfúrico/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Biantennary beta-D-(1-->6) glucosamine hexa-, octa-, and dodecaoligosaccharide derivatives were synthesized convergently using isopropyl thioglycosides as donors in NIS/TMSOTf-catalyzed glycosylation.
Assuntos
Glucosamina/síntese química , Oligossacarídeos/síntese química , Sequência de Carboidratos , Catálise , Glucosamina/química , Glicosilação , Dados de Sequência Molecular , Oligossacarídeos/química , Relação Estrutura-AtividadeRESUMO
Octyl 2,3-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2-O-sulfo-alpha-L-fucopyranosyl-(1-->4)-2,3-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2-O-sulfo-alpha-L-fucopyranosyl-(1-->4)-2,3-di-O-sulfo-beta-L-fucopyranoside, a fucosyl pentasaccharide with a regular structure resembling the repeating unit of a natural sulfated fucan, was chemically synthesized using a convergent '2+3' strategy. Regioselective 3-O-silylation of beta-thiofucopyranoside and AgOTf-catalyzed glycosylation of the protected glycosyl trichloroacetimidate facilitated a one-pot trisaccharide synthesis. The synthesized target compound showed good antitumor activity in vivo, and promising anticoagulant activity in vitro.