RESUMEN
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.
RESUMEN
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.
Asunto(s)
Oligosacáridos/síntesis química , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Glucosa/análogos & derivados , Glucosa/química , Células HL-60 , Humanos , Ratones , Oligosacáridos/farmacología , Polisacáridos/síntesis química , Polisacáridos/farmacología , Ramnosa/análogos & derivados , Ramnosa/químicaRESUMEN
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.
Asunto(s)
Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Oligosacáridos/síntesis química , Oligosacáridos/farmacología , Animales , Anticoagulantes/química , Antineoplásicos/química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Datos de Secuencia Molecular , Oligosacáridos/química , EstereoisomerismoRESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Glicósidos/síntesis química , Glicósidos/farmacología , Oligosacáridos/síntesis química , Oligosacáridos/farmacología , Ésteres del Ácido Sulfúrico/síntesis química , Ésteres del Ácido Sulfúrico/farmacología , Animales , Antineoplásicos/química , Secuencia de Carbohidratos , Línea Celular Tumoral , Glicósidos/química , Ratones , Datos de Secuencia Molecular , Oligosacáridos/química , Ésteres del Ácido Sulfúrico/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
[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.
Asunto(s)
Saponinas/síntesis química , Glicosilación , Oligosacáridos/síntesis química , EstereoisomerismoRESUMEN
Biantennary beta-D-(1-->6) glucosamine hexa-, octa-, and dodecaoligosaccharide derivatives were synthesized convergently using isopropyl thioglycosides as donors in NIS/TMSOTf-catalyzed glycosylation.
