RESUMO
In this study, we present the development of two catalytic processes: a Pd-PEPPSI-catalyzed aminocarbonylation and a Pd(OAc)2-Xantphos-catalyzed alkoxycarbonylation of d-glycals, utilizing carbonylative cross-coupling reactions. We explored successfully various types of aromatic amines, as well as alkyl amines and amino acids, to synthesize new d-glycal amides. However, we observed limitations in the reactivity of alkyl and heteroaromatic amines. The processes enabled the synthesis of 20 novel C1-branched glycoamides and 7 new d-gluco esters.
RESUMO
A series of hybrid inhibitors, combining pharmacophores of known kinase inhibitors bearing anilino-purines (ruxolitinib, ibrutinib) and benzohydroxamate HDAC inhibitors (nexturastat A), were generated in the present study. The compounds have been synthesized and tested against solid and hematological tumor cell lines. Compounds 4d-f were the most promising in cytotoxicity assays (IC50 ≤ 50 nM) vs. hematological cells and displayed moderate activity in solid tumor models (EC50 = 9.3-21.7 µM). Compound 4d potently inhibited multiple kinase targets of interest for anticancer effects, including JAK2, JAK3, HDAC1, and HDAC6. Molecular dynamics simulations showed that 4d has stable interactions with HDAC and members of the JAK family, with differences in the hinge binding energy conferring selectivity for JAK3 and JAK2 over JAK1. The kinase inhibition profile of compounds 4d-f allows selective cytotoxicity, with minimal effects on non-tumorigenic cells. Moreover, these compounds have favorable pharmacokinetic profiles, with high stability in human liver microsomes (e.g., see t1/2: >120 min for 4f), low intrinsic clearance, and lack of significant inhibition of four major CYP450 isoforms.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Janus Quinases , Purinas/farmacologia , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
In this study, we present the development of two catalytic processes: a Pd-PEPPSI-catalyzed aminocarbonylation anda Pd(OAc)2-Xantphos-catalyzed alkoxycarbonylation of D-glycals, utilizing carbonylative cross-coupling reactions. We exploredsuccessfully various types of aromatic amines, as well as alkyl amines and amino acids, to synthesize new D-glycal amides. However,we observed limitations in the reactivity of alkyl and heteroaromatic amines. The processes enabled the synthesis of 20 novel C1-branched glycoamides and 7 new D-gluco esters.
RESUMO
Glycal amides were prepared for the first time by reacting 2-iodo-D-glycals with L-amino acid esters via a Pd-catalyzed carbonylative cross-coupling reaction, by using Mo(CO)6 as the carbon monoxide source. Glycal amides were synthesized in moderate to good yields under our optimized conditions. In addition, the acetyl groups of the glucal amides could be readily removed to obtain the corresponding trihydroxy derivatives in good yields.