Molecular mimicry is an essential part of the development of drugs and molecular probes. In the chemical glycobiology field, although many glycomimetics have been developed in the past years, it has been considered that many failures in their use are related to the lack of the anomeric effects in these analogues. Additionally, the origin of the anomeric effects is still the subject of virulent scientific debates. Herein, by combining chemical synthesis, NMR methods, and theoretical calculations, we show that it is possible to restore the anomeric effect for an acetal when replacing one of the oxygen atoms by a CF2 group. This result provides key findings in chemical sciences. On the one hand, it strongly suggests the key relevance of the stereoelectronic component of the anomeric effect. On the other hand, the CF2 analogue adopts the natural glycoside conformation, which might provide new avenues for sugar-based drug design.
In this paper, a series of novel 4-substituted coumarin derivatives were synthesized. Among these compounds 34, 39, 40, 43, 62, 65, and 67 exhibited significant antiproliferative activity toward a panel of tumor cell lines at subnanomolar IC50 values. Compound 65 showed potent antiproliferative ability (IC50 values of 7-47 nM) and retained full activity in multidrug resistant cancer cells. Compound 65 caused G2/M phase arrest and interacted with the colchicine-binding site in tubulin, as confirmed by immune-fluorescence staining, microtubule dynamics assays, and competition assays with N,N'-ethylene-bis(iodoacetamide). Compound 65 reduced the cell migration and disrupted capillary-like tube formation in HUVEC cells. Importantly, compound 65 significantly and dose-dependently reduced tumor growth in four xenografts models including paclitaxel sensitive and resistant ovarian tumors (A2780s and A2780/T), adrmicycin sensitive and resistant breast tumors (MCF-7 and MCF-7/ADR), suggesting that compound 65 is a promising novel antimitotic compound for the potential treatment of cancer.
Sugar function, structure and dynamics are intricately correlated. Ring flexibility is intrinsically related to biological activity; actually plasticity in L-iduronic rings modulates their interactions with biological receptors. However, the access to the experimental values of the energy barriers and free-energy difference for conformer interconversion in water solution has been elusive. Here, a new generation of fluorine-containing glycomimetics is presented. We have applied a combination of organic synthesis, NMR spectroscopy and computational methods to investigate the conformational behaviour of idose- and glucose-like rings. We have used low-temperature NMR spectroscopic experiments to slow down the conformational exchange of the idose-like rings. Under these conditions, the exchange rate becomes slow in the (19) F NMR spectroscopic chemical shift timescale and allows shedding light on the thermodynamic and kinetic features of the equilibrium. Despite the minimal structural differences between these compounds, a remarkable difference in their dynamic behaviour indeed occurs. The importance of introducing fluorine atoms in these sugars mimics is also highlighted. Only the use of (19) F NMR spectroscopic experiments has permitted the unveiling of key features of the conformational equilibrium that would have otherwise remained unobserved.
Although androgen deprivation therapy may initially be effective in prostate cancer, the disease can gradually progress to castration-resistant prostate cancer, at which point chemotherapy becomes the major clinical strategy. In this study, we demonstrated the anti-cancer potential of a novel 3',5'-diprenylated chalcone (C10), which selectively inhibited the proliferation of PC3 cells in vitro and in vivo. C10 treatment elevated the proportion of PC3 cells in sub-G1 phase and induced programmed cell death. Interestingly, C10 elicited concurrent Caspase-dependent apoptotic and gasdermin E-dependent pyroptotic events. RNA-Seq and bioinformatics analyses revealed a strong correlation between protein kinase C delta (PKCδ) and mitogenactivated protein kinase pathway activation in prostate cancer. PKCδ silencing in PC3 cells suppressed the activation of the JNK pathway and the expression of its downstream genes, including Bax, interleukin-6 and interleukin-1β, which are involved in apoptotic and pyroptotic processes. Moreover, in PC3 cell xenograft tumor tissues, C10 treatment inhibited tumor growth and upregulated PKCδ. These findings suggest that C10 treatment induces the PKCδ/JNK pathway, thereby activating Caspase-3 and inducing the cleavage of PARP and gasdermin E to execute apoptosis and cell-lytic pyroptosis in prostate cancer cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.