Design, synthesis and bioevaluation of PI3Kα-selective inhibitors as potential colorectal cancer drugs.

The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold. Compared to the control 8a, 18a exhibited 4.4-fold more potent inhibitory activity against PI3Kα (IC50: 2.5 vs 11 nM) and better isoform-selective profiles over other PI3Ks. In addition, 18a showed a 1.5-fold more potent antiproliferative effect against HCT-116 cell lines (IC50: 3.79 vs 5.80 µM) and a better selectivity over the normal tissue cells. The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a.

Two new compounds from Verbena bonariensis.

Two new compounds verboncin A (1) and verboncin B (4) and 14 known compounds (2-3 and 5-16) were isolated from Verbena bonariensis, and these 14 compounds were first obtained from this plant. Their chemical structures were established by one and two-dimensional NMR and HRESIMS analysis and the results were compared with literature values. The absolute configuration of 1 was determined by calculating electronic circular dichroism (ECD). The cytotoxicity of some of the compounds against MCF-7, HCT-116, MDA-MB-231, and SW620 human cancer cell lines were evaluated, in which compound 4 showed negligible cytotoxic activity with an IC50 value of 68.08 ± 0.35 µM against the MCF-7 cell line.

Callicarpnoids A-C, structurally intriguing ent-Clerodane diterpenoid dimers with cytotoxicity against MCF-7 and HCT-116 cell lines from Callicarpa arborea Roxb.

Callicarpnoids A-C (1-3), three new ent-clerodane diterpenoid dimers formed via a [4 + 2] hetero Diels-Alder cycloaddition, appeared as a third example of this type of dimers, were isolated from the stems of Callicarpa arborea Roxb.. Their structures were elucidated by comprehensive spectroscopic analysis, and the absolute configurations were confirmed by single-crystal X-ray diffraction and electronic circular dichroism (ECD) calculations, as well as DP4 + analysis. Cytotoxicity test in two cell lines indicated that compounds 2 and 3 had significant cytotoxic effect against breast cancer cell (MCF-7) and colorectal cancer cell (HCT-116) with IC50 ranging from 5.2 to 7.2 µM, comparable to those of the positive control. Furthermore, the western blot analysis revealed that the protein expression levels of Bax were increased following compounds 2 and 3 treatment, whereas the expression levels of caspase 8, caspase 3, caspase 9 and Bcl2 were decreased in a dose-dependent manner, indicating that compounds 2 and 3 may induce apoptosis via both intrinsic and extrinsic pathways in MCF-7 and HCT-116 cells.

Ten new prenylated flavonoids from Macaranga denticulata and their antitumor activities.

Ten new prenylated flavonoids, named denticulains A-J (1-10), together with seven known prenylated flavonoids (11-17) were isolated from Macaranga denticulata. Their structures were elucidated on the basis of detailed spectroscopic analysis and by comparison with literature data. In addition, compounds 1 and 14 inhibited the proliferation of SW620 and HCT-116 cell lines with an IC50 value of 46.08 µM and 56.83 µM, respectively.