Design, synthesis and biological evaluation of novel morpholinopyrimidine-5-carbonitrile derivatives as dual PI3K/mTOR inhibitors.

In this study, novel morpholinopyrimidine-5-carbonitriles were designed and synthesized as dual PI3K/mTOR inhibitors and apoptosis inducers. The integration of a heterocycle at position 2, with or without spacers, of the new key intermediate 2-hydrazinyl-6-morpholinopyrimidine-5-carbonitrile (5) yielded compounds 6-10, 11a-c and 12a-h. The National Cancer Institute (USA) tested all compounds for antiproliferative activity. Schiff bases, 12a-h analogs, were the most active ones. The most promising compounds 12b and 12d exhibited excellent antitumor activity against the leukemia SR cell line, which is the most sensitive cell line, with IC50 0.10 ± 0.01 and 0.09 ± 0.01 µM, respectively, along with significant effects on PI3Kα/PI3Kß/PI3Kδ with IC50 values of 0.17 ± 0.01, 0.13 ± 0.01 and 0.76 ± 0.04 µM, respectively, for 12b and 1.27 ± 0.07, 3.20 ± 0.16 and 1.98 ± 0.11, respectively, for 12d compared to LY294002. Compared to Afinitor, these compounds inhibited mTOR with IC50 values of 0.83 ± 0.05 and 2.85 ± 0.17 µM, respectively. Annexin-V and propidium iodide (PI) double labeling showed that compounds 12b and 12d promote cytotoxic leukemia SR apoptosis. Compounds 12b and 12d also caused a G2/M cell cycle arrest in the leukaemia SR cell line. The findings of this study indicate that the highest effect was observed for 12b, which was supported by western blot and docking analysis.

Discovery of New Uracil and Thiouracil Derivatives as Potential HDAC Inhibitors.

Background: Histone deacetylase inhibitors (HDACIs) are a relatively new class of potential drugs for treating cancer. Aim: Discovery of new anticancer agents targeting HDAC. Methods: New uracil and thiouracil derivatives panels were designed and synthesized as HDAC inhibitors. The synthesized compounds were tested against MCF-7, HepG2, and HCT-116. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. The most active member was tested for its potential against cell cycle, apoptosis, caspase-3, and caspase-8. Docking studies were carried out against HDAC1. Results: Compounds 5a, 5b, 5f, 5i, 5k, and 5m exhibited promising cytotoxic activities. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. Regarding the HDAC1 inhibitory activity, compound 5m was the most potent member (IC50 = 0.05 µg/mL) compared to trichostatin A (IC50 = 0.0349 µg/mL). For HDAC4, compound 5m showed superior activity (IC50 = 2.83 µg/mL) than trichostatin A (IC50 = 3.349 µg/mL). Compound 5m showed a high potential to arrest the HCT116 cell cycle at the G0-G1 phase. In addition, it showed an almost 17 times apoptotic effect (37.59%) compared to the control cells (2.17%). Furthermore, Compound 5m showed significant increases in the levels of caspase-3 and caspase-8. Finally, the uracil and thiouracil derivatives showed accepted binding mods against HDAC. Conclusions: Compound 5m has potential anticancer activity targeting HDAC with a significant apoptotic effect.

New thiouracil derivatives as histone deacetylase inhibitors and apoptosis inducers: design, synthesis and anticancer evaluation.

Background: Histone deacetylase (HDAC) inhibitors have good contributions in cancer management. Aim: To introduce new active HDAC inhibitors. Methods: Design and synthesis of 16 thiouracil derivatives with deep biological and computational investigation. Results: Compounds 7a, 7c, 7d, 7e, 8a and 8f showed the highest antiproliferative effects against MCF7, HepG2 and HCT116 cell lines. Compound 7e exhibited the highest activities against HDAC1 and HDAC4. Compound 7e arrested the cell cycle of HCT116 cells at G0-G1 with significant apoptotic effect. In addition, treatment with compound 7e was associated with a significant increase in the levels of caspase-3 and caspase-8. The docking studies gave good insight about the binding patterns of the synthesized compounds against HDAC1. Conclusion: Compound 7e has a promising anticancer activity targeting HDAC.

Discovery of new quinolines as potent colchicine binding site inhibitors: design, synthesis, docking studies, and anti-proliferative evaluation.

Discovering of new anticancer agents with potential activity against tubulin polymerisation is still a promising approach. Colchicine binding site inhibitors are the most relevant anti-tubulin polymerisation agents. Thus, new quinoline derivatives have been designed and synthesised to possess the same essential pharmacophoric features of colchicine binding site inhibitors. The synthesised compounds were tested in vitro against a panel of three human cancer cell lines (HepG-2, HCT-116, and MCF-7) using colchicine as a positive control. Comparing to colchicine (IC50 = 7.40, 9.32, and 10.41 µM against HepG-2, HCT-116, and MCF-7, respectively), compounds 20, 21, 22, 23, 24, 25, 26, and 28 exhibited superior cytotoxic activities with IC50 values ranging from 1.78 to 9.19 µM. In order to sightsee the proposed mechanism of anti-proliferative activity, the most active members were further evaluated in vitro for their inhibitory activities against tubulin polymerisation. Compounds 21 and 32 exhibited the highest tubulin polymerisation inhibitory effect with IC50 values of 9.11 and 10.5 nM, respectively. Such members showed activities higher than that of colchicine (IC50 = 10.6 nM) and CA-4 (IC50 = 13.2 nM). The impact of the most promising compound 25 on cell cycle distribution was assessed. The results revealed that compound 25 can arrest the cell cycle at G2/M phase. Annexin V and PI double staining assay was carried out to explore the apoptotic effect of the synthesised compounds. Compound 25 induced apoptotic effect on HepG-2 thirteen times more than the control cells. To examine the binding pattern of the target compounds against the tubulin heterodimers active site, molecular docking studies were carried out.