The invention provides compounds and compositions useful for the modulation of certain enzymes. The compounds and compositions can induce of cell death, particularly cancer cell death. The invention also provides methods for the synthesis and use of the compounds and compositions, including the use of compounds and compositions in therapy for the treatment of cancer and selective induction of apoptosis in cells.
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Paragraph 0088; 0093-0094
(2013/04/24)
Exploration of (S)-3-aminopyrrolidine as a potentially interesting scaffold for discovery of novel Abl and PI3K dual inhibitors
Based on the literature-reported compensatory effect of PI3K on Abl inhibition and the improved preclinical effect of drug combination of Abl and PI3K inhibitors, a series of compounds bearing novel scaffold of (S)-3-aminopyrrolidine was identified as Abl and PI3K dual inhibitors through support vector machine screening tool, which were subsequently synthesized and tested. Most compounds demonstrated promising cytoxicity against a CML leukemia cell-line K562 and moderate inhibition against Abl and PI3K kinases. These compounds induced no apoptosis in K562 cell-line, suggesting that their cytotoxic activities are unlikely duo to other known anti-CML mechanisms. Molecular docking study further showed that the compound 5k could bind with both Abl and PI3K, but the weaker binding with Abl compared to Imatinib is consistent with its low kinase inhibitory rates. These plus literature-reported evidences suggest that the promising cytotoxic effect of our novel compounds might be due to the collective effect of Abl and PI3K inhibition.
Design and Synthesis of Novel Insecticides Based on the Serotonergic Ligand 1-[(4-Aminophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl]piperazine(PAPP)
1-[(4-Aminophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl]piperazine (PAPP) is a 5-HT1A agonist and was reported to display high affinity for serotonin (5-HT) receptor from the parasitic nematode Haemonchus contortus. The present investigation explored the possibility of using PAPP as a lead compound of new insecticides with novel mode of action. On the basis of the PAPP scaffold, a series of 1-arylmethyl-4-[(trifluoromethyl)pyridin-2-yl]piperazine derivatives were designed, synthesized, and evaluated for biological activities against the armyworm Pseudaletia separata (Walker). Bioassays showed that most of the target compounds displayed certain growth-inhibiting activities or larvicidal activities against armyworm. The quantitative structure-activity relationship (QSAR) for growth-inhibiting activities was also analyzed and established.