55654-68-7Relevant articles and documents
Anti-leukemic properties of aplysinopsin derivative ee-84 alone and combined to bh3 mimetic a-1210477
Song, Sungmi,Kim, Sua,El-Sawy, Eslam R.,Cerella, Claudia,Orlikova-Boyer, Barbora,Kirsch, Gilbert,Christov, Christo,Dicato, Mario,Diederich, Marc
, (2021/06/11)
Aplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess antiproliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro and in vivo proliferation and viability screening of newly synthesized aplysinopsin analogs on myelogenous leukemia cell lines and zebrafish toxicity tests, as well as analysis of differential toxicity in noncancerous RPMI 1788 cells and PBMCs, we identified EE-84 as a promising novel drug candidate against chronic myeloid leukemia. This indole derivative demonstrated drug-likeness in agreement with Lipinski’s rule of five. Furthermore, EE-84 induced a senescent-like phenotype in K562 cells in line with its cytostatic effect. EE-84-treated K562 cells underwent morphological changes in line with mitochondrial dysfunction concomitant with autophagy and ER stress induction. Finally, we demonstrated the synergistic cytotoxic effect of EE-84 with a BH3 mimetic, the Mcl-1 inhibitor A-1210477, against imatinib-sensitive and resistant K562 cells, highlighting the inhibition of antiapoptotic Bcl-2 proteins as a promising novel senolytic approach against chronic myeloid leukemia.
Design, synthesis, biological evaluation and molecular modelling studies of indole glyoxylamides as a new class of potential pancreatic lipase inhibitors
Sridhar,Palawat, Saksham,Paul, Atish T.
, p. 373 - 381 (2019/01/16)
A series of eighteen indole glyoxylamide analogues were synthesized, characterized and evaluated for their pancreatic lipase inhibitory activity. Porcine pancreatic lipase (Type II) was used with 4-nitrophenyl butyrate (as substrate) for the in vitro assay. Compound 8f exhibited competitive inhibition against pancreatic lipase with IC50 value of 4.92 μM, comparable to that of the standard drug, orlistat (IC50 = 0.99 μM). Compounds 7a-i and 8a-i were subjected to molecular docking into the active site of human PL (PDB ID: 1LPB) wherein compound 8f possessed a potential MolDock score of ?153.037 kcal/mol. Molecular dynamics simulation of 8f complexed with pancreatic lipase, confirmed the role of aromatic substitution in stabilizing the ligand through hydrophobic interactions (maximum observed RMSD = 3.5 ?).
Three-component synthesis of ynediones by a glyoxylation/ Stephens-Castro coupling sequence
Merkul, Eugen,Dohe, Janis,Gers, Charlotte,Rominger, Frank,Mueller, Thomas J. J.
supporting information; experimental part, p. 2966 - 2969 (2011/05/04)
(Chemical Equation Presented) One step back, two steps forward! Starting from diverse heterocycles, the title reaction furnishes ynediones under very mild conditions in a direct and preparatively simple one-pot process. The key to avoiding decarbonylation
