16851-69-7Relevant articles and documents
Synthesis and biological evaluation of indoloquinoline alkaloid cryptolepine and its bromo-derivative as dual cholinesterase inhibitors
Nuthakki, Vijay K.,Mudududdla, Ramesh,Sharma, Ankita,Kumar, Ajay,Bharate, Sandip B.
, (2019/06/20)
Alkaloids have always been a great source of cholinesterase inhibitors. Numerous studies have shown that inhibiting acetylcholinesterase as well as butyrylcholinetserase is advantageous, and have better chances of success in preclinical/ clinical settings. With the objective to discover dual cholinesterase inhibitors, herein we report synthesis and biological evaluation of indoloquinoline alkaloid cryptolepine (1) and its bromo-derivative 2. Our study has shown that cryptolepine (1) and its 2-bromo-derivative 2 are dual inhibitors of acetylcholinesterase and butyrylcholinesterase, the enzymes which are involved in blocking the process of neurotransmission. Cryptolepine inhibits Electrophorus electricus acetylcholinesterase, recombinant human acetylcholinesterase and equine serum butyrylcholinesterase with IC50 values of 267, 485 and 699 nM, respectively. The 2-bromo-derivative of cryptolepine also showed inhibition of these enzymes, with IC50 values of 415, 868 and 770 nM, respectively. The kinetic studies revealed that cryptolepine inhibits human acetylcholinesterase in a non-competitive manner, with ki value of 0.88 μM. Additionally, these alkaloids were also tested against two other important pathological events of Alzheimer's disease viz. stopping the formation of toxic amyloid-β oligomers (via inhibition of BACE-1), and increasing the amyloid-β clearance (via P-gp induction). Cryptolepine displayed potent P-gp induction activity at 100 nM, in P-gp overexpressing adenocarcinoma LS-180 cells and excellent toxicity window in LS-180 as well as in human neuroblastoma SH-SY5Y cell line. The molecular modeling studies with AChE and BChE have shown that both alkaloids were tightly packed inside the active site gorge (site 1) via multiple π-π and cation-π interactions. Both inhibitors have shown interaction with the allosteric “peripheral anionic site” via hydrophobic interactions. The ADME properties including the BBB permeability were computed for these alkaloids, and were found within the acceptable range.
The "gatekeeper" Residue Influences the Mode of Binding of Acetyl Indoles to Bromodomains
Unzue, Andrea,Zhao, Hongtao,Lolli, Graziano,Dong, Jing,Zhu, Jian,Zechner, Melanie,Dolbois, Aymeric,Caflisch, Amedeo,Nevado, Cristina
, p. 3087 - 3097 (2016/05/19)
Small-molecule hits for the bromodomains of CREBBP and BAZ2B have been identified by scaffold hopping followed by docking of a set of ～200 compounds containing the acetyl indole scaffold. Chemical synthesis of nearly 30 derivatives has resulted in ligands of representatives of three subfamilies of human bromodomains with favorable ligand efficiency. The X-ray crystal structures of three different bromodomains (CREBBP, BAZ2B, and BRPF1b) in complex with acetyl indole derivatives reveal the influence of the gatekeeper residue on the orientation of small-molecule ligands in the acetyl lysine binding site.
A concise synthesis of the DNA-intercalating and antimalarial alkaloid cryptolepine and its fluorescence behaviour in solvents of different polarities
Lai, Tapan Kumar,Chatterjee, Asima,Banerji, Julie,Sarkar, Deboleena,Chattopadhyay, Nitin
experimental part, p. 1975 - 1983 (2009/02/07)
A microwave-induced rapid and facile synthesis of the DNA-intercalating and antimalarial drug cryptolepine is described. The key step in this synthesis involves the aqueous-phase base-catalyzed condensation of isatin and 1-acetyl-1H-indol-3-yl acetate which has been simplified and expedited by dielectric heating, employing an ordinary domestic microwave oven. The method transforms the synthesis of an important drug molecule from a prohibitively lengthy process to a matter of a few minutes with a much improved yield. Dual absorption and fluorescence is observed from the molecular system in solvents of different polarity thus providing valuable insight into its binding modes toward protein or DNA.
