Anahit Pews-Davtyan

Novel indolylmaleimide acts as GSK-3β inhibitor in human neural progenitor cells

The Wnt pathway is involved in cellular processes linked to either proliferation or differentiation. Therefore small molecules offer an attractive opportunity to modulate this pathway, whereas the key enzyme GSK-3beta is of special interest. In this study, non-symmetrically substituted indolylmaleimides have been synthesized and their ability to function as GSK-3beta inhibitors has been investigated in a human neural progenitor cell line. Among the newly synthesized compounds, the substance IM-12 showed a significant activity in several biological tests which was comparable or even outplayed the effects of the known GSK-3beta inhibitor SB-216763. Furthermore the treatment of human neural progenitor cells with IM-12 resulted in an increase of neuronal cells. Therefore we conclude that indolylmaleimides act via the canonical Wnt signalling pathway by inhibition of the key enzyme GSK-3beta.

A general and practical oxidation of alcohols to primary amides under metal-free conditions

A general procedure for oxidation of both benzyl alcohols and alkyl alcohols to primary amides under catalyst free conditions has been developed. 34 examples of primary amides were produced from their corresponding alcohols in moderate to excellent yields. This is a practical procedure for primary amides synthesis; water and tert-butanol are the only by-products. A commercial drug, Piracetam, was prepared in one step with 73% yield as well.

A Convenient Palladium‐Catalyzed Carbonylative Synthesis of 2‐Aminbenzoxazinones from 2‐Bromoanilines and Isocyanates

Mon ami(ne)! A general and convenient methodology for 2-aminobenzoxazinone synthesis has been developed (see scheme). Readily available 2-bromoanilines and isocyanates were used as substrates and various products have been prepared in good yields. Notably, [Mo(CO)6] as a solid CO source was applied instead of gas.

Interference of a novel indolylmaleimide with microtubules induces mitotic arrest and apoptosis in human progenitor and cancer cells.

Indolylmaleimides display a broad spectrum of biological activity and offer great opportunity to influence several aspects of cell fate, as proliferation and differentiation. In this study we describe the effect of PDA-66, a newly synthesised indolylmaleimide, showing a strong dose dependent anti-proliferative effect on immortalised human progenitor and cancer cells. We demonstrated a highly depolymerizing effect on in vitro tubulin assembly and conclude that PDA-66 acts as microtubule destabilising agent. In addition we found that PDA-66 induces mitotic arrest of cells in the G₂/M phase of the cell cycle. Subsequently cells undergo apoptosis, indicating the major mechanism of the anti-proliferative effect. To prove a potential anti-cancer activity of PDA-66 we examined the effect of PDA-66 on human SH-SY5Y neuroblastoma and A-459 lung cancer cells, showing a significant reduction in cancer cell proliferation in a dose dependent manner. Thus PDA-66 is a new anti-mitotic compound with an indole-core with the potential to be used for cancer therapy.

Synthesis of new diphosphine ligands and their application in Pd-catalyzed alkoxycarbonylation reactions.

Carbocyclic and N-heterocyclic analogues of the industrially applied ligand bis(di-tert-butylphosphinomethyl)benzene (1) have been synthesized in moderate to very good yields. The new ligands are based on benzene, tetralin, lutidine, pyrazine, quinoxaline, and maleimide backbones. Electronic and steric variations of the phosphorous donor sites were performed. As a benchmark reaction, the palladium-catalyzed methoxycarbonylation of 1-octene has been tested. Ester yields up to 64% and high linear selectivities up to 92% were achieved.

Comparison of Several Glucuronate Glycosyl Donors

Methyl 3,4‐di‐O‐benzyl‐[(S)‐1,2‐O‐(1‐cyanoethylidene)]‐α‐d‐glucopyranuronate (12), methyl 3,4‐di‐O‐benzyl‐[(S)‐1,2‐O‐(1‐ethoxyethylidene)]‐α‐d‐glucopyranuronate (14), methyl 2‐O‐acetyl‐3,4‐di‐O‐benzyl‐α‐d‐glucopyranuronate bromide (15), methyl (2‐O‐acetyl‐3,4‐di‐O‐benzyl‐α‐d‐glucopyranosyl)uronate trichloroacetimidate (17), and methyl (2,3,4‐tri‐O‐benzyl‐α/β‐d‐glucopyranosyl)uronate trichloroacetimidate (30) were synthesized and used as glycosyl donors. Glycosylation reactions of 12 with (5‐R)‐2,3,4,5 − tetrahydro‐5‐trityloxymethyl‐2‐furanone (32) and 14,15,17 with the corresponding (5‐R)‐2,3,4,5‐tetrahydro‐5‐hydroxymethyl‐2‐furanone (31) provided the exclusively β‐linked glucuronide 33 in 69%, 28%, 45%, and 71% yield, respectively. The coupling of donor 30 with acceptor 31 furnished the glucuronated lactone 35 in 70% yield with a surprisingly high content (20%) of the undesired α‐linked sugar residue. The structure of 33 was proved by NMR and X‐ray diffraction studies. In a model reaction a complete deprotection procedure of the glucuronic acid lactone conjugation was demonstrated.

Characterization of the novel indolylmaleimides’ PDA-66 and PDA-377 effect on canine lymphoma cells

Protein kinase inhibitors are widely used in chemotherapeutic cancer regimens. Maleimide derivatives such as SB-216763 act as GSK-3 inhibitor targeting cell proliferation, cell death and cell cycle progression. Herein, the two arylindolylmaleimide derivatives PDA-66 and PDA-377 were evaluated as potential chemotherapeutic agents on canine B-cell lymphoma cell lines. Canine lymphoma represents a naturally occurring model closely resembling the human high-grade non-Hodgkins lymphoma (NHL). PDA-66 showed more pronounced effects on both cell lines. Application of 2.5μM PDA-66 resulted in a significant induction of apoptosis (approx. 11 %), decrease of the metabolic activity (approx. 95 %), anti-proliferative effect (approx. 85 %) and cell death within 48h. Agent induced mode of action was characterized by whole transcriptome sequencing, 12 h and 24 h post-agent exposure. Key PDA-66-modulated pathways identified were cell cycle, DNA replication and p53 signaling. Expression analyses indicated that the drug acting mechanism is mediated through DNA replication and cycle arrest involving the spindle assembly checkpoint. In conclusion, both PDA derivatives displayed strong anti-proliferation activity in canine B-cell lymphoma cells. The cell and molecular PDA-induced effect characterization and the molecular characterization of the agent acting mechanism provides the basis for further evaluation of a potential drug for canine lymphoma serving as model for human NHL.