RT info:eu-repo/semantics/article
T1 Click-chemistry mediated synthesis of OTBN-1,2,3-Triazole derivatives exhibiting STK33 inhibition with diverse anti-cancer activities
A1 Padrón Carrillo, José Manuel
A1 Vala, Disha P.
A1 Dunne Miller, Amy
A1 Atmasidha, Aditi
A1 Parmar, Mehul P.
A1 Patel, Chirag D.
A1 Upadhyay, Dipti B.
A1 Bhalodiya, Savan S.
A1 González-Bakker, Aday
A1 Khan, Adam N.
A1 Nogales, Joaquina
A1 Banerjee, Sourav
A1 Patel, Hitendra M.
A2 Química Orgánica
A2 Grupo BioLab
Instituto Universitario de Bio-Orgánica Antonio González
K1 Click chemistry
K1 OTBN
K1 Kinase
K1 CuAAC
K1 Copper acetate monohydrate
K1 DIPGGBM
K1 Live-cell imaging
AB There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of 4′-((4-substituted-4,5-dihydro-1H-1,2,3-triazol-1-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile (OTBN-1,2,3-triazole) derivatives were synthesized by click chemistry. The series of bioactive compounds were designed and synthesized from diverse alkynes and N3-OTBN, using copper (II) acetate monohydrate in aqueous dimethylformamide at room temperature. Besides being highly cost-effective and significantly reducing synthesis, the reaction yielded 91–98 % of the target products without the need of any additional steps or chromatographic techniques. Two analogues exhibit promising anti-cancer biological activities. Analogue 4l shows highly specific cytostatic activity against lung cancer cells, while analogue 4k exhibits pan-cancer anti-growth activity. A kinase screen suggests compound 4k has single-digit micromolar activity against kinase STK33. High STK33 RNA expression correlates strongly with poorer patient outcomes in both adult and pediatric glioma. Compound 4k potently inhibits cell proliferation, invasion, and 3D neurosphere formation in primary patient-derived glioma cell lines. The observed anti-cancer activity is enhanced in combination with specific clinically relevant small molecule inhibitors. Herein we establish a novel biochemical kinase inhibitory function for click-chemistry-derived OTBN-1,2,3-triazole analogues and further report their anti-cancer activity in vitro for the first time.
SN 1090-2120
YR 2024
FD 2024
LK http://riull.ull.es/xmlui/handle/915/40759
UL http://riull.ull.es/xmlui/handle/915/40759
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 13-abr-2025