Premium
Discovery of a Novel Series of Tetrahydro‐β‐carbolines Inducing Autophagic Cell Death in Human Metastatic Melanoma
Author(s) -
Ahmed Nermin S.,
Elgendy Mohamed,
Laufer Stefan,
Abadi Ashraf H.
Publication year - 2014
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201300437
Subject(s) - autophagy , programmed cell death , small hairpin rna , melanoma , cell culture , autophagosome , cancer research , chemistry , apoptosis , gene , biology , microbiology and biotechnology , rna , biochemistry , genetics
Herein, we report the synthesis of novel tetrahydro‐β‐carbolines that induce cell death via the autophagic pathway. Five of the new compounds induced cell death in a panel of patient‐derived human metastatic melanoma cells. The autophagic pathway was confirmed using LC3 autophagosome markers; the involvement of ATG7 and Beclin 1 autophagy regulating genes was confirmed using infection with short hairpin RNA (shRNA) to silence Beclin 1 and ATG7. Compound VIII (IC 50 = 2.34–5.15 μM) displayed activities greater than cisplatin against a panel of patient‐derived human metastatic melanoma cell lines. The structure–activity relationship (SAR) of this class and the role of the absolute stereochemistry and geometrical isomerism are evaluated.