Title: Novel 3,5-bis(arylidene)-4-oxo-1-piperidinyl dimers: Structure-activity relationships and potent antileukemic and antilymphoma cytotoxicity
Authors: Santiago-Vazquez, Yahaira ×
Das, Swagatika
Das, Umashankar
Robles-Escajeda, Elisa
Ortega, Nora M
Lema, Carolina
Varela-Ramírez, Armando
Aguilera, Renato J
Balzarini, Jan
De Clercq, Erik
Dimmock, Stephen G
Gorecki, Dennis K J
Dimmock, Jonathan R #
Issue Date: Mar-2014
Series Title: European Journal of Medicinal Chemistry vol:77 pages:315-322
Article number: S0223-5234(14)00213-X
Abstract: Novel clusters of 3,5-bis(benzylidene)-4-oxo-1-piperidinyl dimers 3-5 were evaluated against human Molt4/C8 and CEM T-lymphocytes and human HeLa cervix adenocarcinoma cells as well as murine L1210 leukemia neoplasms. Several of these compounds demonstrated IC50 values in the submicromolar and low micromolar range and compounds possessing 4-fluoro, 4-chloro and 3,4,5-trimethoxy substituents in the series 3 and 4 were identified as potent molecules. A heat map revealed the very high cytotoxic potencies of representative compounds against a number of additional leukemic and lymphoma cell lines and displayed greater toxicity to these cells than nonmalignant MCF10A and Hs-27 neoplasms. These dienones are more refractory to breast and prostate cancers. The evaluation of representative compounds in series 3-5 against a panel of human cancer cell lines revealed them to be potent cytotoxins with average IC50 values ranging from 0.05 to 8.51 μM. In particular, the most potent compound 4g demonstrated over 382-fold and 590-fold greater average cytotoxic potencies in this screen than the reference drugs, melphalan and 5-fluorouracil, respectively. A mode of action investigation of two representative compounds 3f and 4f indicated that they induce apoptosis which is due, at least in part, to the activation of caspase-3 and depolarization of the mitochondrial membrane potential.
ISSN: 0223-5234
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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