Novel 3,5-bis(arylidene)-4-oxo-1-piperidinyl dimers: Structure-activity relationships and potent antileukemic and antilymphoma cytotoxicity

作者：Santiago Vazquez Yahaira; Das Swagatika; Das Umashankar^*; Robles Escajeda Elisa; Ortega Nora M; Lema Carolina; Varela Ramirez Armando; Aguilera Renato J; Balzarini Jan; De Clercq Erik; Dimmock Stephen G; Gorecki Dennis K J; Dimmock Jonathan R

来源：European Journal of Medicinal Chemistry, 2014, 77(2): 315-322.

DOI：10.1016/j.ejmech.2014.03.009

• Unsaturated ketones
• Cytotoxicity
• Apoptosis
• Structure-activity relationships
• 4-Piperidone
• Mitochondria

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 mu M. 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 41 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.

• 出版日期2014-4
• 单位Saskatchewan; Saskatoon; 河北医科大学; 南阳理工学院