Abstract
New apoptosis modulating agents are widely sought, because failure in regulation of apoptosis is associated with many diseases. In this study, we have evaluated apoptosis inducing the potential of ten new hydrophobic derivatives of 5‐(hydroxymethyl)isophthalic acid. Cancerous leukemia cells (HL‐60) and non‐malignant fibroblasts (Swiss 3T3) were incubated with test compounds for 24 h and morphologically evaluated. The changes in mitochondrial membrane potential (Δψm) and caspase‐3 activity were used to confirm the results and to study early induction of apoptosis. Cytotoxicity was determined using the lactate dehydrogenase (LDH) assay and mutagenicity with miniaturized Ames‐test. The most potent selective apoptosis inducers were compounds 1c and 1 h having IC~50~ values of 41 and 23 µM, respectively, in leukemia cells (HL‐60) while effects in fibroblasts (Swiss 3T3) were insignificant. Reduction of δψm and increase in caspase‐3 activity were observed already during the first 2 hr in the HL‐60 cells treated with compounds 1 c and 1 h. Neither of the compounds was cytotoxic or mutagenic. The results indicate that compounds 1 c and 1 h are selective apoptosis inducers and should be studied further for possible use in cancer therapy. Drug Dev. Res. 69: 185–195, 2008. © 2008 Wiley‐Liss, Inc.