mannich-bases and Leukemia--T-Cell

Various bis (3-aryl-3-oxo-propyl)methylamine hydrochlorides 1 and their corresponding structural and non-classical isomers 4-aryl-3-arylcarbonyl-1-methyl-4-piperidinols 3 were evaluated against human leukemic T (Jurkat) cells and found to possess significant cytotoxicity. Among the series 1 (bis-Mannich bases) and 3 (corresponding piperidinols), compounds la, 1c and 1e showed cytotoxic potency which was approximately 1.6, 3.7 and 3.4 times that of the reference drug 5-fluorouracil, respectively. Except for compound 1d, conversion of bis-Mannich bases to their corresponding piperidinols 3a, 3b and 3e lowered the potency. Besides chloro derivative 1d, bis-Mannich bases displayed greater cytotoxicity compared with their mono-Mannich bases, series 5. Representative bis-Mannich bases (1a, 1e) and piperidinols (3a, 3e) decreased the glutathione level of Jurkat cells. Molecular modeling was utilized in order to evaluate whether the shape, size, critical volume, solvent accessible area and partition coefficient of the different compounds had contributed to the varying potencies observed. Bis-Mannich bases 1a, 1c and 1e may serve as candidate anticancer agents for future development.

Topics: Antineoplastic Agents, Alkylating; Chemical Phenomena; Chemistry, Physical; Glutathione; Humans; Jurkat Cells; Lethal Dose 50; Leukemia, T-Cell; Mannich Bases; Methylamines; Piperidines; Structure-Activity Relationship

Various 1-arylidene-2-tetralones 1 had been shown previously to possess moderate cytotoxic properties unaccompanied by murine toxicity. The objective of the present investigation was to undertake different molecular modifications of representative members of series 1 with a view to discerning those structural features leading to increased potencies. All compounds were evaluated using human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells. The Mannich bases 2, 4, 5 and 7 possessed increased potencies compared to the corresponding unsaturated ketones 1 and in general were potent cytotoxics having IC50 values in the 0.2-10 microM range. QSAR using the cytotoxicity data for 2a-e suggested that potency was positively correlated with the size of the substituents in the arylidene aryl ring. Compounds 2a-f were evaluated using a panel of approximately 53 human tumour cell lines and, when all cell lines were considered, were more potent than the reference drug melphalan. In particular, marked antileukemic activity was displayed. Molecular modeling was utilized in order to evaluate whether the shapes of the different compounds contributed to the varying potencies observed. Representative compounds demonstrated minimal or no inhibiting properties towards human N-myristoyltransferase (NMT) and did not bind to calf thymus DNA. This study has revealed a number of unique lead molecules as candidate anti-neoplastic agents serving as prototypes for future development.

Topics: Acyltransferases; Animals; Antineoplastic Agents; Cell Line, Tumor; Humans; Leukemia L1210; Leukemia P388; Leukemia, T-Cell; Mannich Bases; Mice; Piperidines; Structure-Activity Relationship; T-Lymphocytes; Tetralones