Based on previous studies on bis-
acetamides that act as hybrid polar compounds to induce
leukemia cell differentiation, an attempt was made to bioisosterically replace the
amide moiety with the lipophilic non-classical bioisostere
tetrazole. A
pyrrole group was also included in the molecule in order to retain the hydrogen bond donor capability. Thus, by linking the two polar ring systems with a highly lipophilic methylene chain compounds 2-4 were synthesized and assessed for their anti-proliferative activity in combination with their ability to induce murine
erythroleukemia (MEL) cell differentiation. Furthermore, an initial investigation of the structure-activity relation points for the active compound 3 was undertaken by synthesizing compound 5 (a
p-xylene analog) and compound 8 (a methylamidopyrrolyl analog). All compounds caused a dose-dependent inhibition of MEL cell growth but to a different extent. Compound 3 (1,6-bis[5-(1H-pyrrol-1-yl)-2H-tetrazol-2-yl]
hexane) promoted erythroid differentiation in a fifty-fold lower concentration than hexamethylenebisacetamide (
HMBA). Though induction of differentiation was to a lesser extent than
HMBA, it caused accumulation of 80% Hb-producing cells as compared to that produced by
HMBA, leading to differentiation-depended cell growth inhibition equal to that of
HMBA after 96 h in culture. Compound 3 represents a potent inducer of
hemoglobin gene activation in leukemic cells.