A series of ureido derivatives of
pyridine (UDPs) were developed as inducers of leukemic cell differentiation. Fifteen agents prepared by coupling
aminopyridines with appropriate
isocyanates were structurally identified and tested for both antiproliferative and differentiation inducing activity in cultures of murine and human leukemic cells. Five of these lipophilic compounds [2-(3-ethylureido)-
pyridine (1),
2-(3-ethylureido)-6-methylpyridine (4), 2,6-bis-(3-ethylureido)-pyridine (7), 2-(3-ethylureido)-5-methylpyridine (14) and 2-(3-ethylureido)-4,5-dimethylpyridine (15)], promoted terminal erythroid maturation of murine
erythroleukemia cells (MEL) (95%
hemoglobin producing cells) and stimulated
hemoglobin synthesis at concentrations as low as 0.075-0.5 mM. These concentrations are 50-70 fold lower than the optimum inducing concentration of
hexamethylene bisacetamide (
HMBA), a potent known inducer of differentiation. The proportion of cells induced by each ureido derivative of
pyridine was concentration-dependent. Moderate inhibition of cell growth was obtained by these agents at optimum inducing concentrations. Agent 1 also stimulated
hemoglobin synthesis in 18% of human
erythroleukemia K-562 cells and promoted granulocytic differentiation in 24% of human promyelocytic
leukemia HL-60 cells. Structure-activity relationships indicate that 7 was the most potent inducer of all UDPs which contain an ethylureido group attached at 2 position of the
pyridine ring as a major structural feature needed for inducing activity. These findings indicate that the ureido derivatives of
pyridine are a new class of inducers of murine
erythroleukemia cells and, to a lesser extent of granulocytic differentiation, of leukemic HL-60 cells in vitro.