Ureido derivatives of pyridine: a new class of inducers of murine erythroleukemia cell differentiation.

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.