No abstract

A series of derivatives of tetramethylurea, a known inducer of the differentiation of Friend erythroleukemia cells, has been synthesized and tested for its capacity to induce erythroid maturation, as measured by the synthesis of hemoglobin. Cyclic urea and thiourea derivatives consisting of five-, six-, and seven-membered ring systems containing N-alkyl substituents were prepared. Most of these agents were relatively effective inducers od differentiation, with N-alkyl substitution appearing to be essential for maximum response. The most potent agents developed were N,N'-dimethyl cyclic ureas. Exposure to concentrations of 2 to 4 mM of these derivatives resulted in more than 90% of the cell population achieving a differentiated state. Under these conditions, the parent compound, tetramethylurea, was slightly less efficacious, causing differentiation of only 68% of the population at its maximum effective level of 4 mM.

Li and SemliEka was isolated as a precipitate from hexane and dried to give 10.2 mg (61%) of material which was homogeneous on TLC in ethyl acetatetetrahydrofuran ( l : l , R/ 0.22) and in tetrahydrofuran (Rl0.54). This material was purified for analysis by recrystallization from tetrahydrofuran and isolated as a bis solvate: mp 168-170 OC (loss of solvent at 152-155 "C); A, , , (CH30H) 267 nm (c 2.8 X lo4), Ami, 234 nm. Anal. Calcd for CjlH54N801~2C4H80: C, 60.91; H, 6.06; N, 9.63. Found: C, 60.75; H, 6.07; N, 9.34.The trityl blocking group was removed from compound 7 (30 mg) by the usual treatment with hot 80% acetic acid. After preparative TLC on a 1 mm thick silica plate with dioxane, compound 8 was isolated in a 70% yield: Rf 0.51 in tetrahydrofuran; A, , , 267 nm; paper chromatography R f 0.38.

No abstract

Tetramisole and its analogues are potent inhibitors of alkaline phosphatase, including isoenzymes of Sarcoma 180/TG which appear to be involved in the mechanism of resistance of this neoplastic cell line to the 6-thiopurines. To determine the requirement for the thiazole ring system of tetramisole for inhibitor potency, 2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]oxazole, 2,3-dihydro-6-phenylimidazo[2,1-b]oxazole, and 2,3,5,6-phenylimidazo[2,1-a]imidazole were synthesized and tested for inhibitory activity against alkaline phosphatase isolated from Sarcoma 180/TG. The results indicate that 2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]oxazole caused 50% inhibition at 0.21 mM, while the other synthesized compounds were inactive at a concentration of 1 mM; in contrast, tetramisole required only 0.045 mM for 50% inhibition of alkaline phosphatase activity. The findings support the concept that the thiazole ring system of the tetramisole structure is required for maximum inhibitory potency of this series against alkaline phosphatase.