Synthesis and Anti-leukemia Evaluation of Tetrahydro-4H-pyrano[3,2-c]pyridines and Corresponding Anti-CD14 Monoclonal Antibody Conjugates

A series of novel tetrahydro-4H-pyrano3,2-c]pyridines(3a―3p) were synthesized and found to possess potent antiproliferative activity against leukemia K562 cells in vitro. Preliminary bioassay indicates that compounds 3a and 3e afford the best activity, the IC₅₀ values of them were 6.93 and 7.51 μg/mL, respectively, which were lower than that of the anticancer drug 5-FU(IC₅₀=8.56 μg/mL). To reduce the toxicity of compounds 3a―3p to the proliferation of normal hematopoietic cells, a tumor targeted CD14 monoclonal antibody(McAb) was used in conjugation with compounds 3a―3p to get conjugates 4a―4p, respectively. The inhibitory activities of conjugates 4a―4p toward K562 cells were discovered to approach those of compounds 3a―3p. In the presence of CD14 McAb, tumor cells were found to be much more susceptible to conjugates 3a―3p than normal hematopoietic cells. Therefore, the toxi-city of conjugates 4a―4p to normal hematopoietic cells declined obviously. For example, as for the toxicity of compound 3a compared with that of compound 4a, the value of IC₅₀ increased from 35.90 μmol/L to 39.52 μmol/L.