Synthesis, Photoreactivity and Cytotoxic Activity of Caged Compounds of L-Leucyl-L-Leucine Methyl Ester, an Apoptosis Inducer

I,-Leucyl-L-leucine methyl ester (Leu-Leu-OMe), an apoptosis inducer in natural killer cells and macro-phages, was caged with trans -o-hydroxycinnamoyl (3ad), trans-o -mercaptocinnamoyl (4) and o -nitrobenzyl derivatives (5a, b), and the photochemical reactivity of these derivatives in phosphate-buffered saline containing 1% dimethyl sulfoxide and their immunological properties were studied. All of the derivatives exhibited absorplion at wavelengths longer than the UVB region. Although 3a–d and 4 were expected to isomerize to a cis isomer, which thgn cyclizes intramolecularly to give Leu-Leu-OMe and a coumarin derivative, cyclization efficiency was not satisfactory except for 3a. However, 3a itself caused necrosis (cell swelling) of U937 cells (a myeloid cell line). In contrast, 5a and b released Leu-Leu-OMe quickly and efficiently and did not affect U937 cells. Although irradiated 5b induced necrosis, irradiated 3a and 5a induced apoptosis in these cells, as evidenced by a decrease in cell size.