Fusicoccin (FC) and cotylenin (CN), fusicoccane diterpene glycosides, have been known to exhibit strong plant hormone-like activities through activation of H^+-ATPase in plant cells. Recently, the mode of action has been clarified at molecular level. FC forms a stable ternary complex with membrane-boundary H^+-ATPase and cytoplasmic 14-3-3 protein, and maintains the activated stage of the H^+-ATPase. Since 14-3-3 proteins are ubiquitously expressed in all eukaryotic cells, it has been anticipated that FC/CN might affect on animal cells as well. In fact, we found that CN induces functional and morphological differentiation of human myeloid leukemia cells (HL-60). However, FC was less efficient in differentiation of HL-60 in spite of the fact that FC and CN have identical activities on plant tissues. There are several differences in chemical structures of FC and CN such as i) +/-3-OH; ii)+/- 12-OH; iii) complex sugar in CN; iv)+ /- epoxide on sugar moiety. We have carried out SAR study using natural FC/CN congeners and several semi-synthetic FC derivatives. Eventually, we have succeeded in clarifying that the absence of 12-OH is essential for DIA; it is striking that the only one hydroxyl group crucially affects on DIA. The epoxide on the sugar is not essential but strengthens the activity. Considering the mode of action of FC on plant tissues, it is plausible that DIA of CN is also related to 14-3-3 protein function. So we then carried out preliminary experiments to prove modulation ability of CN on 14-3-3: phospho-peptide complexes. Isothermal titration calorimetry (ITC) revealed that CN can stabilize the complex of 14-3-3 protein and its target peptide having a …RSX_1pSX_2P… motif, only when X_2 is Val.