Novel N-substituted phthalimides (2-substituted 1H-isoindole-1,3-diones) were prepared, and their effects on tumor necrosis factor-alpha (TNF-alpha) production by human leukemia cell line HL-60 stimulated with 12-O-tetradecanoylphorbol 13-acetate (TPA) or okadaic acid (OA) were examined. A structure-activity relationship study of the N-phenylphthalimides and N-benzylphthalimides revealed that their enhancing effect on TPA-induced TNF-alpha production by HL-60 cells and their inhibiting effect on OA-induced TNF-alpha production by HL-60 cells are only partially correlated.

No abstract

CD26, a membrane-bound ectopeptidase, is known as an activated T cell marker with dipeptidyl peptidase IV (DPPIV) activity that has diverse functional roles in the regulation of peptide hormones, neuropeptides, chemokines and growth factors. We recently isolated a novel inhibitor of DPPIV, sulphostin, from culture broth of Streptomyces sp. MK251-43F3. We investigated herein the hematopoietic effect of sulphostin in mice and found that sulphostin induced the production of granulocyte colony-stimulating factor (G-CSF), stimulated myeloblasts in bone marrow, and increased neutrophil numbers in peripheral blood in both normal mice and mice with cyclophosphamide-induced leucopenia. Sulphostin desulfonate, in addition to sulphostin, has a similar inhibitory effect on DPPIV and stimulatory effect on neutrophils. These results suggest that DPPIV/CD26 might be a novel target for hematopoietic stimulation and DPPIV inhibitors including sulphostin and derivatives may be candidates for further development.

Novel Biological Response Modifiers: Phthalimides with TumorNecrosis Factor-α Production-Regulating Activity.-The effects of a series of phthalimides, e.g. (I)-(IV), on tumor necrosis factor-α (TNF-α) production by human leukemia cell line HL-60 stimulated with 12-Otetradecanoylphorbol 13-acetate or okadaic acid are investigated. Especially, compounds (IVa) and (IVb) are of interest for further development as novel biological response modifiers to control TNF-α production. -(MIYACHI, H.; AZUMA, A.; OGASAWARA, A.; UCHIMURA, E.; WATANABE, N.; KOBAYASHI, Y.; KATO, F.; KATO, M.; HASHIMOTO, Y.; J.

Other bioactive products U 1300 Sulfostin (I), a Novel Inhibitor of Dipeptidyl Peptidases IV (DPPIV) that Stimulates Hematopoiesis inMice. -(ABE, M.; ABE*, F.; NISHIMURA, C.; ICHIMURA, E.; OGASAWARA, A.; ICHINEI, M.; MURAOKA, Y.; SAINO, T.; J. Antibiot. 58 (2005) 2, 111-117; Res. Dev. Div., Pharm.