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Cyclic Hydroxamic-acid-containing Peptide 31, a Potent Synthetic Histone Deacetylase Inhibitor with Antitumor Activity

Pharmaceuticals and Biotechnology Laboratory, Japan Energy Corporation, Saitama 335-8502 [Y. K., H. H.]; Department of Applied Chemistry, Faculty of Engineering, Kyushu Institute of Technology, Fukuoka 804-8550 [K. T., M. T., T. K., N. N.]; Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 170-0017 [S. S., T. Y.]; Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032 [T. T.]; Department of Biotechnology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657 [R. F., M. Y., S. H.]; and CREST, Japan Science and Technology Corporation [Y. K., T. K., N. N., R. F., M. Y.], Japan

Cyclic hydroxamic-acid-containing peptide 1 (CHAP1), designed as a hybrid of trichostatin A and trapoxin, is a lead compound for the development of potent inhibitors of histone deacetylase (HDAC). In this study, we synthesized a series of CHAP derivatives and evaluated their biological activities by monitoring the potency of their inhibition of HDAC activity, their ability to augment the expression of MHC class-I molecules in B16/BL6 cells, and their effect on cell proliferation. A structure-activity relationship study using these three assay systems revealed several requirements of their structure for the strong inhibition of HDAC not only in the cell-free situation, but also in cells. When the structures of CHAP derivatives are represented as cyclo(-Asu(NHOH)-AA₂-AA₃-Pro or Pip-)_n, where Asu(NHOH) and Pip are -hydroxamide--aminosuberic acid and pipecolic acid, respectively, (a) the tetrapeptide structure (n = 1) was better than the octapeptide one (n = 2); (b) AA₂ and AA₃ should be hydrophobic; and (c) the combination of amino acid chirality should be LDLD for the strongest inhibition of HDAC in cells (LDLD > LLLD, LDLL > LLDL). cyclo(-L-Asu(NHOH)-D-Tyr(Me)-L-Ile-D-Pro-) or CHAP31 was selected as one of the strongest CHAPs, and its biological activity was characterized further. CHAP31 was much more stable in the presence of cultured cells (t_1/2 > 3000 h) than trichostatin A (t_1/2 = 14.7 h) or trapoxin A (t_1/2 = 2.10 h). CHAP31 exhibited antitumor activity in C57BL x DBA/2 F₁ (BD2F₁) mice bearing B16/BL6 tumor cells. Furthermore, CHAP31 inhibited the growth in four of five human tumor lines implanted into nude mice. These results suggest CHAP31 to be promising as a novel therapeutic agent for cancer treatment.

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