Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity

Citation
Y. Komatsu et al., Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity, CANCER RES, 61(11), 2001, pp. 4459-4466
Citations number
39
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
0008-5472 → ACNP
Volume
61
Issue
11
Year of publication
2001
Pages
4459 - 4466
Database
ISI
SICI code
0008-5472(20010601)61:11<4459:CHP3AP>2.0.ZU;2-M
Abstract
Cyclic hydroxamic-acid-containing peptide 1 (CHAP1), designed as a hybrid o f trichostatin A and trapoxin, is a lead compound for the development of po tent inhibitors of histone deacetylase (HDAC). In this study, we synthesize d 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 t heir effect on cell proliferation. A structure-activity relationship study using these three assay systems revealed several requirements of their stru cture for the strong inhibition of HDAC not only in the cell-free situation , but also in cells. When the structures of CHAP derivatives are represente d as cyclo(-Asu(NHOH)-AA(2)-AA(3)-Pro or Pip-)(n), where Asu(NHOH) and Pip are zeta -hydroxamide-alpha -aminosuberic acid and pipecolic acid, respecti vely, (a) the tetrapeptide structure (n = 1) was better than the octapeptid e one (n = 2); (b) AA(2) and AA(3) should be hydrophobic; and (c) the combi nation 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 F-1 (BD2F(1)) 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.