Reference - Detail
| RRC ID | 41383 |
|---|---|
| Author | Komatsu Y, Tomizaki KY, Tsukamoto M, Kato T, Nishino N, Sato S, Yamori T, Tsuruo T, Furumai R, Yoshida M, Horinouchi S, Hayashi H. |
| Title | Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity. |
| Journal | Cancer Res |
| Abstract |
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)-AA(2)-AA(3)-Pro or Pip-)(n), where Asu(NHOH) and Pip are zeta-hydroxamide-alpha-aminosuberic acid and pipecolic acid, respectively, (a) the tetrapeptide structure (n = 1) was better than the octapeptide one (n = 2); (b) AA(2) and AA(3) 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 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. |
| Volume | 61(11) |
| Pages | 4459-66 |
| Published | 2001-6-1 |
| PMID | 11389076 |
| MeSH | Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Drug Screening Assays, Antitumor Enzyme Inhibitors / chemistry Enzyme Inhibitors / pharmacology* Histone Deacetylase Inhibitors* Humans Hydroxamic Acids / chemistry Melanoma, Experimental / drug therapy Melanoma, Experimental / enzymology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Inbred DBA Mice, Nude Peptides, Cyclic / chemistry Peptides, Cyclic / pharmacology* Proline / chemistry Stereoisomerism Structure-Activity Relationship Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| IF | 9.727 |
| Times Cited | 165 |
| WOS Category | ONCOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 49 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | SP2/0-Ag14(RCB0209) |