Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives.
Newly synthesized benzamide derivatives were evaluated for their inhibitory activity against histone deacetylase. The structure of these derivatives was unrelated to the known inhibitors, and IC(50) values of the active compounds were in the range of 2-50 microM. Structure-activity relationship on the benzanilide moiety showed that the 2'-substituent, an amino or hydroxy group, was indispensable for inhibitory activity. Although the electronic influence of the substituent in the anilide moiety showed only a small effect on inhibitory activity, the steric factor in the anilide moiety, especially at positions 3'and 4', played an important role in interaction with the enzyme. Among these benzamide derivatives, MS-275 (1), which showed significant antitumor activity in vivo, has been selected for further investigation.
Suzuki
T
T
Institute of Biological Science, Mitsui Pharmaceuticals Inc., 1900-1, Togo, Mobara-shi, Chiba 297-0017, Japan.
Ando
T
T
Tsuchiya
K
K
Fukazawa
N
N
Saito
A
A
Mariko
Y
Y
Yamashita
T
T
Nakanishi
O
O
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; C118739:entinostat