Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities

A successful structure-based design of novel cyclic depsipeptides that selectively target class I HDAC isoforms is described. Compound <b>11</b> has an IC₅₀ of 2.78 nM for binding to the HDAC1 protein, and the prodrugs <b>12</b> and <b>13</b> also exhibit promising antiproliferative activities in the nanomolar range against various cancer cell lines. Compounds <b>12</b> and <b>13</b> show more than 20-fold selectivity toward human cancer cells over human normal cells in comparison with romidepsin (FK228), demonstrating low probability of toxic side effects. In addition, compound <b>13</b> exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft model with no observed toxicity. Thus, prodrug <b>13</b> has therapeutic potential as a new class of anticancer agent for further clinical translation

Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities

A successful structure-based design of novel cyclic depsipeptides that selectively target class I HDAC isoforms is described. Compound <b>11</b> has an IC₅₀ of 2.78 nM for binding to the HDAC1 protein, and the prodrugs <b>12</b> and <b>13</b> also exhibit promising antiproliferative activities in the nanomolar range against various cancer cell lines. Compounds <b>12</b> and <b>13</b> show more than 20-fold selectivity toward human cancer cells over human normal cells in comparison with romidepsin (FK228), demonstrating low probability of toxic side effects. In addition, compound <b>13</b> exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft model with no observed toxicity. Thus, prodrug <b>13</b> has therapeutic potential as a new class of anticancer agent for further clinical translation

Biological Evaluation of New Largazole Analogues: Alteration of Macrocyclic Scaffold with Click Chemistry

We report the design, synthesis, and biological evaluation of a new series of largazole analogues in which a 4-methylthiazoline moiety was replaced with a triazole and tetrazole ring, respectively. Compound <b>7</b> bearing a tetrazole ring was identified to show much better selectivity for HDAC1 over HDAC9 than largazole (10-fold). This work could serve as a foundation for further exploration of selective HDAC inhibitors using a largazole molecular scaffold