1,3,4-Oxadiazole-Containing Histone Deacetylase Inhibitors: Anticancer Activities in Cancer Cells

We describe 1,3,4-oxadiazole-containing hydroxamates (<b>2</b>) and 2-aminoanilides (<b>3</b>) as histone deacetylase inhibitors. Among them, <b>2t</b>, <b>2x</b>, and <b>3i</b> were the most potent and selective against HDAC1. In U937 leukemia cells, <b>2t</b> was more potent than SAHA in inducing apoptosis, and <b>3i</b> displayed cell differentiation with a potency similar to MS-275. In several acute myeloid leukemia (AML) cell lines, as well as in U937 cells in combination with doxorubicin, <b>3i</b> showed higher antiproliferative effects than SAHA

Cinnamic Anilides as New Mitochondrial Permeability Transition Pore Inhibitors Endowed with Ischemia-Reperfusion Injury Protective Effect in Vivo

In this account, we report the development of a series of substituted cinnamic anilides that represents a novel class of mitochondrial permeability transition pore (mPTP) inhibitors. Initial class expansion led to the establishment of the basic structural requirements for activity and to the identification of derivatives with inhibitory potency higher than that of the standard inhibitor cyclosporine-A (CsA). These compounds can inhibit mPTP opening in response to several stimuli including calcium overload, oxidative stress, and thiol cross-linkers. The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of CsA, suggesting for these inhibitors a molecular target different from cyclophylin-D. In vitro and in vivo data are presented for (<i>E</i>)-3-(4-fluoro-3-hydroxy-phenyl)-<i>N</i>-naphthalen-1-yl-acrylamide <b>22</b>, one of the most interesting compounds in this series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of acute myocardial infarction

Toward Highly Potent Cancer Agents by Modulating the C‑2 Group of the Arylthioindole Class of Tubulin Polymerization Inhibitors

New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds <b>18</b> and <b>57</b> were superior to the previously synthesized <b>5</b>. Compound <b>18</b> was exceptionally potent as an inhibitor of cell growth: it showed IC₅₀ = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds <b>18</b>, <b>20</b>, <b>55</b>, and <b>57</b> were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds <b>18</b> and <b>57</b> showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative <b>18</b> showed water solubility and higher metabolic stability than <b>5</b> in human liver microsomes