Twelve undescribed jatrophane diterpenoids, euphpepluones A-L (<b>1</b>-<b>12</b>), together with seven known analogues (<b>13</b>-<b>19</b>), were isolated from the whole plant of <i>Euphorbia peplus</i>, and their structures were elucidated by spectroscopic studies. The absolute configurations of <b>1</b> and <b>4</b> were assigned by X-ray crystallographic analysis. All isolates were investigated for their inhibitory effects against the ATR-Chk1 pathway using a Western blotting assay. As a result, <b>1</b>, <b>2</b>, <b>5</b>, <b>8</b>, <b>10</b>, and <b>16</b> were found to suppress the camptothecin (CPT)-induced phosphorylation of Chk1, indicating that these compounds inhibit the activation of the ATR-Chk1 pathway. A preliminary structure-activity relationship (SAR) study of the isolates was conducted. When compound <b>10</b> and CPT were combined, apoptosis was induced in A549 cells with PARP cleavage, while there was no apoptotic effect by treatment with CPT or <b>10</b> alone. The data obtained indicate that <b>10</b> potentiates the chemotherapeutic sensitivity of A549 cells to CPT.