| Summary: | <i>Euphorbia usambarica</i> is a traditional medicine used for gynecologic, endocrine, and urogenital illnesses in East Africa; however, its constituents and bioactivities have not been investigated. A variety of compounds isolated from <i>Euphorbia</i> species have been shown to have activity against latent HIV-1, the major source of HIV-1 persistence despite antiretroviral therapy. We performed bioactivity-guided isolation to identify 15 new diterpenoids (<b>1</b>–<b>9</b>, <b>14</b>–<b>17</b>, <b>19</b>, and <b>20</b>) along with 16 known compounds from <i>E. usambarica</i> with HIV-1 latency reversal activity. Euphordraculoate C (<b>1</b>) exhibits a rare 6/6/3-fused ring system with a 2-methyl-2-cyclopentenone moiety. Usambariphanes A (<b>2</b>) and B (<b>3</b>) display an unusual lactone ring constructed between C-17 and C-2 in the jatrophane structure. 4<i>β</i>-Crotignoid K (<b>14</b>) revealed a 250-fold improvement in latency reversal activity compared to crotignoid K (<b>13</b>), identifying that configuration at the C-4 of tigliane diterpenoids is critical to HIV-1 latency reversal activity. The primary mechanism of the active diterpenoids <b>12</b>–<b>14</b> and <b>21</b> for the HIV-1 latency reversal activity was activation of PKC, while lignans <b>26</b> and <b>27</b> that did not increase CD69 expression, suggesting a non-PKC mechanism. Accordingly, natural constituents from <i>E. usambarica</i> have the potential to contribute to the development of HIV-1 eradication strategies.
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