Synthesis, Antitumor Activity, and Mechanism of Action of Benzo[<i>b</i>]chromeno[6,5‑<i>g</i>][1,8]naphthyridin-7-one Analogs of Acronycine

A series of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-<i>7H</i>-benzo­[<i>b</i>]­chromeno­[6,5<i>-g</i>]­[1,8]­naphthyridin-7-one (<b>4</b>), 13-aza derivatives of benzo­[<i>b</i>]­acronycine, the isomeric 5-methoxy-2,2,13-trimethyl-2,13-dihydro-<i>6H-</i>benzo­[<i>b</i>]­chromeno­[7,6<i>-g</i>]­[1,8]­naphthyridin-6-one (<b>5</b>), and related <i>cis</i>-diols mono- and diesters were designed and synthesized. Their <i>in vitro</i> and <i>in vivo</i> biological activities were evaluated. As previously observed in the acronycine series, esters were the most potent derivatives exhibiting submicromolar activities; among them monoesters are particularly active. Racemic diacetate <b>21</b> showed a strong activity against KB-3-1 cell lines and was selected for <i>in vivo</i> evaluation and proved to be active, inhibiting tumor growth by more than 80%. After separation of the two enantiomers, compounds <b>21a</b> and <b>21b</b> were also evaluated against C38 colon adenocarcinoma; their activities were found to be significantly different

Natural Inhibitors of the RhoA–p115 Complex from the Bark of <i>Meiogyne baillonii</i>

In an effort to find potent natural inhibitors of RhoA and p115 signaling G-proteins, a systematic in vitro evaluation using enzymatic and plasmonic resonance assays was undertaken on 11 317 plant extracts. The screening procedure led to the selection of the New Caledonian endemic species <i>Meiogyne baillonii</i> for a chemical investigation. Using a bioguided isolation procedure, three enediyne-γ-butyrolactones (<b>1</b>–<b>3</b>) and two enediyne-γ-butenolides (<b>4</b> and <b>5</b>), named sapranthins H–L, respectively, two enediyne carboxylic acid (<b>6</b> and <b>7</b>), two depsidones, stictic acid (<b>8</b>) and baillonic acid (<b>9</b>), aristolactams AIa and AIIa (<b>10</b> and <b>11</b>), and two aporphines, dehydroroemerine (<b>12</b>) and noraristolodione (<b>13</b>), were isolated from the ethyl acetate extract of the bark. The structures of the new compounds (<b>1</b>–<b>6</b>, <b>9</b>, and <b>11</b>) and their relative configurations were established by NMR spectroscopic analysis and by X-ray diffraction analysis for compound <b>9</b>. Only stictic acid (<b>8</b>) exhibited a significant inhibiting activity of the RhoA–p115 complex, with an EC₅₀ value of 0.19 ± 0.05 mM. This is the first time that a natural inhibitor of the complex RhoA–p115’s activity was discovered from an HTS performed over a collection of higher plant extracts. Thus, stictic acid (<b>8</b>) could be used as the first reference compound inhibiting the interaction between RhoA and p115

Natural Inhibitors of the RhoA–p115 Complex from the Bark of <i>Meiogyne baillonii</i>

In an effort to find potent natural inhibitors of RhoA and p115 signaling G-proteins, a systematic in vitro evaluation using enzymatic and plasmonic resonance assays was undertaken on 11 317 plant extracts. The screening procedure led to the selection of the New Caledonian endemic species <i>Meiogyne baillonii</i> for a chemical investigation. Using a bioguided isolation procedure, three enediyne-γ-butyrolactones (<b>1</b>–<b>3</b>) and two enediyne-γ-butenolides (<b>4</b> and <b>5</b>), named sapranthins H–L, respectively, two enediyne carboxylic acid (<b>6</b> and <b>7</b>), two depsidones, stictic acid (<b>8</b>) and baillonic acid (<b>9</b>), aristolactams AIa and AIIa (<b>10</b> and <b>11</b>), and two aporphines, dehydroroemerine (<b>12</b>) and noraristolodione (<b>13</b>), were isolated from the ethyl acetate extract of the bark. The structures of the new compounds (<b>1</b>–<b>6</b>, <b>9</b>, and <b>11</b>) and their relative configurations were established by NMR spectroscopic analysis and by X-ray diffraction analysis for compound <b>9</b>. Only stictic acid (<b>8</b>) exhibited a significant inhibiting activity of the RhoA–p115 complex, with an EC₅₀ value of 0.19 ± 0.05 mM. This is the first time that a natural inhibitor of the complex RhoA–p115’s activity was discovered from an HTS performed over a collection of higher plant extracts. Thus, stictic acid (<b>8</b>) could be used as the first reference compound inhibiting the interaction between RhoA and p115