The Active Centres of Agelastatin A, a Strongly Cytotoxic Alkaloid of the Coral Sea Axinellid Sponge Agelas dendromorpha, as Determined by Comparative Bioassays with Semisynthetic Derivatives

Abstract

<jats:title>Abstract</jats:title><jats:p>Agelastatin A (<jats:bold>1</jats:bold>), an unusual alkaloid of the axinellid sponge <jats:italic>Agelas dendromorpha</jats:italic> from the Coral Sea, can be selectively acetylated (→<jats:bold>7</jats:bold>) or methylated at OHC(8a) (→<jats:bold>4</jats:bold>), peracetylated (→<jats:bold>8</jats:bold>) or permethylated at OHC(8a), NH(5), and NH(6) (→<jats:bold>5</jats:bold>), or, finally, subjected to C(9)C(8a) (→<jats:bold>14</jats:bold>) or C(5b)C(8a) β‐elimination (→<jats:bold>11–13</jats:bold>), in a regiospecific manner or not, depending on the reaction conditions. Under acidic conditions, compound <jats:bold>12</jats:bold> adds H<jats:sub>2</jats:sub>O or MeOH, regioselectively though not <jats:italic>endo/exo</jats:italic> stereoselectively, giving <jats:italic>transoid/cisoid</jats:italic> mixtures <jats:bold>1/18</jats:bold> or <jats:bold>4/19</jats:bold>, respectively. Similarly <jats:bold>11</jats:bold> or <jats:bold>13</jats:bold> add MeOH to give mixtures (−)‐<jats:bold>2/20</jats:bold> or <jats:bold>15/16</jats:bold>, respectively. Compound <jats:bold>13</jats:bold> also adds AcOH giving mixture <jats:bold>8/17</jats:bold>. The intermediate <jats:italic>cisoid</jats:italic> form obtained on treatment of <jats:bold>21</jats:bold> with H<jats:sub>3</jats:sub>O<jats:sup>+</jats:sup> undergoes N(5)N(6) bridging affording pentacyclic <jats:bold>22</jats:bold> which constitutes a proof for the <jats:italic>cisoid</jats:italic> configuration. From conformational studies, rules are devised that allow assigning the configuration of these compounds from NMR data. <jats:italic>In vitro</jats:italic> comparative cytotoxicity assays of these compounds show that for high cytotoxic activity, such as of <jats:bold>1</jats:bold> <jats:italic>in vivo</jats:italic>, unsubstituted OHC(8a), HN(5), HN(6) moieties are needed in the natural B/D <jats:italic>transoid</jats:italic> configuration.