Nodulisporic acids D-F. Structure, biological activities, and biogenetic relationships

Nodulisporic acids D, E, and F (7-12) are the newest members of a family of nontremorogenic indole-diterpenoids that are potent, orally bioavailable, antiflea agents derived from a fungus belonging to the genus Nodulisporium. The four members of the D series (7a-10a) are each devoid of an isoprene residue that is present at C-26 in the three nodulisporic acids described originally (the A series, 1a-3a). Nodulisporic acid E (11a) has a simpler structure, which lacks not only the isoprene residue at C-26 but also two that form the A/B rings. Nodulisporic acid F (12) is the simplest of all nodulisporic acids and is devoid of all three isoprene residues of the indole unit; as such, it represents the earliest biosynthetic intermediate in this series. A biogenetic grid based on mutation studies is proposed that encompasses all the known nodulisporic acids. Structure-activity relationships of the known natural nodulisporic acids have been elucidated. Within a series the most active compound possesses a dienoic acid chain, and overall, the end product of the biogenetic grid, i.e., nodulisporic acid A (1a), exhibits the most potent antiflea activity. Additionally, the stereochemistries of C-3 and C-4 of nodulisporic acid D-2 (9a) and therefore of nodulisporic acids A(2) (3a), B-2 (3b), and C-2 (6) have been assigned.