title: Nodulisporic acids D-F: structure, biological activities, and biogenetic relationships.
abstract: Nodulisporic acids D, E, and F 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 are each devoid of an isoprene residue that is present at C-26 in the three nodulisporic acids described originally (the A series). 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 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, exhibits the most potent antiflea activity. Additionally, the stereochemistries of C-3' ' and C-4' ' of nodulisporic acid D(2) and therefore of nodulisporic acids A(2), B(2), and C(2) have been assigned.
authors.affiliation: Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. sheo_singh@merck.com
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.forename: John G
authors.initials: JG
authors.lastname: Ondeyka
authors.forename: Hiranthi
authors.initials: H
authors.lastname: Jayasuriya
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Zink
authors.forename: Sookhee N
authors.initials: SN
authors.lastname: Ha
authors.forename: Arlene
authors.initials: A
authors.lastname: Dahl-Roshak
authors.forename: Joyce
authors.initials: J
authors.lastname: Greene
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kim
authors.forename: McHardy M
authors.initials: MM
authors.lastname: Smith
authors.forename: Wesley
authors.initials: W
authors.lastname: Shoop
authors.forename: Jan S
authors.initials: JS
authors.lastname: Tkacz
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D001203:Ascomycota / Q000737:chemistry*; D004175:Diptera; D004224:Diterpenes; D007211:Indoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D015394:Molecular Structure; D005423:Siphonaptera / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000977:Antiparasitic Agents; D004224:Diterpenes; D007211:Indoles; C493113:nodulisporic acid D; C493114:nodulisporic acid E; C493115:nodulisporic acid F; C110703:nodulisporic acid A