Nodulisporic acids D-F: structure, biological activities, and biogenetic relationships.
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.
Singh
Sheo B
SB
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. sheo_singh@merck.com
Ondeyka
John G
JG
Jayasuriya
Hiranthi
H
Zink
Deborah L
DL
Ha
Sookhee N
SN
Dahl-Roshak
Arlene
A
Greene
Joyce
J
Kim
Jennifer A
JA
Smith
McHardy M
MM
Shoop
Wesley
W
Tkacz
Jan S
JS
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
D000977:Antiparasitic Agents; D004224:Diterpenes; D007211:Indoles; C493113:nodulisporic acid D; C493114:nodulisporic acid E; C493115:nodulisporic acid F; C110703:nodulisporic acid A