Conformationally restricted (+)-cacospongionolide B analogues. Influence on secretory phospholipase A2 inhibition.
A new approach to (+)-cacospongionolide was developed to access conformationally restricted variants of the natural product. The flexible aliphatic region between the decalin and side chain portion of the natural product was replaced with alkenyl and alkynyl linkers to probe the influence of structural rigidity in the inhibition of secretary phospholipase A2 (sPLA2). It was found that when the aliphatic section is replaced with a Z-olefin or an alkyne, sPLA2 inhibitory activity suffered relative to the natural product; however, an E-olefin-containing analogue led to an enhanced activity. These results suggest that preferred sPLA2 binding conformation of the natural product is similar to the geometry of the E-olefin-containing analogue.
Murelli
Ryan P
RP
Department of Chemistry, Merkert Chemistry Center, Boston College, 2609 Beacon Street, Chestnut Hill, MA 02467, USA.
Cheung
Atwood K
AK
Snapper
Marc L
ML
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001514:Bee Venoms / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D005662:Furaldehyde / Q000737:chemistry; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D011161:Porifera / Q000737:chemistry*; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry
D001514:Bee Venoms; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011714:Pyrans; D011994:Recombinant Proteins; C098384:cacospongionolide B; D005662:Furaldehyde; D010741:Phospholipases A; D054467:Phospholipases A2; D015107:4-Butyrolactone