Pseudopterosins

Pseudopterosin A is a member of a group of marine natural products which show potent antiinflammatory properties, but which are not prostaglandin biosynthesis inhibitors. Structurally similar to phosphatidyl inositol, they may function as phospholipase inhibitors, and, as such, may be the forerunners of a new class of therapeutic agents. 

Scheme 7.30. DMP-induced domino oxidation/hetero-Diels-Alder procedure for the rapid entry into complex elisabethin and pseudopterosin structures.

The oxidative formation of p-benzoquinones from anilides such as 7-108 was used for the synthesis of the core scaffold of the natural products elisabethin A (7-106) and pseudopterosin A aglycone (7-107) (Scheme 7.30). Exposure of anilide 7-108 to DMP [53] led to the formation of the o-imidoquinone 7-109, which underwent an intramolecular Diels-Alder reaction to give 7-110 in 28% yield after hydration. In a competitive pathway, the p-quinone 7-111 is also formed from 7-108, which on heating in toluene again underwent an intramolecular Diels-Alder reaction to give cycloadduct 7-112 in 25% overall yield. Hydrolysis of 7-112 furnished the carbocyclic skeleton 7-113 of elisabethin A (7-106). 

A recent example demonstrates that corals rely on induced biosynthesis of terpenes as a dynamic defense strategy as well. The induction of terpenoid secondary metabolites was observed in the sea whip Pseudopterogorgia elisabethae [162]. Levels of pseudopterosins 89-92, a group of diterpene glycosides with anti-inflammatory and analgesic properties (Scheme 23) [163-165], are increased in response predation by the mollusk Cyphoma gibbosum. First bioassays indicate that these natural products are involved in the chemical defense. 

Scheme 23 Inducible pseudopterosins in the sea whip Pseudopterogorgia elisabethae...

Pseudopterosin X (1) was isolated as a yellow colored gum. The UV spectrum of 1 showed maximum absorption at 280 nm due to the presence of a highly substituted benzene chromophore [10], Its IR spectmm displayed intense absorption bands at 3,470 (OH), 2,904 (CH), 1,705 (C = O), 1,595 (C = C) and 1,100 (C-0) cm . The high-resolution electron-impact mass spectmm (HREIMS) of 1 showed M+ at m/z 474.2622, and this mass provided molecular formula indicating the presence of nine double bond equivalents in 1. The C-NMR chemical shift assignments of 1 are shown around stracture 1. On the basis of the detailed NMR studies and comparison with the reported pseudopterosins in the literature and L-xylose [3-5], stmcture 1 was proposed for this new natural product. 

The second new compound, pseudopterosin Y (2) was also purified a yellow gum. Its UV and IR spectra were identical to those of compound 1, indicating the presence of same n system and functional groups in 2. The HREIMS of 2 showed the M+ at m/z 516.2420 corresponding to the molecular formula A combination of H-, C-NMR, COSY, HSQC and HMBC spectral data revealed that compound 2 was C-3 acetyl derivative of compound 1. Based on these spectral data, stmcture 2 was assigned to this new compound. 

A C9-C14 cycHzation forms the ring C and leads to the amphilectane skeleton which is foimd for instance in pseudopterosins A-F (10, aglycone) [10] isolated from Pseudopterogorgia elisabethae extracts stemming from a Bahamian collection site (Fig. 5). This class of natural products can be characterized as... 

Elisabethol (13) [4] shows the same stereochemistry as the pseudopterosin aglycone 10. Elisabatins A-C (14,15,16) [ 14] have the same amphilectane skeleton found in the aglycone portion of the pseudopterosins. The elisabatins are unique among the amphilectane-type diterpenoids because they possess an unusually high unsaturation number that leads to extended aromatic conjugation. 

Recently it was shown by radiolabeling studies that the formation of the serrulatane skeleton is catalyzed by the pseudopterosin diterpene cyclase, which can be considered as a key enzyme in terpene biosynthetic pathways (Scheme 2). The elisabethatriene cyclase is a monomer with a molecular mass of47kDa [25]. 

Pseudopterosins coexist with the seco-pseudopterosins, suggesting that these two classes of diterpenes are produced from a single cyclase product. Elisabethatriene (42) undergoes aromatization to erogorgiaene (1) presumably a series... 

Scheme 4 Plausible biosynthetic pathway of the seco-pseudopterosins and pseudopterosins...

The pseudopterosins and seco-pseudopterosin isolated from Bahamian specimens of Pseudopterogorgia elisabethae display strong anti-inflammatory and analgesic activity. These diterpene glycosides had potencies superior to those of... 

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