Isolation, synthesis and complement inhibiting activity of the naturally occurring K-76, its analogues and derivatives

Abstract

The Complement inhibitor K-76 was isolated from the supernatant of the culture broth of the fungus Stachybotrys complementi, nov. sp. K-76. The natural product is a sesquiterpenic dialdehyde which can be partially oxidized to the monocarboxylic acid derivative (K-76 COOH, MX-1), the sodium salt of which is more soluble and less toxic than the natural product. Both, K-76 and K-76 COOH inhibit Complement activation by the classical and alternative pathways, mainly at the C5 level. Reviewed here are the isolation and total syntheses of the natural product as well as aspects of its Complement inhibitory activity. Approaches to the synthesis of grisan, which bears the BCD skeleton of the natural product, as well as the synthesis of CD-, BCD-and ACD-ring structural analogues of K-76, including the use of natural products as starting materials, and evaluation of their biological activity as Complement inhibitors, are also discussed.

NIS–PPh3: A Selective Reagent for the Spiroannulation of o-Allyl Phenols. Total Synthesis of Corallidictyal D

“…During the last few decades, a variety of spiro­dihydro­benzo­furan derivatives and related compounds, characterized by their wide-ranging, potent biological activities, have been isolated from different natural sources. Representative examples (Figure ) are corallidictyal B ( 1 ) and D ( 2 ), two spirosesquiterpene aldehydes isolated from the marine sponge Aka coralliphaga, with protein kinase C inhibitory activity; the complement inhibitor K-76 ( 4 ); the antiviral stachybotrydial ( 5 ); and the myoinositol monophosphatase (IMPase) inhibitor L-671,776 ( 6 ) . Various spiro­dihydro­benzo­furan lactams have been isolated from the cultures of different Stachybotrys species, such as compounds 7 – 11 , with pancreatic cholesterol esterase inhibitor activity, and lactams 12 – 15 , antagonists of endothelin and inhibitors of HIV-1 protease .…”

Natural sesquiterpenoids

“…76 The isolation, synthesis and complement inhibiting activity of the sesquiterpene K-76, its analogues and derivatives, have been reviewed. 77 The stereoselective total synthesis of the drimane sesquiterpenes kuehneromycin A, antrocin, anhydromarasmone and marasmene have been accomplished. 78 The synthesis of pyripyropene A, a potent ACAT2 inhibitor, has been carried out.…”

Stereoselective Transformations of (+)-Abietic Acid into (+)-Vitedoin B and (+)-Negundoin A

“…Over recent decades, a large number of terpenoids with a spiroether or a spirolactone moiety in their structure have been isolated from diverse natural sources. Among the spiroethers, spirodihydrobenzofuran derivatives, such as corallidictyal D ( 1 ), K-76 ( 2 ), F1839-A ( 3 ), or stachybotrylactam ( 4 ), must be highlighted. These compounds and others structurally related to them are characterized by a potent and diverse biological activity.…”