CHEMISTRY AND BIOLOGY OF CYLINDROLS - NOVEL INHIBITORS OF RAS FARNESYL-PROTEIN TRANSFERASE FROM CYLINDROCARPON LUCIDUM

Farnesyl-protein transferase (FPTase) is an enzyme responsible for the farnesylation of Ras protein. Farnesylation is required for cell-tran sforming activity in several tumor-types, and therefore, inhibition of FPTase activity may be a potential target for anticancer drugs. Our c ontinued search for novel inhibitors led to the isolation of a number of bicyclic resorcinaldehyde cyclohexanone derivatives named here cyli ndrols A(1) to A(4), cylindrols B and B-1, and a number of known compo unds, from Cylindrocarpon Lucidum. The compounds were isolated by bioa ssay-guided separation using Sephadex LH-20, silica gel, and reverse p hase HPLC. Structures were elucidated by extensive application of 2D N MR and X-ray crystallography. The determination of absolute stereochem istry was accomplished by CD measurements. Chemical transformations of the most abundant compound resulted in a number of key derivatives wh ich were critical for the evaluation of structure activity relationshi p. These compounds are members of ascochlorin family and showed a wide range of inhibitory activity (0.7 mu M to > 140 mu M) against FPTase. The FPTase activity was noncompetitive with respect to both substrate s. Isolation, structures, chemical transformations, and FPTase activit y are discussed in detail.