title: Chemistry and Biology of Cylindrols: Novel Inhibitors of Ras Farnesyl-Protein Transferase from Cylindrocarpon lucidum.
abstract: Farnesyl-protein transferase (FPTase) is an enzyme responsible for the farnesylation of Ras protein. Farnesylation is required for cell-transforming activity in several tumor-types, and therefore, inhibition of FPTase activity may be a potential target for anticancer drugs. Our continued search for novel inhibitors led to the isolation of a number of bicyclic resorcinaldehyde cyclohexanone derivatives named here cylindrols A(1) to A(4), cylindrols B and B(1), and a number of known compounds, from Cylindrocarpon lucidum. The compounds were isolated by bioassay-guided separation using Sephadex LH-20, silica gel, and reverse phase HPLC. Structures were elucidated by extensive application of 2D NMR and X-ray crystallography. The determination of absolute stereochemistry was accomplished by CD measurements. Chemical transformations of the most abundant compound resulted in a number of key derivatives which were critical for the evaluation of structure activity relationship. These compounds are members of ascochlorin family and showed a wide range of inhibitory activity (0.7 &mgr;M to >140 &mgr;M) against FPTase. The FPTase activity was noncompetitive with respect to both substrates. Isolation, structures, chemical transformations, and FPTase activity are discussed in detail.
authors.affiliation: Merck Research Laboratories, P.O. Box 2000 Rahway, New Jersey 07065 and West Point, Pennsylvania 19486 and Centro de Investigación Básica, Merck Sharp & Dohme de España S.A., Josefa Valcárcel 38, 28027, Madrid, Spain.
authors.forename: Sheo B.
authors.initials: SB
authors.lastname: Singh
authors.forename: Richard G.
authors.initials: RG
authors.lastname: Ball
authors.forename: Gerald F.
authors.initials: GF
authors.lastname: Bills
authors.forename: Carmen
authors.initials: C
authors.lastname: Cascales
authors.forename: Jackson B.
authors.initials: JB
authors.lastname: Gibbs
authors.forename: Michael A.
authors.initials: MA
authors.lastname: Goetz
authors.forename: Karst
authors.initials: K
authors.lastname: Hoogsteen
authors.forename: Rosalind G.
authors.initials: RG
authors.lastname: Jenkins
authors.forename: Jerrold M.
authors.initials: JM
authors.lastname: Liesch
authors.forename: Russell B.
authors.initials: RB
authors.lastname: Lingham
authors.forename: Keith C.
authors.initials: KC
authors.lastname: Silverman
authors.forename: Deborah L.
authors.initials: DL
authors.lastname: Zink