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-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.
Singh
Sheo B.
SB
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.
Ball
Richard G.
RG
Bills
Gerald F.
GF
Cascales
Carmen
C
Gibbs
Jackson B.
JB
Goetz
Michael A.
MA
Hoogsteen
Karst
K
Jenkins
Rosalind G.
RG
Liesch
Jerrold M.
JM
Lingham
Russell B.
RB
Silverman
Keith C.
KC
Zink
Deborah L.
DL