ABSTRACT
A new class of potent farnesyltransferase inhibitors based on a 1,4-diazepane scaffold was synthesized with protein farnesyltransferase inhibition potencies in the low nanomolar range. The compounds block the growth on two hormone-resistant tumor prostatic cell lines (DU145 and PC3). The advanced cellular evaluation of the more potent farnesyltransferase inhibitors was explored and revealed a disorganization of tubulin in PC3 cells.
Subject(s)
Androgen Antagonists/therapeutic use , Azepines/chemical synthesis , Farnesyltranstransferase/antagonists & inhibitors , Prostatic Neoplasms/drug therapy , Tubulin Modulators/chemical synthesis , Azepines/pharmacokinetics , Azepines/pharmacology , Cell Line , Cell Line, Tumor , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Humans , Hydrophobic and Hydrophilic Interactions , Male , Models, Molecular , Structure-Activity Relationship , Tubulin/drug effects , Tubulin/ultrastructure , Tubulin Modulators/pharmacokinetics , Tubulin Modulators/pharmacologyABSTRACT
A new series of FTase inhibitors containing a tricyclic moiety--dioxodibenzothiazepine or dibenzocycloheptane--has been designed and synthesized. Among them, dioxodibenzothiazepine 18d displayed significant inhibitory FTase activity (IC(50)=17.3 nM) and antiproliferative properties.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase/antagonists & inhibitors , Animals , Cell Proliferation/drug effects , Drug Design , Humans , Leukemia L1210 , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , Tetrazolium Salts , ThiazolesABSTRACT
FTase inhibitors constitute a new class of potential cancer therapeutics, especially in colorectal cancer where K-ras-selective mutations exist and have a role in tumorigenesis. The synthesis and biological evaluation of two nonpeptidic molecules (13 and 16) designed on the basis of a zinc chelator imidazole linked to two aromatic fragments able to fit in the "exit groove" and in the "A2 binding site" of FTase are described. These molecules are characterized respectively by a flexible phenylmethyl chain and a more constrained scaffold so as to evaluate their respective influences on site recognition. They have been evaluated in vitro and in vivo against human colon cancer cell lines and 13 not only inhibited tumor growth but also showed no toxic effects at the dose used.
