Discovery and Structure−Activity Relationships of Imidazole-Containing Tetrahydrobenzodiazepine Inhibitors of Farnesyltransferase

Abstract

2,3,4,5-Tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepines were found to be potent inhibitors of farnesyltransferase (FT). A hydrophobic substituent at the 4-position of the benzodiazepine, linked via a hydrogen bond acceptor, was important to enzyme inhibitory activity. An aryl ring at position 7 or a hydrophobic group linked to the 8-position through an amide, carbamate, or urea linkage was also important for potent inhibition. 2,3,4, 5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-7-(4-pyridinyl)-4-[2-(t rifluo romethoxy)benzoyl]-1H-1,4-benzodiazepine (36), with an FT IC(50) value of 24 nM, produced 85% phenotypic reversion of Ras transformed NIH 3T3 cells at 1.25 microM and had an EC(50) of 160 nM for inhibition of anchorage-independent growth in soft agar of H-Ras transformed Rat-1 cells. Selected analogues demonstrated ip antitumor activity against an ip Rat-1 tumor in mice.

Synthesis and Catalytic Properties of Imidazole-Functionalized Poly(propylene imine)Dendrimers

“…By calculating and comparing the areas of integration of the peaks of the aromatic protons present on the imidazole ring (7.81 and 8.62 ppm for PPI-Im 16 , 7.65 and 8.59 ppm for PPI-Im 64 ) versus the areas of integration from the dendrimer backbone peaks (2.0 ppm) (Figure 1) a high degree of functionalization for both dendrimer generations is obtained (81% for PPI-Im 16 and 84% for PPI-Im 64 ). Additionally, 13 C NMR showed no evidence of free primary amines.…”

“…Triphenymethyl-protected 4-imidazole carboxylic acid (trityl-ImCOOH) was prepared using a literature procedure. 13 Briefly, 3.178 g of 4-imidazole carboxylic acid (0.0283 M) and 10 mL of anhydrous triethylamine were dissolved in 30 mL of anhydrous dimethyl formamide. The solution was stirred and 8.247 g (0.0295 M) of triphenylmethyl chloride was added.…”

Farnesyltransferase Inhibitors: From Squalene Synthase Inhibitors to the Clinical Agent BMS-214662

“…One variation of the piperazine template which we explored involved cyclization of the methoxyethyl side chain onto the piperazine (a), and concomitant aromatization of the resulting ring, effectively replacing the alkyl hydrophobe with an aryl hydrophobe. Although the tetrahydroquinazoline compound which resulted (not shown) did not show improved FT inhibitory potency (IG 50 = 2.2 μΜ), homologation of the piperazine to a diazepine ring afford the submicromolar tetrahydrobenzodiazepine 17 (22).…”

Inhibition of farnesyltransferase: A rational approach to treat cancer?

“…Members of this class of FTIs exhibited the highest cell potency yet described for inhibitors of FTase. Compound 10, for example inhibited the processing of HDJ2 in PSN-1 cells with an EC 50 value of 180 pM [48].…”

“…Researchers at Bristol-Myers Squibb sought analogues of thiol 6, in which the mercaptan was replaced by imidazole [49] and evolved their initial micromolar leads into a tetrahydrobenzodiazepinebased series of compounds represented by 11 (FTase IC 50 ¼ 24 nM) [50]. It was discovered that the potency of analogues such as 11 was enhanced by addition of a phenylmethyl moiety at the 3-position and replacement of the 4-position amide with a sulfonamide.…”