Synthesis of potential antifilarial agents. 1-(5-Benzoylbenzimidazol-2-yl)-3-alkyl- and -arylureas.

A series of 1-(5-benzoylbenzimidazol-2-yl)-3-substituted ureas have been synthesized by reacting an appropriate isocyanate with 2-amino-5-benzoylbenzimidazole or by reacting methyl (5-benzoylbenzimidazol-2-yl)carbamate with various amines. Several of the compounds have demonstrated antifilarial activity against Brugia pahangi and Litomosoides carinii.

Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase.

Potent and selective non-thiol-containing inhibitors of protein farnesyltransferase are described. FTI-276 (1) was transformed into pyridyl ether analogue 19. The potency of pyridyl ether 19 was improved by modification of the biphenyl core to that of an o-tolyl substituted biphenyl core to give 29. In addition to 0.4 nM in vitro potency, 29 displayed 350 nM potency in whole cells as the parent carboxylic acid. The o-tolyl biphenyl core dramatically and unexpectedly enhanced the potency of other compounds as exemplified by 46, 47, 48, and 49.

Discovery of a series of cyclohexylethylamine-containing protein farnesyltransferase inhibitors exhibiting potent cellular activity.

Synthesis of a library of secondary benzylic amines based on the Sebti-Hamilton type peptidomimetic farnesyltransferase (FTase) inhibitor FTI-276 (1) led to the identification of 6 as a potent enzyme inhibitor (IC(50) of 8 nM) which lacked the problematic thiol residue which had been a common theme in many of the more important FTase inhibitors reported to date. It has previously been disclosed that addition of o-tolyl substitution to FTase inhibitors of the general description 2 had a salutary effect on both FTase inhibition and inhibition of Ras prenylation in whole cells. Combination of these two observations led us to synthesize 7, a potent FTase inhibitor which displayed an IC(50) of 0.16 nM for in vitro inhibition of FTase and an EC(50) of 190 nM for inhibition of whole cell Ras prenylation. Modification of 7 by classical medicinal chemistry led to the discovery of a series of potent FTase inhibitors, culminating in the identification of 25 which exhibited an IC(50) of 0.20 nM and an EC(50) of 4.4 nM. In vivo tests in a nude mouse xenograft model of human pancreatic cancer (MiaPaCa cells) showed that oral dosing of 25 gave rise to impressive attenuation of the growth of this aggressive tumor cell line.

DNA breakage activity of the methanol extract of auromomycin.

The constituents of the antitumor agent auromomycin have been analyzed to determine their DNA-breakage activities. Spectral analysis showed that the methanol extract contained 70% of the non-peptide chromophore, whereas the residue contained 20%. Amino acid analysis of the methanol extract showed that it contained 21%-26% of the original auromomycin polypeptides. The DNA-degradation activity of the extract was 121% +/- 28% of that of the untreated auromomycin, whereas that of the residue was only 22% +/- 3.8%. Mixing of the residue and the methanol extract resulted in the loss of three-fourths of the total activity. Agarose gel electrophoretic analysis showed that the single-strand DNA breakage activity of the methanol extract was 6.5-fold greater than that of the double-strand DNA-breakage activity. The difference in the total DNA-cleavage activity of the untreated, methanol-treated, and remixed auromomycin preparations may suggest the occurrence of certain non-peptide chromophore-polypeptide interactions in both the untreated and the remixed preparations. This is consistent with the fluorescent changes observed upon mixing of the extract and residue. Fractionation of the methanol extract by Sephadex chromatography revealed that several column fractions which were enriched with non-peptide chromophore relative to the polypeptides contained in them still had significant DNA-degradation activity. These studies suggest that the non-peptide chromophore in the auromomycin preparation may contribute to most of the observed DNA breakage activity.

Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase.

Potent and orally bioavailable nonthiol-containing inhibitors of protein farnesyltransferase are described. Oral bioavailability was achieved by replacement of the pyridyl ether moiety of 1 with a 2-substituted furan ether to give 4. Potency was regained with 2,5-disubstituted furan ethers while maintaining the bioavailability inherent in 4. p-Chlorophenylfuran ether 24 is 0.7 nM in vitro (FTase) and is 32% bioavailable in the mouse, 30% bioavailable in rats, and 21% bioavailable in dogs.