Non-thiol Farnesyltransferase Inhibitors Research Articles

Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: synthesis and activity

A series of analogs of tipifarnib ( 1) has been synthesized as inhibitors of FTase by substituting the benzimidazolones and indoles for the 2-quinolone of tipifarnib. The novel benzimidazolones are potent and selective FTase inhibitors (FTIs) with IC 50 values of the best compounds close to that of tipifarnib. The current series demonstrate good cellular activity as measured in their inhibiting the Ras processing in NIH-3T3 cells, with compounds 2c and 2f displaying EC 50 values of 18 and 22 nM, respectively.

Design, synthesis, and activity of achiral analogs of 2-quinolones and indoles as non-thiol farnesyltransferase inhibitors

Beginning with the structure of tipifarnib ( 1), a series of inhibitors of FTase have been synthesized by transposition of the D-ring to the imidazole and subsequent modification of the 2-quinolone motif. The compounds in the new series may be achiral and have structural features that allow for analogs that are difficult or impossible to make in the tertiary carbon-based tipifarnib series. The most potent compound ( 4d) is 4 times more active in vitro against FTase than tipifarnib.

Non-thiol farnesyltransferase inhibitors: N-(4-aminoacylamino-3-benzoylphenyl)-3-[5-(4-nitrophenyl)-2 furyl]acrylic acid amides and their antimalarial activity

Water solubility was previously found to be essential for in vivo-antimalarial activity of a novel type of benzophenone-based farnesyltransferase inhibitors. Introduction of a α-amino group into the phenylacetic acid substructure provided more soluble compounds with high farnesyltransferase inhibitory activity. The in vitro-antimalarial activity was detrimentally influenced by this structural modification.

Synthesis and activity of 1-aryl-1′-imidazolyl methyl ethers as non-thiol farnesyltransferase inhibitors

A series of imidazole-containing methyl ethers ( 4– 5) have been designed and synthesized as potent and selective farnesyltransferase inhibitors (FTIs) by transposition of the D-ring to the methyl group on the imidazole of the previously reported FTIs 3. Several compounds such as 4h and 5b demonstrate superior enzymatic activity to the current benchmark compound tipifarnib ( 1) with IC 50 values in the lower subnanomolar range, while maintaining excellent cellular activity comparable to tipifarnib. The compounds are characterized as being simple, easier to make, and possess no chiral center involved.

Non-thiol farnesyltransferase inhibitors: N-(4-tolylacetylamino-3-benzoylphenyl)-3-arylfurylacrylic acid amides

We have designed arylfurylacryl-substituted benzophenones as non-thiol farnesyltransferase inhibitors utilizing a novel aryl binding site of farnesyltransferase. These compounds display activity in the low nanomolar range.

Non-thiol farnesyltransferase inhibitors: utilization of the near aryl binding site by 5-arylacetylaminobenzophenones.

We recently described two novel aryl binding sites of farnesyltransferase. The arylacetyl residue was designed as an appropriate substituent for our benzo-phenone-based AAX-peptidomimetic compound capable of occupying the near aryl binding site which is located next to the catalytic zinc ion. Non-thiol farnesyl-transferase inhibitors with micromolar to submicromolar activity were obtained.

Non-thiol farnesyltransferase inhibitors: FTase-inhibition and cellular activity of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors.

Some 5-acylaminoacylamino-benzophenone derivatives were designed as bisubstrate analogue farnesyltransferase inhibitors. These compounds turned out to be only weakly active against farnesyltransferase, but displayed an antiproliferative effect rendering them suitable for further development as a novel type of cytostatic agents.

Non-thiol farnesyltransferase inhibitors: n-(4-acylamino-3-benzoylphenyl)-3-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides

We have designed the nitrophenylfurylacryl-substituted benzophenone 4f as a non-thiol farnesyltransferase inhibitor utilizing a novel aryl binding site of farnesyltransferase. Variation of the 2-acylamino substituent at the benzophenone core structure of our initial lead 4f yielded several non-thiol farnesyltransferase inhibitors with improved activity. These compounds display activity in the low nanomolar range.

Structure based design of benzophenone-based non-thiol farnesyltransferase inhibitors.

Farnesyltransferase catalyzes the transfer of a farnesyl residue from farnesylpyrophosphate to the thiol of a cysteine side chain of proteins which carry at the C-terminus the so called CAAX-sequence. Although the exact cellular events affected by farnesyltransferase inhibiton remain to be determined, farnesyltransferase has become a major target in the development of potential anti-cancer drugs. Numerous farnesyltransferase inhibitors have been described from which the majority are CAAX-peptidomimetics possessing a free thiol group which coordinates the enzyme-bound zinc ion. The development of farnesyltransferase inhibitors is clearly directed towards the so-called non-thiol farnesyltransferase inhibitors because of adverse drug effects connected to free thiols. This review mainly deals with the efforts of the authers group towards the design of non-thiol-farnesyltransferase inhibitors. Our first step on the way to non-thiol farnesyltransferase inhibitors was the development of an CAAX-peptidomimetic based on a pharmacophore model. On the basis of this benzophenone core, bisubstrate analogues were developed as one class of non-thiol farnesyltransferase inhibitors. In most non-thiol farnesyltransferase inhibitors known in literature nitrogene containing heterocycles are used as cysteine replacements supposedly coordinating the enzyme bound zinc. However, we and others have shown that nitrogen heterocycles can be replaced by aryl residues lacking the ability to coordinate metal atoms, an observation which let to the postulation of two hitherto unknown aryl binding sites. Using flexible docking of model compounds and GRID analysis we were able to locate these postulated aryl binding sites. Subsequently, we used one of this aryl binding sites for the structure based design of highly active non-thiol farnesyltransferase inhibitors.

Non-Thiol Farnesyltransferase Inhibitors: Evaluation of Different AA(X)-Peptidomimetic Substructures in Combination with Arylic Cysteine Replacements

In the course of our studies on non-thiol farnesyltransferase inhibitors based on the 2, 5-diaminobenzophenone AAX-peptidomimetic substructure, we have developed the (4-nitrophenyl)butyryl (R(1)), the (2-naphthyl)acryloyl (R(2)), the 4-nitrocinnamoyl (R(3)), and the 5-(4-nitrophenyl)furylacryloyl (R(4)) groups as useful cysteine replacements. In this study, we combined these four groups with other AA(X)-peptidomimetic substructures (5-10: R = H) reported in the literature. The 5-(4-nitrophenyl)furylacryloyl moiety (R(4)) turned out to be the most useful non-thiol cysteine replacement yielding in all cases the most active inhibitors. By combination of this 5-(4-nitrophenyl) furylacryloyl moiety (R(4)) with the structurally simple AAX-peptidomimetics 4-aminobenzophenone (5) and 4-aminodiphenylsulfone (6) potent, readily accessible non-thiol farnesyltransferase inhibitors were obtained (IC(50) = 12 nMand 10 nM).

Non-Thiol farnesyltransferase inhibitors: utilization of an aryl binding site by 5-arylacryloylaminobenzophenones

We recently described a novel aryl binding site of farnesyltransferase. The 2-naphthylacryloyl residue was developed as an appropriate substituent for our benzophenone-based AAX-peptidomimetic capable of occupying this binding site, resulting in a non-thiol farnesyltransferase inhibitor with nanomolar activity. The activity of this inhibitor is readily explained on the basis of docking studies which show the 2-naphthyl residue fitting into the aryl binding site.

Non-thiol farnesyltransferase inhibitors: structure–activity relationships of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors

Investigations on the structure–activity relationships of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors yielded a bisubstrate analogue farnesyltransferase inhibitor lacking any prenylic or peptidic substructures with nanomolar activity. This represents a considerable progress in comparison to those non-prenylic, non-peptidic bisubstrate analogue farnesyltransferase inhibitors we have described before which utilized AAX-peptidomimetic substructures different from the benzophenone since those inhibitors displayed activity only in the micromolar range.

Non-thiol Farnesyltransferase Inhibitors: N-(4-Acylamino-3-benzoylphenyl)-4-nitrocinnamic Acid Amides

We have developed the 4-nitrocinnamoyl substituted benzophenone 4a as a novel non-thiol farnesyltransferase inhibitor. Replacement of the p-tolyl moiety of our initial lead structure 4a by different para and ortho substituted phenyl residues as well as by 1-naphthyl resulted in derivatives with considerably enhanced activity displaying IC 50 values between 42 and 52 nM. These compounds represent novel, readily accessible non-thiol farnesyltransferase inhibitors being more active than the corresponding thiol-containing analogues.

Exploration of novel aryl binding sites of farnesyltransferase using molecular modeling and benzophenone-based farnesyltransferase inhibitors.

Most non-thiol CAAX-peptidomimetic farnesyltransferase inhibitors bear nitrogen-containing heterocycles in place of the terminal cysteine which are supposed to coordinate the enzyme-bound zinc. However, it has been shown that those nitrogen-containing heterocycles can be replaced by carbocyclic aromatic moieties which are unable to coordinate the zinc ion, a conclusion that resulted in the postulation of one or two hitherto unknown aryl binding sites. No indication has been given about the spatial location of these novel binding sites. Employing flexible docking of several non-thiol farnesyltransferase inhibitors known from the literature and some model compounds based on our benzophenone scaffold as well as performing GRID searches, we have identified two regions in the farnesyltransferase's active site which we suggest being the postulated aryl binding sites. One aryl binding region is located in close proximity to the zinc ion and is defined by the aromatic side chains of Tyr 300beta, Trp 303beta, Tyr 361beta, and Tyr 365beta. The second aryl binding site is defined by the side chains of Tyr 300beta, Leu 295beta, Lys 294beta, Lys 353beta, and Lys 356beta. This second aryl binding site has been used for the design of a non-thiol farnesyltransferase inhibitor (9c) with an IC(50) of 35 nM.

Non-thiol farnesyltransferase inhibitors: structure-activity relationships of aralkylsubstituted benzophenones.

We describe a novel class of benzophenone-based farnesyltransferase inhibitors exploiting a novel aryl binding region in the farnesyltransferase's active site. The present study was mainly focussed on structural modifications of the trimethylene spacer of the 4-phenyl butyroyl residue of our lead structure (IC50 = 530 nM). These modifications turned out to have little effect on activity as had the replacement of the terminal aryl by cyclohexyl (IC50 = 440 nM vs. IC50 = 530 nM).

ChemInform Abstract: Non-thiol Farnesyltransferase Inhibitors: The Concept of Benzophenone-Based Bisubstrate Analogue Farnesyltransferase Inhibitors.

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Non-thiol farnesyltransferase inhibitors: the concept of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors

Replacement of the thiol in a benzophenone-based CAAX-peptidomimetic farnesyltransferase inhibitor by a carboxylic acid moiety resulted in a marked drop in inhibitory potency. Transformation of these carboxylic acid derivatives into bisubstrate analogues by addition of a lipophilic alkyl chain, which should be able to occupy considerable portions of the farnesyl binding region in the farnesyltransferase’s active site, resulted in a regain of the inhibitory activity. These bisubstrate analogues represent new lead structures for non-thiol farnesyltransferase inhibitors.