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.

Structure-activity relationships of novel anti-malarial agents: 1. arylacyl and cyclohexylacyl derivatives of 5-amino-2-tolylacetylaminobenzophenone.

We have identified compound 1 as a lead structure of a novel class of anti-malarial agents. Here, we report on our continuing studies towards the establishment of structure-activity relationships by varying the terminal phenyl moiety and the alkyl linker of the acyl substituent at the 5-amino function of the benzophenone core structure. Most of the derivatives of our lead structure 1 essentially display the same anti-plasmodial activity as the lead.

Discovery of a novel lead structure for anti-malarials.

From a library of 61 compounds available from former studies 2,5-bis-acylaminobenzophenone 7p was identified as a lead structure for a novel class of anti-malaria agents active against multi-resistant Plasmodium falciparum strain Dd2. Some structural modifications of this initial lead demonstrated the potential for further improvement of the anti-plasmodial activity of this novel class of anti-malarials.

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).

Structure activity relationship of antiproliferative N-acyl-aspartic acid dimethyl ester. 2. Variation of the aspartyl moiety.

Structural variations of the L-aspartic acid substructure of (S)-N-3-phenoxycinnamoylaspartic acid dimethyl ester which shows a selective antiproliferative activity against THP-1 tumor cells, demonstrated that the L-aspartic acid moiety is absolutely mandatory for antiproliferative activity as well as for selectivity.

Structure-activity relationships of novel anti-malarial agents. Part 2: cinnamic acid derivatives.

We have described compound 1 as a lead structure for a novel class of anti-malarial agents. Replacement of the 3-phenylpropionyl moiety of the lead structure 1 by a 4-propoxycinnamic acid residue resulted in a significant improvement in antimalarial activity. Compound 3q represents an important step in the development of lead structure 1 into an anti-malarial drug candidate.