| Farnesyltransferase and geranylgeranyltransferase-I have recently become important targets in the advancement of novel anticancer agents. Additionally, the discovery that Plasmodium falciparum possesses the farnesyltransferase enzyme, has led to efforts towards the development of farnesyltransferase inhibitors as antimalarial agents. Three novel scaffolds have been designed, synthesized, and evaluated for biological activity towards inhibiting mammalian and P. falciparum farnesyltransferase as well as mammalian geranylgeranyltransferase-I.;Utilizing a peptidomimetic strategy, a biphenyl system was introduced as the semi-rigid scaffold in a series of inhibitors designed as CAAX peptide surrogates. In order to investigate the zinc binding properties of these compounds, a library of imidazole-containing compounds was synthesized and evaluated for activity towards inhibiting mammalian FTase. Introduction of this imidazole functionality led to compound 2.35 (in vitro IC50 = 0.86 nM) and its methyl ester 2.36 (H-Ras processing IC50 = 0.02 muM) exhibiting potent activity in vitro and in whole cells, respectively.;Application of the peptidomimetic strategy to inhibition geranylgeranyltransferase-I led to the design of compounds based upon a piperazin-2-one scaffold. SAR studies revealed that introduction of methylimidazole as the zinc binding moiety, as well as a leucine residue as the X portion of the CAAX mimetic, increased the potency of this series. Incorporation of these essential pharmacophores led to GGTI-2417 (3.22), which demonstrated potent activity in vitro with an IC50 of 9.5 nM and GGTI-2418 ( 3.23) that exhibited an IC50 in whole cells of 0.4 muM. Additionally, GGTI-2418 was found to reduce the size of tumors by 57% in xenograft nude mouse models. In an effort to reduce the peptidic character of GGTI-2418, docking studies were employed in order to design a suitable replacement for the leucine residue of this compound. Progress towards the synthesis of these compounds led to the N-arylpiperazinone precursor 3.84.;In contrast to the previously described peptidomimetic approach, a final series of Plasmodium falciparum FTase inhibitors was designed using a structure based approach with the aid of docking studies. The investigation into a novel scaffold led to a library of compounds based upon an ethylenediamine tether, linking a variety of appended substituents. |
