Bovine brain FPTase activity

Table 6. Bovine brain FPTase Activity of Cylindrois and Related Compounds...

Valinoctins A and B inhibited bovine brain FPTase with IC50 values of 3.2 and 3.5 pM, respectively [150]. The FPTase activity of stereoisomers derived from stereospecific synthesis was also evaluated. The 25, 3R- or 25, 35-stereochemistry of the 2-hydroxy-3-amino acid were optimal for FPTase inhibitory activity. Substitution of valine with isoleucine or phenylalanine (IC50 values of 1.7-4 pM) had a trivial impact on inhibitory activity while substitution with alanine completely eliminated activity (IC50= > 75 pM) [151]. Mechanism of inhibition or selectivity data for these compounds has not been reported. 

Saquayamycins A-F inhibited bovine brain FPTase with IC50 values of 1.5-2.0 ijM. Aquayamycin was the most active member of this class with an IC50 value of 1.3 /tM. The activity of the latter compound suggests that the FPTase activity is probably associated with the tetracyclic core since the pyran linkages contribute minimally to the inhibitory activity. Adriamycin, a related linear tetracyclic compound, is virtually inactive indicating that the anthracene-type bent structure is required for activity. In contrast to the paucity of data for the several compounds described earlier, mechanistic kinetic data indicate that saquayamycins were noncompetitive with respect to Ras-peptide, but surprisingly, no data was presented with respect to FPP. 

Actinoplanic acids A and B exhibited IC50 values of 230 and 50 nM, respectively, against rHFPTase. Both compounds are competitive with FPP and displayed Kj values of 98 and 8 nM, respectively. The inhibition profile of these compounds was uncompetitive with respective to the Ras peptide substrate. The inhibition of FPTase by actinoplanic acids is selective and reversible and these compounds did not inhibit the human squalene synthase and bovine brain GGPTase (ICso s > 1 jjM) [87,88]. Similar to other examples of inhibitors that are competitive with respect to FPP, esterification of the carboxy groups of actinoplanic acids completely eliminated inhibitory activity. The increased potency of actinoplanic acid B is associated with the increased number of negative charges when compared with acid A [87,88]. 

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