Cuprate-Mediated Synthesis and Biological Evaluation of Cyclopropyl- and tert-Butylfarnesyl Diphosphate Analogs

Abstract

The novel farnesyl diphosphate (FPP) analog 3-cyclopropyl-3-desmethylfarnesyl diphosphate (3-cpFPP, 1) was designed as a potential mechanism-based inhibitor of the FPP-utilizing enzyme protein-farnesyl transferase (PFTase). The key step in the synthesis of 1 involved the stereoselective coupling of vinyl triflate 8 with a lower order cyclopropyl cyanocuprate to afford the desired cyclopropyl ester 13. The sterically encumbered analog 3-desmethyl-3-tert-butylfarnesyl diphosphate (3-tbFPP, 7) was synthesized via a similar route. The use of the more reactive higher order tert-butyl cyanocuprate led to lower yields of ester 11, the key intermediate in the synthesis of 7. Biological evaluation of 3-cpFPP demonstrates that it is not a time-dependent inhibitor of recombinant yeast PFTase. Instead, 3-cpFPP is an alternative substrate for this enzyme that exhibits a K(m) comparable to FPP and a k(cat) only 5-fold lower than the natural substrate. In contrast, 3-tbFPP is an exceptionally poor substrate for yeast PFTase and acts as an inhibitor of this enzyme.

Non-Peptidic Prenyltransferase Inhibitors: Diverse Structural Classes and Surprising Anti-Cancer Mechanisms

“…(14)) and 3-cyclopropylFPP (Fig. (14)) also argue against a strictly dissociative mechanism for FTase [165,166].…”

“…(14)) was designed as a potential mechanism-based inhibitor, but was instead a poor alternative substrate for yeast FTase [165]. In contrast, the sterically encumbered analog 3-tbFPP (1c) is an exceptionally poor substrate and a potent competitive inhibitor of this enzyme [166]. The results seen with 3-tbFPP led us to evaluate it and 3-vFPP against mammalian…”

Synthetic Routes to Methylerythritol Phosphate Pathway Intermediates and Downstream Isoprenoids

“…Hence, synthesis of FPP analogs as anti-cancer therapeutics is an area of intense research [113]. Primary to this goal was the synthesis of suicide inhibitors against PFTase to prevent farnesylation through covalent attachment of the FPP analog to the enzyme by trapping a carbocation intermediate within the enzyme active site [114]. …”

Copper‐Mediated Synthesis of Natural and Unnatural Products

“…In a total synthesis of brevetoxin B (33), an active principle of the poisonous waters associated with the red tide phenomenon, substitution on an sp 2 carbon center by a functional organocopper reagent is employed as one of the key reactions (Scheme 9.8) [31]. To carry out the formation of the D ring, alkyl iodides 35 and 36 were transformed into their lithio derivatives by halogen-metal exchange with t-BuLi and into the cyano-Gilman reagents R(2-thienyl)CuLiÁLiCN [32], which coupled easily with the lactone-derived enol triflate 34 to afford desired oxepenes 38 and 39 in 50% and 49% yields, respectively.…”

“…S N 2 substitution using organocopper reagents is an efficient method for the synthesis of 3-substituted olefins. In the synthesis of farnesyl diphosphate analogues (43,45) as potential inhibitors of the enzyme protein-farnesyl transferase, for example, organocopper methodology was compared with the Stille reaction [33] and the Suzuki reaction [34], frequently used in the coupling of vinyl triflates with 9 Copper-Mediated Synthesis of Natural and Unnatural Products Scheme 9.8. a variety of organotin nucleophiles and boronic acids to introduce functional groups onto sp 2 carbon atoms [35]. In this case, neither of these palladium-catalyzed coupling reactions was amenable to the introduction of a cyclopropyl or t-butyl nucle-…”