Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT

Physiologic Activity of Bisphosphonates – Recent Advances

“…These compounds inhibit bone resorption in vivo, however, to a lesser extent than the parent drugs [5, 32, 38 -40]. Later, it was found that they act as inhibitors of Rab geranylgeranyl transferase and prevent geranylgeranylation of small Rab GTPases [5,40,41]. Thus, these compounds might be considered as a novel class of anti-cancer agents.…”

Synthesis and Biological Evaluation of Imidazole‐Bearing α‐Phosphonocarboxylates as Inhibitors of Rab Geranylgeranyl Transferase (RGGT)

“…Our data indicate that 1 i , j are selective micromolar RGGT inhibitors with similar or slightly weaker activity than the reference compound F‐ZolPC (LED for inhibition of Rab11A: 10 μ m ) and α‐fluorinated analogues of 3‐IPEHPC (LED for inhibition of Rab11A: 10 or 25 μ m , depending on the substituent′s character) …”

“…We first synthesized six new analogues of the N‐series, 1 a – 1 f , derived from F‐ZolPC, modified with a methyl or phenyl group, or bromine atom at either the 2‐ or 4(5)‐position of the imidazole ring (Figure a) . Target compounds 1 a – f were prepared according to a modified procedure previously developed by us . It involved aza‐Michael addition of commercially available substituted imidazoles 4 to the ethyl 2‐(diethoxyphosphoryl)acrylate 3 (Scheme ).…”

“…[15] Ta rget compounds 1a-f were prepared according to am odified procedure previously developed by us. [11] It involved aza-Michael addition of commercially available substituted imidazoles 4 to the ethyl 2-(diethoxyphosphoryl)acrylate 3 (Scheme 1). Thus obtained triesters 5 were relatively unstablea nd spontaneously underwents ubsequent reaction with an acceptor,f orming so-called" double Michael addition" products (Scheme S1).…”

Pharmacological diversity among drugs that inhibit bone resorption

“…One interesting example are phosphonocarboxylate analogues of bisphosphonates, in which one of the phosphonate groups is replaced by a carboxylate moiety which results in reduced affinity for bone mineral. Some such compounds inhibit other enzymes in the mevalonate pathways such as RAB prenyl transferases [78]. Prenyl transferases are attractive potential targets in cancer therapy [79].…”