141538-75-2Relevant academic research and scientific papers
Novel farnesol and geranylgeraniol analogues: A potential new class of anticancer agents directed against protein prenylation
Gibbs, Barbara S.,Zahn, Todd J.,Mu, YongQi,Sebolt-Leopold, Judith S.,Gibbs, Richard A.
, p. 3800 - 3808 (1999)
Protein farnesyltransferase (FTase), the enzyme responsible for protein farnesylation, has become a key target for the rational design of cancer cheraotherapeutic agents. Herein it is shown that certain novel prenyl diphosphate analogues are potent inhibitors of mammalian FTase. Furthermore, the alcohol precursors of two of these compounds are able to bloch anchorage- independent growth of ras-transformed cells. While 3-allylfarnesol inhibits protein farnesylation, 3-vinylfarnesol instead leads to abnormal prenylation of proteins with the 3-vinylfarnesyl group. In a similar manner, 3- allylgeranylgeraniol acts as a highly specific inhibitor of protein geranylgeranylation, while 3-vinylgeranylgeraniol restores protein geranylgeranylation in cells. This study indicates that certain prenyl alcohol analogues can act as prenyltransferase inhibitors in situ, via a novel prodrug mechanism. These analogues may prove to be valuable tools for investigating the therapeutic consequences of inhibiting geranylgeranylation relative to farnesylation. Furthermore, the 3-vinyl alcohol analogues can inhibit transformed cell growth through a mechanism not involving prenyltransferase inhibition.
Inhibition of glucose- and calcium-induced insulin secretion from βTC3 cells by novel inhibitors of protein isoprenylation
Amin, Rajesh,Chen, Hai-Qing,Tannous, Marie,Gibbs, Richard,Kowluru, Anjaneyulu
, p. 82 - 88 (2002)
The majority of low molecular weight G proteins undergoes a series of post-translational modification steps, e.g., isoprenylation, at their C-terminal cysteine, which seem to be critical for the transport of the modified proteins to the membrane sites for interaction with their respective effector proteins. Using lovastatin, an inhibitor of mevalonic acid, and hence, isoprenoid biosynthesis, we demonstrated previously that protein isoprenylation is critical for physiological insulin secretion from normal rat islets. Herein, we used more selective synthetic inhibitors of protein prenylation to examine their effects on glucose- and calcium-mediated insulin secretion from βTC3 cells. Both 3-allyl- and vinylfarnesols, which inhibit and/or modulate protein farnesyl transferases, significantly (80-95%) inhibited glucose-and KCI-stimulated insulin secretion from these cells. In a similar manner, the allyl and vinyl forms of geranylgeraniol, reagents targeted toward protein geranylation, attenuated insulin secretion elicited by glucose and KCI. Furthermore, manumycin A, a natural inhibitor of protein farnesylation, and geranylgeranyl transferase inhibitor-2147 (GGTI-2147), a peptidomimetic inhibitor of protein geranylgeranylation, also inhibited glucose-and KCI-induced insulin secretion to comparable degrees. Treatment of βTC3 cells with either 3-vinylfarnesol or 3-vinyl geranylgeraniol resulted in accumulation of unprenylated proteins in the cytosolic fraction. These data further support our original formulation that inhibition of isoprenylation of small molecular weight G proteins might impede their interaction with their putative effectors, which may be required for physiological insulin secretion.
Identification of CDP-archaeol synthase, a missing link of ether lipid biosynthesis in Archaea
Jain, Samta,Caforio, Antonella,Fodran, Peter,Lolkema, Juke S.,Minnaard, Adriaan J.,Driessen, Arnold J.M.
, p. 1392 - 1401 (2014/12/11)
Archaeal membrane lipid composition is distinct from Bacteria and Eukarya, consisting of isoprenoid chains etherified to the glycerol carbons. Biosynthesis of these lipids is poorly understood. Here we identify and characterize the archaeal membrane prote
Modular synthesis of diphospholipid oligosaccharide fragments of the bacterial cell wall and their use to study the mechanism of moenomycin and other antibiotics
Gampe, Christian M.,Tsukamoto, Hirokazu,Wang, Tsung-Shing Andrew,Walker, Suzanne,Kahne, Daniel
experimental part, p. 9771 - 9778 (2012/02/15)
We present a flexible, modular route to GlcNAc-MurNAc-oligosaccharides that can be readily converted into peptidoglycan (PG) fragments to serve as reagents for the study of bacterial enzymes that are targets for antibiotics. Demonstrating the utility of these synthetic PG substrates, we show that the tetrasaccharide substrate lipid IV (3), but not the disaccharide substrate lipid II (2), significantly increases the concentration of moenomycin A required to inhibit a prototypical PG-glycosyltransferase (PGT). These results imply that lipid IV and moenomycin A bind to the same site on the enzyme. We also show the moenomycin A inhibits the formation of elongated polysaccharide product but does not affect length distribution. We conclude that moenomycin A blocks PG-strand initiation rather than elongation or chain termination. Synthetic access to diphospholipid oligosaccharides will enable further studies of bacterial cell wall synthesis with the long-term goal of identifying novel antibiotics.
Transpeptidase-mediated incorporation of d-amino acids into bacterial peptidoglycan
Lupoli, Tania J.,Tsukamoto, Hirokazu,Doud, Emma H.,Wang, Tsung-Shing Andrew,Walker, Suzanne,Kahne, Daniel
supporting information; experimental part, p. 10748 - 10751 (2011/09/13)
The β-lactams are the most important class of antibiotics in clinical use. Their lethal targets are the transpeptidase domains of penicillin binding proteins (PBPs), which catalyze the cross-linking of bacterial peptidoglycan (PG) during cell wall synthesis. The transpeptidation reaction occurs in two steps, the first being formation of a covalent enzyme intermediate and the second involving attack of an amine on this intermediate. Here we use defined PG substrates to dissect the individual steps catalyzed by a purified E. coli transpeptidase. We demonstrate that this transpeptidase accepts a set of structurally diverse d-amino acid substrates and incorporates them into PG fragments. These results provide new information on donor and acceptor requirements as well as a mechanistic basis for previous observations that noncanonical d-amino acids can be introduced into the bacterial cell wall.
Towards the synthesis of bisubstrate inhibitors of protein farnesyltransferase: Synthesis and biological evaluation of new farnesylpyrophosphate analogues
Duez, Stéphanie,Coudray, La?titia,Mouray, Elisabeth,Grellier, Philippe,Dubois, Jo?lle
experimental part, p. 543 - 556 (2010/05/02)
Protein farnesyltransferase (FTase) has recently appeared as a new target of parasitic diseases, a field poor in drugs in development. With the aim of creating new bisubstrate inhibitors of FTase, new farnesyl pyrophosphate analogues have been studied. Fa
Efficient synthesis and biological evaluation of demethyl geranylgeranoic acid derivatives
Wada, Akimori,Wang, Fei,Suhara, Yoshitomo,Yamano, Yumiko,Okitsu, Takashi,Nakagawa, Kimie,Okano, Toshio
experimental part, p. 5795 - 5806 (2010/09/18)
Synthetic retinoids have generated in the fields of dermatology and oncology due to their potent anti-proliferative and differentiation activities. We efficiently synthesized different demethyl geranylgeranoic acid (GGA) analogs, and evaluated their biological activities. Among the demethyl analogs synthesized, 3-demethyl derivative exhibited the highest anti-proliferative activity in HL-60 cells. In addition, a 3-demethyl derivative induced apoptosis more potently than 9Z-retinoic acid. These activities were due to the high binding affinity of 3-demethyl derivative for retinoid receptors. We found that, in a conjugated polyene system combined with a methyl substituent, the position of the methyl played an important role in the regulation of gene transcription and apoptosis-inducing activity. These results provided useful information on the structure-activity relationships of GGA derivatives that function as acyclic retinoic acid analogs. This information is likely to be useful in the development of new anti-cancer drugs.
Biosynthesis of indole diterpenes, emindole, and paxilline: Involvement of a common intermediate
Fueki, Shuhei,Tokiwano, Tetsuo,Toshima, Hiroaki,Oikawa, Hideaki
, p. 2697 - 2700 (2007/10/03)
The key step for construction of the carbon skeleton in the indole diterpenes, paxilline, and emindole DA was examined. Intact incorporation of multiply 2H-labeled 3-geranylgeranylindole into two different fungal metabolites proves 3-geranylgeranylindole to be a biosynthetic intermediate. These results give evidence that indole diterpenes are biosynthesized via epoxidation of a common intermediate, and the subsequent cationic cyclization, analogous to those in the steroid biosynthesis.
Coupling of isoprenoid triflates with organoboron nucleophiles: synthesis and biological evaluation of geranylgeranyl diphosphate analogues.
Mu, YongQi,Eubanks, Lisa M,Poulter, C Dale,Gibbs, Richard A
, p. 1207 - 1219 (2007/10/03)
The Suzuki coupling reaction has been used to introduce a methyl group derived from commercially available methylboronic acid into a vinyl triflate. This has led to a concise synthesis of all-trans-geranylgeraniol, with the key step being the palladium-catalyzed, silver-mediated methylation of triflate to give ethyl geranylgeranoate. This coupling protocol has also been used to produce the novel geranylgeranyl diphosphate (GGPP) analogue 3-phenyl-3-desmethylgeranylgeranyl diphosphate (3-PhGGPP, ). Our previously developed organocuprate coupling protocol has been used to introduce the cyclopropyl and tert-butyl moieties into the 3-position of vinyl triflate. The four GGPP analogues 3-vinyl-3-desmethylgeranylgeranyl diphosphate (3-vGGPP, ), 3-cyclopropyl-3-desmethylgeranylgeranyl diphosphate (3-cpGGPP, ), 3-tert-butyl-3-desmethyl-geranylgeranyl diphosphate (3-tbGGPP, ), and were then evaluated as potential inhibitors of recombinant yeast protein-geranylgeranyl transferase I (PGGTase I). The potential mechanism-based inhibitors 3-vGGPP and 3-cpGGPP did not exhibit time-dependent inactivation of PGGTase I. Instead, both analogues were alternative substrates, in accord with the interaction of the corresponding farnesyl analogues 3-vFPP and 3-cpFPP with PFTase. The tert-butyl and phenyl analogues were not substrates, but were instead competitive inhibitors of PGGTase I. Note that all four of the GGPP analogues were bound less tightly by the enzyme than the natural substrate, in contrast to the behavior of the 3-substituted FPP analogues.
