334687-36-4Relevant academic research and scientific papers
A protecting group-free synthesis of deazathiamine: A step toward inhibitor design
Zhao, Hong,De Carvalho, Luiz Pedro S.,Nathan, Carl,Ouerfelli, Ouathek
, p. 6472 - 6474 (2010)
The discovery of 3-deazathiamine diphosphate (deazaThDP) as a potent inhibitor analog of the cofactor thiamine diphosphate (ThDP) has highlighted the need for an efficient and scalable synthesis of deazaThDP. Such a method would facilitate development of analogs with the ability to inhibit individual ThDP-dependent enzymes selectively. Toward the goal of developing selective inhibitors of the mycobacterial enzyme 2-hydroxy-3-oxoadipate synthase (HOAS), we report an improved synthesis of deazaThDP without use of protecting groups. Tribromo-3-methylthiophene served as a versatile starting material whose selective functionalization permitted access to deazaThDP in five steps, with potential to make other analogs accessible in substantial amounts.
Differences in the efficiency of 3-deazathiamine and oxythiamine pyrophosphates as inhibitors of pyruvate dehydrogenase complex and growth of HeLa cells in?vitro
Grabowska, Ewa,Czerniecka, Magdalena,Czy?ewska, Urszula,Zambrzycka, Aneta,?otowski, Zenon,Tylicki, Adam
, p. 122 - 129 (2020/11/16)
Oxythiamine (OT) and 3-deazathiamine (DAT) are the antimetabolites of thiamine. The aim of study was to compare the effects of OT and DAT pyrophosphates (-PP) on the kinetics of mammalian pyruvate dehydrogenase complex (PDHC) and the in?vitro culture of HeLa cells. The kinetic study showed that 3-deazathiamine pyrophosphate (DATPP) was a much stronger competitive inhibitor (Ki = 0.0026 μM) of PDHC than OTPP (Ki = 0.025 μM). Both Ki values were much lower versus K m for thiamine pyrophosphate (0.06 μM). However, DATPP added to the culture medium for the HeLa cells culture did not hamper the rate of cell growth and showed not significant impact on the viability of the cells, whereas OTPP and OT showed a significant cytostatic effect. The differences between the thiamine antivitamins in their effect on cell growth in?vitro may be due to differences in physicochemical properties and difficulty in DAT transport across the cell membrane.
Design and synthesis of thiamine analogues to study their binding to the ECF transporter for thiamine in bacteria
Monjas,Swier,De Voogd,Oudshoorn,Hirsch,Slotboom
, p. 966 - 971 (2016/06/09)
Energy-coupling factor (ECF) transporters mediate the uptake of vitamins in bacteria. Given that these ECF transporters are not present in eukaryotic cells, they represent an interesting target for the development of novel antibiotics. Here, we present the design and synthesis of compounds that bind to ThiT, the substrate-binding domain of the ECF transporter for thiamine from Lactococcus lactis. We modified the methyl substituent of the pyrimidine ring of thiamine, in order to evaluate its contribution to the binding affinity. Our results indicate that as long as a hydrophobic substituent is maintained, the high binding affinity is almost unchanged, opening up opportunities for the design of selective compounds.
Structure-based design of potent small-molecule binders to the S-component of the ECF transporter for thiamine
Swier, Lotteke J.Y.M.,Monjas, Leticia,Guskov, Albert,De Voogd, Alrik R.,Erkens, Guus B.,Slotboom, Dirk J.,Hirsch, Anna K. H.
, p. 819 - 826 (2015/03/30)
Energy-coupling factor (ECF) transporters are membrane-protein complexes that mediate vitamin uptake in prokaryotes. They bind the substrate through the action of a specific integral membrane subunit (S-component) and power transport by hydrolysis of ATP
