Mechanism of action of sparsomycin in protein synthesis

Abstract

Before CI isomerizes to C*I, we detect a competitive phase of inhibition (Ki = k5/k4 = 0.05 microM) which eventually, by increasing the concentration of I, becomes linear mixed noncompetitive and involves C*I in place of CI. The equilibration of C and I according to reaction 2 is much slower than the equilibration between C and S in reaction 1 (time-dependent inhibition). The inactivation plots obey reaction 2 and allow us to estimate k6 as equal to 2.2 min-1. The isomerized C*I, free of excess I, can be studied as a mixture with complex C. From the kinetics of the regeneration of C from C*I, in the presence of puromycin, we can estimate k7 to be between 0.22 min-1 and 0.06 min-1. Although the isomerized C*I survives after adsorption on cellulose nitrate filter disks, it does not survive after gel chromatography on a Sepharose CL-4B column but is converted quantitatively to complex C containing D of unchanged reactivity. This result does not support the proposed [Flynn, G. A., & Ash, R. J., (1990) Biochem. Biophys. Res. Commun. 166, 673-680] chemical reaction between D and I toward new products. The isomerized C*I can be obtained not only from the already-made complex C but also de novo from D, R, and M. In the latter case, the reactions which lead to C are represented by the following hypothetical scheme: D + R + M in equilibrium with DRM or C (binding reaction). When C*I is formed de novo, this reaction is coupled to reaction 2 and the ultimate product is a mixture of C and C*I.(ABSTRACT TRUNCATED AT 250 WORDS)

Dehydrogenative alkenylation of uracils via palladium-catalyzed regioselective C–H activation

“…2 The C5-position of pyrimidines is the location of choice for structural modification because this site is not involved in Watson-Crick base pairing. 3 5-Alkenyluracils have been shown to exhibit antitumor 4 and potent antiviral activities. 5 Structure-activity relationship (SAR) studies demonstrated that the antiviral activity was enhanced when the C5-position was equipped with an unsaturated, E -configured substituent bearing a hydrophobic electronegative functionality (such as an ester) in conjugation with the pyrimidine ring.…”

Pd-Catalyzed Dehydrogenative Cross-Coupling of 1,4-Quinones with N,N′-Dialkyluracils

“…1), demonstrated suppression of pituitary-ovarian axis in cynomolgus monkeys via chronic oral administration. [12] Other examples include sparsomycin which is an antibiotic and a potential antitumour agent, [13] Zidovudine which is a HIV drug, [14] and Pentothal which is often used as a general anaesthetic [15] (Fig. 1).…”

“…Ethyl acetate gave the best yield while solvents such as 1,4-dioxane, acetonitrile, and toluene afforded moderate yields of the product. NMP, DMAc, and t-amyl alcohol (t-AmOH) afforded poor results (Table 1, entries [13][14][15][16][17][18][19][20][21][22][23][24].…”

Synthesis and Activity of Pyrimidinylpropenamide Antibiotics: The Alkyl Analogues of Sparsomycin

“…The biological activity resulted from its ability to inhibit the peptide bond-forming step of protein biosynthesis by interacting with the large ribosomal subunit. [7][8][9][10] These potentially important biological activities have made 3 an attractive target for a potential antineoplastic compound. 11) Since thê rst synthetic study of sparsomycin in 1976, 12) synthetic studies of sparsomycin, [13][14][15] total synthesis, [16][17][18] biosynthesis, 19,20) and structure-activity relationship studies [21][22][23][24][25][26][27] have been widely reported.…”