Analogs of 2'(3')-O-L-phenylalanyladenosine as substrates and inhibitors of ribosomal peptidyltransferase

Abstract

The chemical syntheses of 2'(3')-O-(L-3-amino-3-phenylpropionyl)adenosine (2e), the corresponding D stereoisomer 2f, 2'(3')-O-(DL-phenylglycyl)adenosine (2g), 2'(3')-O-(N-benzylglycyl)adenosine (2h), and 9(2-O-L-phenylalanyl-beta-D-xylofuranosyl)adenine (3b) are described. Compounds 2e-h were obtained by acylation of 5'-O-(4-methoxytrityl)adenosine with the appropriate N-benzyloxycarbonyl or N-tert-butoxycarbonyl amino acids with dicyclohexylcarbodiimide in pyridine. The corresponding reaction of N-(benzyloxycarbonyl)-D-phenylglycine led to an almost complete racemization of the aminoacyl residue (compounds 2c and 2g). Subsequent chromatographic separation and deprotection of intermediates 2a-d afforded the desired target derivatives 2e-h. Product 3b was obtained by a similar acylation of 9-(3,5-O-isopropylidene-beta-D-xylofuranosyl)adenine with N-(benzyloxycarbonyl)-L-phenylalanine, followed by deblocking. The NMR spectra of 2' and 3' isomers of stereoisomers 2a and 2b are discussed. Compounds 2g and 3b are both substrates and inhibitors of Escherichia coli ribosomal peptidyltransferase, although the activity of 3b is low. Derivatives 2e,f,h do not accept AcPhe from N-AcPhe-tRNA in a peptidyltransferase-catalyzed reaction, but they inhibit the puromycin reaction in the same system. The order of inhibitory activity is 2e greater than 2f greater than 2h. The implications of these findings for the mechanism of peptidyltransferase and comparison of the latter with the action of chymotrypsin are discussed.

Donor site of ribosomal peptidyltransferase: investigation of substrate specificity using 2'(3')-O-(N-acylaminoacyl)dinucleoside phosphates as models of the 3'-terminus of N-acylaminoacyl transfer ribonucleic acid

“…However, it should be emphasized that in the virtual absence of suitable donor models with fixed conformation (for comparison, see models for the A site; ¿emlicka & Bhuta, 1979), the question of conformation preference at the P site cannot be answered unambiguously. On the other hand, it is of considerable interest that an 8-bromoadenosine residue in the syn conformation is presumably capable of forming an assymetrical complementary pair (by using two hydrogen bonds)…”

A Chiral Rhodium Carboxamidate Catalyst for Enantioselective C−H Amination

“…In one case, the isolated heterocycle (entry 1) has been converted to the corresponding (S)-N-CBz-βamino acid following a two-step protocol (see Figure 1). 11 This correlation establishes the absolute stereochemistry of the product in entry 1 as S. 12,13 Cognizant of the fact that aziridination of homoallyl sulfamates is highly favored with Rh-tetracarboxylate catalysts, we were surprised to observe the five-membered sulfamidate as the major product in the reaction promoted by Rh 2 (S-nap) 4 (entry 1, Table 2). 1b This particular result is striking given the strong preference for sulfamate esters to yield six-membered ring heterocycles and the fact that the closely related Rh 2 (PTPI) 4 catalyst affords primarily the aziridine.…”

“…In one case, the isolated heterocycle (entry 1) has been converted to the corresponding ( S )- N -CBz-β-amino acid following a two-step protocol (see Figure ) . This correlation establishes the absolute stereochemistry of the product in entry 1 as S . , …”

Effect of P and A site substrates on the binding of a macrolide to ribosomes. Analysis of the puromycin-induced stimulation

“…According to Vasquez [lo] and Bhuta [16], adenosyl phenylalanine can be considered as a simple analogue of puromycin : a mixture of adenosine and phenylalanine, adenosine alone or dimethyladenosine alone enhance the binding of [3H]dihydrorosaramicin (Fig. 4).…”