Nonclassical Antimetabolites XX

Simple models of nucleic acid interactions. 2. Aminoacyl derivatives of "bridged" nucleosides: synthesis of 2'(3')-O-L-phenylalanyl- and 2'(3')-O-L-leucyl-1,2-di(adenosin-N6-yl)ethane

“…Calcd for CggHgoNioOn: C, 72.01; H, 5.69; N, 9.88. Found: C, 71.76; H, 5.77; N, 9.60. Evaporation of peak C afforded ditrityl derivative III (6.3 g, 55%): homogeneous on TLC (S3); UV max (ethanol) 274 nm (t 33 500), min 248 (20 200); NMR (CDCI3) b 8.18 and 8.10 (2 s, 2, Hg), 7.97 and 7.55 (2 s, 2, the signal at 7.55 is partially overlapped with phenyl), 7.55-6.70 (m, 28,4-methoxytrityl), 6.30 and 6.08 (2 broad s, 2, Hr), 3.64 and 3.49…”

“…Figure3. Chromatography of the products from the condensation of ZLeuOH with compound III using DCC in pyridine on 50 X 5 cm silica gel column (see Experimental Section).…”

Nonclassical Antimetabolites XXIV

“…When the sodium salt of 3-( 5'-hydroxypentyl)-5fluorouracil phosphate ( V b ) was assayed as an inhibitor of thymidylate synthetase as previously described (2,13), it showed no inhibition a t a concentration of 6 m M in the presence of 0.04 m M 2'-deoxyuridylate (I). Thus, V b was even less effective than 1-(5'-hydroxypentyl)uracil phosphate (IIIa); this result indicated that Vb cannot reorient to a suitable conformation for binding as was the case for nucleotides derived from isoadenosine (14) or for 5-alkylpyrimidines when bound t o dihydrofolic reductase (15).…”

“…that when the phosphate group of I1 was not present, as in 5'-fluoro-2'-deoxyuridine, a 90,000-fold loss in binding t o this enzyme occurred (2). That 5-fluoro-2'-deoxyuridylate (11) was bound to thymidylate synthetase about 1000-fold better than the substrate (I) had been known previously (3,4).…”

Nonclassical Antimetabolites XXIII

“…In a previous paper of this series (5) it was reported that the nucleoside, 5-fluoro-2'-deoxyuridine (IV), was less effective than the nucleotide, 5-fluoro-2'-deoxyuridylate (V), as an inhibitor of thymidylate synthetase by a factor of 9 X 1 0 ' . In contrast, it has now been found that 1-(5'- Since the fluoro group of V causes 1000-fold better binding t o thymidylate synthetase than the substrate (I) (6, 7), it can be estimated that…”