We have prepared three analogues of 16 alpha-fluoroestradiol (FES) substituted either with an 11 beta-methoxy group (1, 11 beta-MeO-FES), an 11 beta-ethyl group (2, 11 beta-Et-FES), or a 17 alpha-ethynyl group (3, 17 alpha-ethynyl-FES). These substituents all lower the binding of FES to the serum proteins alphafetoprotein and sex steroid binding protein, but their effect on estrogen receptor binding varies: Receptor binding is increased by the 11 beta-ethyl and 17 alpha-ethynyl groups, but decreased by the 11 beta-methoxy group. These substituents also have a parallel effect on the lipophilicity, and hence the nonspecific binding estimated for these compounds. All three compounds were prepared in fluorine-18 labeled form, at effective specific activities of 90-1600 Ci/mmol, by fluoride ion displacement reactions as done previously with FES. Tissue distribution studies in immature rats show high uptake selectivity by target tissue (uterus) and effective competition by an excess of unlabeled estradiol. Percent injected dose per gram values (% ID/g) at 1 h are 6% for 11 beta-MeO-FES and 11-13% for 11 beta-Et-FES and 17 alpha-ethynyl-FES (FES itself has a % ID/g of 9%). Uptake selectivity in terms of uterus to blood or muscle ratios at 1 h is highest for 11 beta-MeO-FES and 17 alpha-ethynyl-FES (43-149). Metabolic consumption studies show that most activity in uterus is unmetabolized and in blood is rapidly and nearly completely metabolized. In muscle, FES and the substituted estrogens show intermediate levels of metabolic consumption; in some cases activity in muscle extracts is nearly unmetabolized. Thus, the substituents on FES cause major alterations in receptor and nonreceptor binding affinity, uptake efficiency and selectivity, and extent of metabolism. It is not readily clear, however, whether the alterations in uptake efficiency and selectivity are the result of differences in receptor or nonreceptor binding or lipophilicity, or altered patterns of metabolism. Nevertheless, these compounds should be useful in providing a spectrum of uptake properties that could be used for imaging different estrogen-receptor-containing structures.

No abstract

Amino acids esterified to the ribose group of 5'-adenylic acid (AMP) constantly migrate between the 2' and 3' positions of the ribose at a rate of several times per second, which is slower than the rate of peptide-bond synthesis (15-20 per sec). Because the contemporary protein-synthesizing system only incorporates amino acids into protein when they are at the 3' position of the AMP at the terminus of tRNA, the value of the equilibrium constant relative to the 2' and 3' positions is of considerable interest. Differences between D and L isomers in this regard might be especially revealing. We have used N-acetylaminoacyl esters of AMP as models for the 3' terminus oftRNA and find that glycine and the L amino acids consistently distribute predominantly to the 3' position (=67% 3', o33% 2'), but D amino acids distribute to that position generally to a lesser extent and in a manner inversely related to the hydrophobicity of the amino acid side chain. This consistency of the L amino acid preference for the 3' position, combined with the inconsistency of the D amino acid preference, may be one reason for the origin of our contemporary protein-synthesizing system, which forms the peptide bond preferentially with L amino acids and only when they are in the 3' position of the fibose moiety of the AMP residue at the 3' terminus of every tRNA.For all practical purposes, in vivo template-directed protein synthesis proceeds with the incorporation of only L amino acids. This is true in spite of the fact that there are a number of reports that D amino acids can participate in essentially all of the reactions involved, including peptide-bond synthesis (1-3). The preference for L appears to be due to preferences at each of several steps, resulting in a cumulative preference for the L isomer of 4 orders of magnitude. A basic question remains, though, as to why these enzymatic preferences for the L amino acids have evolved. In fact, it has been difficult to show how abiological reactions could result in preferential synthesis or degradation of one isomer. Stereoselective reactions, which could have served as bases for the origin and evolution of the protein-synthesizing system, would seem more fruitful subjects of study. In that vein Profy and Usher (4, 5) have shown some stereoselectivity for the L isomer in esterification reactions with amino acids and oligo-or polynucleotides. They also have discussed in some detail the fact that amino acids esterified to ribonucleotides constantly migrate between the 2' and 3' positions ofthe ribose and have emphasized the possible significance of studies on the differential distribution of D and L amino acids between the 2' and 3' positions. The interest is in the fact that amino acids esterified to the AMP residue at the 3' terminus of the tRNA are constantly migrating back and forth several times a second (6), and the amino acid is only incorporated into protein when it is in the 3' position (7-10). Furthermore, it was established by Taiji et al. (6) that the rate of amino acid trans...

This minireview is a summary of the basic concepts and pieces of experimental evidence supporting a hypothesis that suggests a mechanism whereby purine monoribonucleotides having D-ribose may be able to preferentially catalyze the synthesis of L-amino acid peptides. The proposed mechanism involves a 2'-3' diaminoacyl intermediate and the preference accrues from several factors that favor the L-isomer, principally for hydrophobic amino acids. Although the hypothesis has not been fully tested, some crucial evidence has been published. Other pieces of evidence are now being submitted or are in press for publication and still other experiments, principally on the step of peptide bond formation, are in the process of being carried out. The purpose of a review at this point is to present the hypothesis to the scientific community in hopes of generating discussion, suggestions, and evaluation by other workers. Should the hypothesis prove correct, it may represent the most primitive and fundamental relationship between the nucleic acid and protein systems. In addition, it would represent another important example of the catalytic ability of RNA.

Dialkyl-l-lithio-l -(phenylthio)allenes (1) add efficiently to ketones only on warming to -20 "C or above; the adducts are readily cyclised by acid, or several other electrophiles, to produce highly substituted 2,5-di hydro-oxoles.We have reported previously1 that the allenyl-lithium (1, R1 = H) is useful in the preparation of a-phenylthioenones. Initial attempts to extend this preparation, to other than methyl ketones, by use of 3,3-dialkylallenyl-lithiums~ (1, R1 = alkyl), were only partially successful since the yields of the ketone adducts (2, R1, R2 = alkyl) were poor (20-30%). Since large proportions of both the quenched allenyl-lithium and ketone were recovered unchanged, even after prolonged reaction times, it was evident that competitive enolisation was the problem.Removing hexamethylphosphoric triamide