The influence of the negative neighboring group has been quantified kinetically using hydrocarbon monomers containing oxygen and sulfur. Rate constants were determined for the ADMET polymerization of bis(4-pentenyl) ether (3), bis(5-hexenyl) ether (4), bis(4-pentenyl) sulfide (5), and bis(5-hexenyl) sulfide (6) using both Schrock's catalyst Mo(CHCMe2Ph)(N-2,6-C6H3-i-Pr2)(OCMe(CF3)2)2 [Mo] and Grubbs' phenyl version of the ruthenium metathesis catalyst RuCl2(CHPh)(PCy3)2 [Ru]. Both catalysts experience the effect of functional group presence. Further, a pure hydrocarbon version of the negative neighboring group effect has also been demonstrated using the monomer 1,5-hexadiene. In this case, [Mo] catalysis produces linear 1,4-polybutadiene in a reaction that exhibits a typical ADMET rate constant and activation energy. On the other hand, [Ru] catalysis leads principally to the formation of cyclic compounds rather than linear polymers. This change in mechanism for [Ru] catalysis can be attributed to multiple factors including the dissociation of phosphine ligands, thermodynamic parameters, and π complexation with the adjacent olefin in the monomer, a phenomenon similar to heteroatom nonbonded electron complexation.

Novel analogues of the naturally occurring purine nucleosides were synthesized in the thiazolo[4,5-d]pyrimidine ring system to determine the immunomodulatory effects of insertion of a sulfur atom in place of nitrogen at position 7 of the purine ring. In particular, 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H) -dione (7, guanosine analogue), 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,5,7(3H,4H,6H) trione (8, xanthosine analogue), 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (10, inosine analogue), and 7-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidin-2(3H)-one (32, adenosine analogue) were prepared, as well as the 8-mercaptoguanosine (14) and 6-mercaptoguanosine (17) analogues. Single-crystal X-ray studies confirmed the structural assignment of 17 and 32 as having the beta-configuration with the site of glycosylation at N3. The nucleosides were evaluated for their ability to potentiate various murine immune functions in direct comparison to the known active agents 8-bromoguanosine (1), 8-mercaptoguanosine (2), and 7-methyl-8-oxoguanosine (3). Two of the guanosine analogues, 7 and 14, were found to exhibit significant immunoactivity relative to the positive control compounds (1-3), while the adenosine, inosine, xanthosine, and 6-mercaptoguanosine analogues were devoid of activity. Compound 7 exhibited greater immunoactivity than any of the other guanosine analogues and derivatives in all test systems. Specifically, 7 was shown to be about twice as potent as 3 in the murine spleen cell mitogenicity assay. In addition, treatment with 7 produced about a 4-fold increase in natural killer cell cytotoxicity, while treatment with 3 afforded a 3-fold increase over controls. Finally, 7 provided excellent protection (92% survivors compared to 0% for placebo controls) against Semliki Forest virus in mice. Induction of interferon may account for the major mode of action of these guanosine analogues.

The Edinburgh Handedness Inventory (EHI) was administered to 600 students from two urban secondary schools and two universities. The respondents were categorized by age (three groups) and sex. The questionnaire was re-administered to a sample of 69 respondents after an interval of 4 weeks. Principal axes factor analysis of the test and retest data showed the EHI to have a single factor which exhibited a high stability over the test-retest time period. However, one item (the use of scissors) was relatively unstable in relation to the derived (handedness) factor. A simple factor structure was also extracted from each 'age x sex' data set. The handedness factor showed a high stability across both age and sex. However, three items (knife, broom and box-lid) did not load well on the handedness factor and were generally unstable in relation to this factor. When assessing handedness with this questionnaire it is recommended that responses to particular items be weighted according to their stability and their contribution to the handedness factor. Alternative scoring procedures would seriously affect the otherwise high validity that this questionnaire has for assessing handedness.Any investigation of cerebral and behavioural asymmetries usually requires some assessment of handedness. For reasons of ease and quickness of administration, the 'handedness questionnaire' is often used for this purpose (see Annett, 1970;Oldfield, 1971 ;Touwen, 1972). Given the wide use of such questionnaires, it is somewhat surprising that only a limited number of studies have examined their factor (construct) validity. One questionnaire which has received some attention in this regard is the Edinburgh Handedness Inventory (EHI) (Oldfield, 1971). White & Ashton (1976), using a slightly modified form of the EHI, found the questionnaire to have a simple factor structure with one major factor which could be called handedness and a second minor factor unrelated to handedness. A more recent study by Bryden (1977) yielded similar results.No investigator has, to date, supplied evidence that this factor structure is maintained between test and retest performance, across age and between the sexes. Bryden (1977) mentioned that 'preliminary calculations revealed approximately the same factor structure for men and women', but specific details were not reported. McMeekan & Lishman (1975) reported on the test-retest reliability of the EHI in terms of changes in the response score distributions. However, it is not known whether the variability in response distributions was due to an instability of the factor structure of the questionnaire, or due to variability arising from sources other than handedness (see also Raczkowski et al., 1974;Coren & Porac, 1978). The present study extends these earlier reports and is specifically concerned with examining the factor stability, and hence the construct validity, of the EHI as a function of test-retest performance, age and sex. MethodThe EHI consists of 10 items which may be summarized as follows: (1) writing, (2) ...

Synthesis of the pyrazolo[3,4‐d]pyrimidin‐3‐one congeners of guanosine, adenosine and inosine is described. Glycosylation of 3‐methoxy‐6‐methylthio‐1H‐pyrazolo[3,4‐d]pyrimidin‐4(5H)‐one (13) with 1‐O‐acetyl‐2,3,5‐tri‐O‐benzoyl‐D‐ribofuranose (16) in the presence of boron trifluoride etherate gave 3‐methoxy‐6‐methylthio‐1‐(2,3,5‐tri‐O‐benzoyl‐β‐D‐ribofuranosyl)pyrazolo[3,4‐d]pyrimidin‐4(5H)‐one (17) which, after successive treatments with 3‐chloroperoxybenzoic acid and methanolic ammonia, afforded 6‐amino‐3‐methoxy‐1‐β‐D‐ribofuranosylpyrazolo[3,4‐d]pyrimidin‐4(5H)one (18). The guanosine analog, 6‐amino‐1‐β‐D‐ribofuranosylpyrazolo[3,4‐d]pyrimidine‐3,4(2H,5H)‐dione (21), was made by sodium iodide‐chlorotrimethylsilane treatment of 6‐amino‐3‐methoxy‐1‐(2,3,5‐tri‐O‐acetyl‐β‐D‐ribofuranosyl)pyrazolo[3,4‐d]pyrimidin‐4(5H)one (19), followed by sugar deprotection. Treatment of the adenine analog, 4‐amino‐1H‐pyrazolo[3,4‐d]pyrimidin‐3(2H)‐one (11), according to the high temperature glycosylation procedure yielded a mixture of N‐1 and N‐2 ribosyl‐attached isomers. Deprotection of the individual isomers afforded 4‐amino‐3‐hydroxy‐1‐βribofuranosylpyrazolo‐[3,4‐d]pyrimidine (26) and 4‐amino‐2‐β‐D‐ribofuranosylpyrazolo[3,4‐d]pyrimidin‐3(7H)‐one (27). The structures of 26 and 27 were established by single crystal X‐ray diffraction analysis. The inosine analog, 1‐β‐D‐ribofuranosylpyrazolo[3,4‐d]pyrimidine‐3,4(2H,5H)‐dione (28), was synthesized enzymatically by direct ribosylation of 1H‐pyrazolo[3,4‐d]pyrimidine‐3,4(2H,5H)‐dione (8) with ribose‐1‐phosphate in the presence of purine nucleoside phosphorylase, and also by deamination of 26 with adenosine deaminase.

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Several guanosine analogues were synthesized in the pyrazolo[3,4-d]pyrimidine ring system with various substituents at the 3-position. The new analogues prepared here include the CH3 (2-amino-3-methyl-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4 (5H)-one, 13a), the phenyl (2-amino-3-phenyl-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4 (5H)-one, 13b), and the NH2 (3,6-diamino-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)- one, 17) substituted derivatives. These new agents, as well as several other 3-substituted derivatives including H, Br, OCH3, COOH, and oxo, were evaluated for their ability to potentiate certain murine immune functions relative to the known active agent 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H) -dione (4, 7-thia-8-oxoguanosine). The biological evaluation included the (1) ex vivo determination of increased natural killer cell function and (2) in vivo antiviral protection against a lethal challenge of Semliki Forest virus. The 3-unsubstituted (5a) and the 3-bromo (5c) derivatives were found to be the most active immunopotentiators in this series.

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Several sugar-modified nucleoside derivatives of the purine analogue 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7-dione (1) were synthesized. Phosphorylation of 1 using POCl3 resulted in 5'-monophosphate 2, which was subsequently converted to 3',5'-cyclic phosphate 3, by reported methods. 5'-Sulfamoyl derivative 4 was synthesized by treatment of the 2,3-O-isopropylidene derivative of 1 with chlorosulfonamide followed by acid deprotection. Compounds 5-7, the 5'-deoxy, the tri-O-acetyl, and the 2'-deoxy derivatives of 1, respectively, were synthesized by glycosylation of 5-aminothiazolo[4,5-d]pyrimidine-2,7-dione, the aglycon of 1, with the appropriate sugar moieties, utilizing the Vorbruggen procedure. Oxidative cleavage of the C2'-C3' bond in 1 followed by reduction with sodium borohydride led to "seco" analogue 8. Nucleosides 2-8 were evaluated for antiviral activity in vivo against the Semliki Forest virus. The activity of compounds 2, 5, and 7 were similar to that of 1. Cyclic phosphate 3 was toxic at the high dose and weakly active at the lower dose. Compounds 4, 6, and 8 were inactive in this system.