Synthetic approaches to syn-diol containing biologically active compounds /

The deoxy derivative of pancratistatin 1.10 was prepared in good yield through the use of a [4+2] Diels-Alder cycloaddition and Bischler-Napieralski cyclization approach. The Bischler-Napieralski cyclization was shown to yield two additional side products 2.9, 2.10, however, under slightly modified hydrolysis conditions, the tetracyclic product 2.11 was obtained exclusively in greater than 84% yield. Initial screening of the di-hydroxylatgd derivative, and the other complementary pair analogue 1.10' previously prepared in our laboratories gave interesting results. Both of these compounds were shown to exhibit cytostatic activity; the mono-alcohol was marginally active while the di-hydroxylated analogue proved to be more potent although one to two magnitudes less potent than pancratistatin itself Human tumour cell line assay results indicated that the di-hydroxylated derivative exhibited selective cytotoxic inhibition in the following cell lines: non-small cell lung cancer line NCI-H226 (ED50 - 0.65 ^g/mL), leukemia cell lines CCRF-CEM (ED30 = 0.55 Hg/mL) and HL-60(TB) (ED50 = 0.89^ig/mL). Our results demonstrated that the pharmacophore is not a mono-alcohol, and that the minimum pharmacophore contains the hydroxyl group at the C4 position in addition to either, or both, of the hydroxyl groups present at C2 and C3.' The minimum pharmacophore has been narrowed to only three possibilities which are current synthetic targets in several research groups. The controlled Grignard addition to the tartaric acid derived bis-Weinreb amide 1.25 afforded a direct entry to a host of 1,4-diflferentiated tartaric acid derived intermediates (2.12-2.18). This potentially usefiil methodology was demonstrated through the efficient synthesis of the naturally occurring lactone 2.23, which bears the inherent syn-dio\ subunit. Based on this result, a similar approach to the synthesis of syn-dio\ bearing natural products looks very promising? A direct 2,3-diol desymmetrization method using TIPS-triflate was shown to be effective on the selective differentiation of Z,-methyl tartrate (and diisopropyl tartrate). The mono-silyl-protected intermediates 2.31 also proved to be useful when they were selectively differentiated at the 1,4-carboxyl position (2.35, 2.36) through the use of a borohydride reducing agent. Furthermore, the mono-silyl-protected derivative underwent periodate cleavage affording two synthetically useful a,P-unsaturated esters 2.43, 2.44, with one of esters being obtained via a silyl-migration method.''

Organizational commitment and perceived relatedness as correlates of the intention to continue officiating in track and field

The objectives of the present study were to explore three components of organizational commitment (affective [AC], normative [NC] and continuance [CC] commitment; Allen & Meyer, 1991), perceived relatedness (Oeci & Ryan, 1985; 2002), and behavioural intention (Ajzen, 2002) within the context of volunteer track and field officiating. The objectives were examined in a 2-phase study. Ouring phase 1, experts (N = 10) with domain familiarity assessed the item content relevance and representation of modified organizational commitment (OC; Meyer, Allen & Smith, 1993) and perceived relatedness (La Guardia, Oeci, Ryan & Couchman, 2000) items. Fourteen of 26 (p < .05) items were relevant (Aiken's coefficient V) and NC (M = 3.88, SO = .64), CC (M = 3.63, SD = .52), and relatedness (M = 4.00, SD = .93) items had mean item content-representation ratings of either "good" or "very good" while AC (M = 2.50, SD = 0.58) was rated "fair". Participants in phase 2 (N = 80) responded to items measuring demographic variables, perceptions of OC to Athletics Canada, perceived relatedness to other track and field officials, and a measure of intention (yiu, Au & Tang, 2001) to continue officiating. Internal consistency reliability estimates (Cronbach's (1951) coefficient alpha) were as follows: (a) AC = .78, (b) CC = .85, (c) NC = .80 (d) perceived relatedness = .70 and, (e) intention = .92 in the present sample. Results suggest that the track and field officials felt only minimally committed to Athletics Canada (AC M = 3.90, SD = 1.23; NC M = 2.47, SD = 1.25; CC M = 3.32; SD = 1.34) and that their relationships with other track and field officials were strongly endorsed (M = 5.86, SD = 0.74). Bivariate correlations (Pearson r) indicated that perceived relatedness to other track and field officials demonstrated the strongest relationship with intention to continue officiating (r = .346, p < .05), while dimensions of OC were not significantly related to intention (all p's > .05). Together perceived relatedness (j3 = .339, p = .004), affective commitment (j3 = -.1 53, p = .308), normative commitment (j3 = -.024, p = .864) and continuance commitment (j3 = .186, P = .287) contribute to the prediction of intention to continued officiating (K = .139). These relationships remained unaffected by the inclusion of demographic (j3age = -.02; P years with Athletics Canada = -.13; bothp's > .05) or alternative commitment (j3sport = -.19; P role = .15; Pathletes = .20; all p' s > .05) considerations. Three open-ended questions elicited qualitative responses regarding participants' reasons for officiating. Responses reflecting initial reasons for officiating formed these higher order themes: convenience, helping reasons, extension of role, and intrinsic reasons. Responses reflecting reasons for continuing to officiate formed these higher order themes: track and field, to help, and personal benefits. Responses reflecting changes that would influence continued involvement were: political, organizational/structural, and personal. These results corroborate the findings of previous investigations which state that the reasons underpinning volunteer motivations change over time (Cuskelly et al., 2002). Overall, the results of this study suggest that track and field officials feel minimal commitment to the organization of Athletics Canada but a stronger bond with their fellow officials. Moreover, the degree to which track and field officials feel meaningfully connected to one another appears to exert a positive influence on their intentions to continue officiating. As such, it is suggested that in order to promote continued involvement, Athletics Canada increases its focus on fostering environments promoting positive interactions among officials.

Expression and function of endothelin and its receptors in vascular adventitial fibroblasts

Objective: The adventitia has been recognized to play important roles in vascular oxidative stress, remodelling and contraction. We recently demonstrated that adventitial fibroblasts are able to express endothelin-1 (ET-1) in response to angiotensin II (ANG II). However, the mechanisms by which ANG II induces ET-1 expression are unknown. It is also unclear whether the ET-1 receptors are expressed in the adventitia. We therefore examined the role of oxidative stress in the regulation of ET-1. We also investigated the expression of both the ETA and ETB receptors and the roles of these two types of receptors in collagen synthesis and ET-1 clearance in adventitial fibroblasts. Methods and Results: Adventitial fibroblasts were isolated and cultured from the thoracic mouse aorta. Cells were treated with ANG II (lOOnM), ET-1 (lOpM), NADPH oxidase inhibitor apocynin (lOOfiM), the superoxide anion scavenger tempol (lOOfiM), the ANG II receptor antagonists (100[aM), losartan (AT| receptor) and PD 1233 19 (AT2 receptor), the ET-1 receptor antagonists (lOOuM), BQ123 (ETA receptor) and BQ788 (ETB receptor), and the ETB receptor agonist (lOOnM) Sarafotoxin 6C. ET-1 peptide levels were determined by ELISA, while ETA ,ETB and collagen levels were determined by Western blot. ANG II increased ET-1 peptide levels in a time-dependent manner reaching significance when incubated for 24 hours. NAD(P)H oxidase inhibitor, apocynin, as well as the superoxide scanverger, tempol, significantly reduced ANG Il-induced ET-1 peptide levels while over-expression of SOD1 (endogenous antioxidant enzyme) significantly decreased ANG Il-induced collagen I expression, therefore implicating reactive oxygen species in the mediation of ET-1. ANG II increased ETA receptor protein as well as collagen in a similar fashion, reaching significance after 4, 6, and 24 hours treatment. ANG II induced collagen was reduced while in the presence of the ETA receptor antagonist suggesting the role of the ETa receptor in the regulation of the extracellular matrix. ANG II treatment also increased ETB receptor protein levels in a time-dependent manner. ANG II treatment in the presence of the ETB receptor antagonist significantly increased ET-1 peptide levels. On another hand, the ETB receptor agonist, Sarafotoxin 6C, significantly decreased ET-1 peptide levels. These data implicate the role of the ETb receptor in the clearance of the ET-1 peptide. Conclusion: ANG II-induced increases of ET-1 peptide appears to be mediated by reactive oxygen species derived from NAD(P)H oxidase. Both the ETA and ETB receptors are expressed in adventitial fibroblasts. The ETA receptor subtype mediates collagen I expression, while the ETB receptor may play a protective role through increasing the clearance of the ET- 1 peptide.

An electrophysiological examination of intentional and inadvertent sleep onset : the effect of intention on the sleep onset process

The main purpose ofthis study was to examine the effect ofintention on the sleep onset process from an electrophysiological point ofview. To test this, two nap conditions, the Multiple Sleep Latency Test (MSLT) and the Repeated Test of Sustained Wakefulness (RTSW) were used to compare intentional and inadvertent sleep onset. Sixteen female participants (aged 19-25) spent two non-consecutive nights in the sleep lab; however, due to physical and technical difficulties only 8 participants produced compete sets of data for analysis. Each night participants were given six nap opportunities. For three ofthese naps they were instructed to fall asleep (MSLT), for the remaining three naps they were to attempt to remain awake (RTSW). These two types of nap opportunities represented the conditions ofintentional (MSLT) and inadvertent (RTSW) sleep onset. Several other sleepiness, performance, arousal and questionnaire measures were obtained to evaluate and/or control for demand characteristics, subjective effort and mental activity during the nap tests. The nap opportunities were scored using a new 9 stage scoring system developed by Hori et al. (1994). Power spectral analyses (FFT) were also performed on the sleep onset data provided by the two nap conditions. Longer sleep onset latencies (approximately 1.25 minutes) were obseIVed in the RTSW than the MSLT. A higher incidence of structured mental activity was reported in the RTSW and may have been reflected in higher Beta power during the RTSW. The decent into sleep was more ragged in the RTSW as evidenced by an increased number shifts towards higher arousal as measured using the Hori 9 stage sleep scoring method. 1ll The sleep onset process also appears to be altered by the intention to remain awake, at least until the point ofinitial Stage 2 sleep (i.e. the first appearance of spindle activity). When only examining the final 4.3 minutes ofthe sleep onset process (ending with spindle activity), there were significant interactions between the type ofnap and the time until sleep onset for Theta, Alpha and Beta power. That is to say, the pattern of spectral power measurements in these bands differed across time as a function ofthe type ofnap. The effect ofintention however, was quite small (,,2 < .04) when compared to the variance which could be accounted for by the passage oftime (,,2 == .10 to .59). These data indicate that intention alone cannot greatly extend voluntary wakefulness if a person is sleepy. This has serious implications for people who may be required to perform dangerous tasks while sleepy, particularly for people who are in a situation that does not allow them the opportunity to engage in behavioural strategies in order to maintain their arousal.

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