Synthetic studies on prostaglandins: "synthesis of a new thia-PGEI analog"

A PGE1 analog, namely (±)-trans-2-(6'-carbomethoxyhexyl)-3- (E-3"-thia-1 "-octene)-4-hydroxycyclopentanone 71, has been prepared for the first time. Towards the synthesis of this compound, several synthetic approaches aimed at the preparation of the required acetylenic and E-halovinylic sulfides as building blocks were investigated. Among all the methods examined, it appeared evident that the best route to ethynyl n.pentyl sulfide 81 is via a double dehydrohalogenation of the corresponding 1,2-dibromoethyl sulfide with sodium amide in liquid ammonia. In addition, the isomerically pure E-2-iodoethenyl n.pentyl sulfide 85 is conveniently prepared in high yield and stereoselectivity by hydrozirconation-iodination of the terminal ethynyl sulfide 81. The classical hydroalumination and hydroboration reactions for the preparation of vinyl halides from alkynes gave only small yields when applied as methods towards the synthesis of 85 . The building block 2-(6'-carbomethoxyhexyl)-4-hydroxy-2- cyclopentenone (±)-1 carrying the upper side-chain of prostaglandin E 1 was prepared by a step-wise synthesis involving transformations of compounds possessing the required carbocyclic framework (see scheme 27). The synthesis proved to be convenient and gave a good overall yield of (±)-1 which was protected as the TH P-derivative 37 or the siloxy derivative 38. With the required building blocks 81 and 37 in hand, the target 1S-thia-PGE1 analog (±)-71 was prepared via the in situ higher cuprate formation-conjugate addition reaction. This method proved to be convenient and stereospecific. The standard cuprate method, involving an organocuprate reagent generated from an isolated vinyl iodide, did not work well in our case and gave a complicated mixture of products. The target compound will be submitted for assessment of bio log ical activity.

Order and membrane organization in chlorhexidine-lipid mixtures /

Formulations of a general bactericidal agent, chlorhexidine, mixed with a phospholipid at different concentrations are investigated using ^H NMR spectroscopy on a chain-deuterated lipid analog. Lipid-chlorhexidine formulation is known to release the drug into an aqueous medium slowly, maintaining a comparable concentration of the drug for up to four times longer than a direct aqueous solution. The NMR data does not support the proposed liposomal entrapment of chlorhexidine in lipid compartments. Complex thermal history of the lipid-chlorhexidine preparations is investigated in detail. In preparation for a counterpart measurement, using ^H NMR of deuterated chlorhexidine mixed with protonated lipid, the synthesis of a deuterated analog of chlorhexidine is performed.

The nucleophillic substitution of various chloroanthraquinones of their possible rearrangement via aryne intermediates

The work in this thesis deals mainly with nucleophilic substitution of chloroanthraquinones as a route to various starting materials which might rearrange, via aryne intermediates to afford fused-ring heterocy1ic carboxylic acids. 1-Amino-5-chloroanthraquinone was successfully prepared by reacting 1,5-dichloroanthraquinone with sodium aZide in ref1uxing dimethylsulfoxide (DMSO). It could also be prepared from the same starting material by reaction with ammonia (gas) in DMSO in the presence of potassium fluoride. Treatment of l-amino-5-chloroanthraquinone with potassium amide in liquid ammonia or with potassium t-butoxide in t-butylbenzene returned mainly starting material, although in the latter case some 1-amino-5-hydroxyanthraquinone was also isolated. 1-Hydroxy-5-chloroanthraquinone was ultimately prepared by diazotization of the amino-analog. It was recovered almost quantitatively after treatmenu'with potassium amide in liquid ammonia. The reaction with potassium t-butoxide in t-buty1benzene was anomalous and gave 1-hydroxyanthraquinone as the only iso1able product. Acridines were successfully prepared by the action of 70% sulfuric acid on 1,5-bis(p-toluidino)-anthraquinone and 1-p-toluidino-5- ch10roanthraquinone, and in the latter case, cleavage to give an acridinecarboxylate was attempted. Substituted anthraquinones reacted with sodium azide in sulfuric acid to give azepindiones by -NH insertion. Methods for separating and identifying isomeric mixtures of these compounds were examined. Attempted decarbonylation of selected azepindiones to give acridones gave mainly what were thought to be amino-benzophenone derivatives. Chloroanthraquinones were found to react with hexamethylphosphoramide (HMPA) to give mixtures of the dimethylamino- and methylaminoderivatives. Under the same conditions halogeno-nitrobenzenes and nitrophenols were substituted to give the appropriate dimethyl aminobenzenes, except in two cases. 3-Chloronitrobenzene reacted anomalously to give a small amount of 3,3'-dichloroazobenzene and a trace of 4-dimethylamino-nitrobenzene. Pentachlorophenol reacted to give a pentachlorophenylphosphorodiamidate in good yield.

Socio-demographic factors, smoking, symptoms, morbidities and pulmonary function and quality of life in individuals with a heavy smoking history

Objective: To determine which socio-demographic, exposure, morbidity and symptom variables are associated with health-related quality of life among former and current heavy smokers. Methods: Cross sectional data from 2537 participants were studied. All participants were at ≥2% risk of developing lung cancer within 6 years. Linear and logistic regression models utilizing a multivariable fractional polynomial selection process identified variables associated with health-related quality of life, measured by the EQ-5D. Results: Upstream and downstream associations between smoking cessation and higher health-related quality of life were evident. Significant upstream associations, such as education level and current working status and were explained by the addition of morbidities and symptoms to regression models. Having arthritis, decreased forced expiratory volume in one second, fatigue, poor appetite or dyspnea were most highly and commonly associated with decreased HRQoL. Discussion: Upstream factors such as educational attainment, employment status and smoking cessation should be targeted to prevent decreased health-related quality of life. Practitioners should focus treatment on downstream factors, especially symptoms, to improve health-related quality of life.

Seasonal reproductive endothermy in tegu lizards

With some notable exceptions, small ectothermic vertebrates are incapable of endogenously sustaining a body temperature substantially above ambient temperature. This view was challenged by our observations of nighttime body temperatures sustained well above ambient (up to 10°C) during the reproductive season in tegu lizards (~2 kg). This led us to hypothesize that tegus have an enhanced capacity to augment heat production and heat conservation. Increased metabolic rates and decreased thermal conductance are the same mechanisms involved in body temperature regulation in those vertebrates traditionally acknowledged as “true endotherms” : the birds and mammals. The appreciation that a modern ectotherm the size of the earliest mammals can sustain an elevated body temperature through metabolic rates approaching that of endotherms enlightens the debate over endothermy origins, providing support for the parental care model of endothermy, but not for the assimilation capacity model of endothermy. It also indicates that, contrary to prevailing notions, ectotherms can engage in facultative endothermy, providing a physiological analog in the evolutionary transition to true endothermy.