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The medicinal chemistry of amino-derivatives of the sesquiterpene lactones is described, beginning with synthetic development, moving into pharmacological applications, and finishing with clinical translation.

SUMMARY We studied the autonomic control of resting heart rate and of systemic and pulmonary vascular blood pressures (BP) in chronically instrumented neonatal lambs 1-8 weeks of age. The maximum response to ganglionic blockade and sympathetic and parasympathetic antagonists was taken as an index of the magnitude of the total neural, adrenergic, and cholinergic tones. The reactivity of the circulatory parameters to adrenergic and cholinergic agonists also was investigated. All findings were compared with those in adult nonpregnant sheep studied concomitantly and with data previously obtained from term fetal lambs. The results of our studies show: (1) resting heart rate declines spontaneously throughout the 8 weeks of neonatal life approaching that of adult sheep; (2) the progressive bradycardia is not related to changes in the parasympathetic or sympathetic tone; (3) resting systemic BP is under strong neurohumoral control during the first two to three weeks of neonatal life; the control decreases progressively, becoming similar to that of adult sheep; (4) resting pulmonary artery pressure of neonatal and adult sheep has no neurohumoral control; (5) the systemic BP response of the neonate to autonomic agonists is greater than that of the term fetus and is similar to that of the adult; (6) in neonatal and adult sheep, compared to the term fetus, the pressor response to norepinephrine is accompanied by a baroreceptormediated bradycardia, and acetylcholine-induced systemic hypotension is accompanied by a "paradoxical" tachycardia mediated through /3-adrenergic stimulation; (7) in contrast to our finding for the fetus, the pulmonary vascular pressure of neonatal and adult sheep is unresponsive to autonomic agonists.PREVIOUS studies on fetal lambs between 60 days and term gestation (fetal weight, 300-5,00,0 g) have shown that (1) the sympathetic control of the cardiovascular functions begins earlier during fetal development than the parasympathetic control; (2) the influence of both systems on the fetal circulation increases with fetal growth until term; and (3) the fetal cardiovascular response to autonomic agonists increases during intrauterine development mainly because of maturation of the effector system. 1 ' 2The present report deals with data that compare the changes in the neurohumoral control of the heart rate, systemic arterial pressure, and pulmonary vascular pressure of the neonatal lamb (3-60 days of age) with changes in the adult nonpregnant sheep. MethodsNear-term ewes of mixed breed with well dated gestation were allowed to deliver spontaneously in our animal facilities; hence, the exact age of each lamb was known. The lambs were housed with their mothers so that normal lactation could be accomplished until they were able to eat the same alfalfa diet given to the ewes and drink on their own during the period of observation. Each lamb was allowed a 2-to 3-day period of neonatal adjustment before it was subjected to surgery. Chronic instrumentation of the lamb or the adult sheep was accomplished under a...

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Changes in resting cardiac output (CO), stroke volume (SV), and systemic vascular resistance (SVR) during neonatal growth were studied in chronically instrumented lambs from the 1st to 5th wk of age; adult nonpregnant sheep values measured simultaneously were used as standard reference. Neonatal responses to autonomic agonists and antagonists were also investigated. Total CO increased linearly with neonatal growth, but decreased strikingly when expressed per weight unit; at 5 wk of age, CO/kg was still significantly higher than the adult value. SV also increased with neonatal growth but did not change when related to body weight; at 5 wk of age, SV/kg values were still higher than those of adult sheep. SVR changed reciprocally to CO. The decrease in CO/kg during neonatal growth paralleled the progressive decline in heart rate (HR). Beta receptor stimulation increased neonatal CO markedly and the increment was the same from the first through the fifth neonatal week. Beta blockade had insignificant effects, but cholinergic blockade produced moderate CO increases.

The design, synthesis, and biological activity of fluorinated amino-derivatives of the sesquiterpene lactone, parthenolide, are described. A fluorinated aminoparthenolide analogue with biological activity similar to the parent natural product was discovered, and its X-ray structure was obtained. This lead compound was then studied using 19F NMR in the presence and absence of glutathione to obtain additional mechanism of action data, and it was found that the aminoparthenolide eliminates amine faster in the presence of glutathione than in the absence of glutathione. The exact changes in concentrations of fluorinated compound and amine were quantified by a concentration-reference method using 19F NMR; a major benefit of applying this strategy is that no deuterated solvents or internal standards are required to obtain accurate concentrations. These mechanistic data with glutathione may contribute to the conversion of the amino-derivative to parthenolide, the active pharmacological agent, in glutathione-rich cancer cells.