The Synthesis of Aigialomycin D Analogues

<p>Aigialomycin D is a fungal natural product possessing kinase inhibition properties. It is a member of a class of compounds known as the resorcylic acid lactones, a expansive group containing compounds exhibiting a vast array of biological activities. These include kinase and Hsp90 inhibition, highly desirable properties in the drug development field. This research project sought to capitalise on previous work involving the successful total synthesis of aigialomycin D. By developing the synthetic methodology, analogues of aigialomycin D could be prepared for biological testing to obtain valuable structure-activity relationship information. The focus of this thesis involves the successful synthesis of aigialomycin D diastereomer, 5',6'-epi,epi-aigialomycin D and the attempted synthesis of 100-epi-aigialomycin D, via the synthetic strategy developed previously in combination with enantiomeric starting material fragments ... The synthesis of functional group analogues, 6'-oxo-aigialomycin D, 7',8'-cyclopropyl aigialomycin D and 5-chloro-agialomycin D were also attempted via derivatisation of late-stage intermediates in the aigialomycin D synthesis. The thesis herein recounts the successes and failures in the synthesis of various aigialomycin D analogues ...</p>

The Synthesis of Aigialomycin D Analogues

<p>Aigialomycin D is a fungal natural product possessing kinase inhibition properties. It is a member of a class of compounds known as the resorcylic acid lactones, a expansive group containing compounds exhibiting a vast array of biological activities. These include kinase and Hsp90 inhibition, highly desirable properties in the drug development field. This research project sought to capitalise on previous work involving the successful total synthesis of aigialomycin D. By developing the synthetic methodology, analogues of aigialomycin D could be prepared for biological testing to obtain valuable structure-activity relationship information. The focus of this thesis involves the successful synthesis of aigialomycin D diastereomer, 5',6'-epi,epi-aigialomycin D and the attempted synthesis of 100-epi-aigialomycin D, via the synthetic strategy developed previously in combination with enantiomeric starting material fragments ... The synthesis of functional group analogues, 6'-oxo-aigialomycin D, 7',8'-cyclopropyl aigialomycin D and 5-chloro-agialomycin D were also attempted via derivatisation of late-stage intermediates in the aigialomycin D synthesis. The thesis herein recounts the successes and failures in the synthesis of various aigialomycin D analogues ...</p>

Nilpotent endomorphisms of expansive group actions

We consider expansive group actions on a compact metric space containing a special fixed point denoted by [Formula: see text], and endomorphisms of such systems whose forward trajectories are attracted toward [Formula: see text]. Such endomorphisms are called asymptotically nilpotent, and we study the conditions in which they are nilpotent, that is, map the entire space to [Formula: see text] in a finite number of iterations. We show that for a large class of discrete groups, this property of nil-rigidity holds for all expansive actions that satisfy a natural specification-like property and have dense homoclinic points. Our main result in particular shows that the class includes all residually finite solvable groups and all groups of polynomial growth. For expansive actions of the group [Formula: see text], we show that a very weak gluing property suffices for nil-rigidity. For [Formula: see text]-subshifts of finite type, we show that the block-gluing property suffices. The study of nil-rigidity is motivated by two aspects of the theory of cellular automata and symbolic dynamics: It can be seen as a finiteness property for groups, which is representative of the theory of cellular automata on groups. Nilpotency also plays a prominent role in the theory of cellular automata as dynamical systems. As a technical tool of possible independent interest, the proof involves the construction of tiered dynamical systems where several groups act on nested subsets of the original space.

Anesthetic Considerations for Patients on Antidepressant Therapy – Part II

Millions of patients take antidepressant medications in the United States for the treatment of depression or anxiety disorders. Some antidepressants are prescribed off-label to treat problems such as chronic pain, low energy, and menstrual symptoms. Antidepressants are a broad and expansive group of medications, but the more common drug classes include tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors. A miscellaneous or “atypical” category covers other agents. Some herbal supplements that claim to have antidepressant activity will also be discussed. Part I of this series reviewed antidepressant pharmacology, adverse effects, and drug interactions with adrenergic agonists. In part II, drug–drug interactions with sedation and general anesthetics, bleeding effects, and serotonin syndrome will be discussed.

Anesthetic Considerations for Patients on Antidepressant Therapy—Part I

Millions of patients take antidepressant medications in the United States for the treatment of depression or anxiety disorders. Some antidepressants are prescribed off-label to treat problems such as chronic pain, low energy, and menstrual symptoms. Antidepressants are a broad and expansive group of medications, but the more common drug classes include tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors. A miscellaneous or “atypical” category covers other agents. Some herbal supplements that claim to have antidepressant activity will also be discussed. In Part I of this review, antidepressant pharmacology, adverse effects, and drug interactions with adrenergic agonists will be discussed. In part II, drug interactions with sedation and general anesthetics will be reviewed. Bleeding effects and serotonin syndrome implications in anesthetic practice will also be highlighted.

The Origin of Neolithic Culture in Northern Europe

Till 1948 the coherent record of farming in Northern Europe began with the neolithic culture represented in the Danish dysser (‘dolmens’) and most readily defined by the funnel-necked beakers, collared flasks and ‘amphorae’ found therein. As early as 1910 Gustav Kossinna had remarked that these distinctive ceramic types, and accordingly the culture they defined, were not confined to the West Baltic coastlands, but recurred in the valleys of the Upper Vistula and Oder to the east, to the south as far as the Upper Elbe and in northwest Germany and Holland too. He saw in this distribution evidence for the first expansion of Urindogermanen from their cradle in the Cimbrian peninsula. In the sequel Åberg filled in the documentation of this expansion with fresh spots on the distribution map and Kossinna himself distinguished typologically four main provinces or geographical groups—the Northern, Eastern, Southern and Western. Finally Jazdrzewski gave a standard account of the whole content of what had come to be called Kultura puharów lejkowatych, Trichterbecherkultur, or Tragtbaegerkulturen. As ‘Funnel-necked-beaker culture’ is a clumsy expression and English terminology is already overloaded with ‘beakers’, I shall use the term ‘First Northern’.The orgin of this vigorous and expansive group of cultivators and herdsmen has always been an enigma. Not even Kossinna imagined that the savages of the Ertebølle shell-mounds spontaneously began cultivating cereals and breeding sheep in Denmark. As dysser were regarded as megalithic tombs and as megaliths are Atlantic phenomena, he supposed that the bases of the neolithic economy were introduced from the West together with the ‘megalithic idea’. But the First Northern Farmers of the South and East groups did not build megalithic tombs. Moreover, in the last ten years an extension of the North group across southern Sweden as far as Södermannland has come to light, and these farmers too, though they used collared flasks and funnel-necked beakers, built no dolmens either. In any case there was nothing Western about the pottery from the Danish dysser, and Western types of arrow-head are conspicuously rare in Denmark.