Synthetic and pharmacophoric studies of quinocarcin

1990 Fall.Includes bibliographical references.A new synthetic approach to the stereoselective total synthesis of the structurally unique antitumor antibiotic quinocarcin (1) is described. The utilization of model studies in this approach has led to novel methodologies concerning the construction of 1-(hydroxymethyl)-8-methoxy-1,2,3,4-tetrahydroisoquinolin-4-one (195) and several variably substituted pyrrolidines (180, 181, 182 and 183). These methodologies are discussed in terms of their synthetic utility as well as their mechanistic aspects. The synthetic approach to quinocarcin described herein allowed for the construction of several oxazolidine containing alkaloids which incorporate various aspects of the 8-11- iminoazepinotetrahydroiso-quinoline skeleton of quinocarcin. To this end the synthesis of a new tetracyclic oxazolidine moiety (240), which mimics quinocarcin's DNA nicking capabilities and represents the isolation of the pharmacophore of this novel antibiotic was achieved. The significance of the chemical stability and biological activity of 240 relative to quinocarcin is discussed

Radical overhaul needed to halt Earth's sixth great extinction event

Life has existed on Earth for roughly 3.7 billion years. During that time we know of five mass extinction events — dramatic episodes when many, if not most, life forms vanished in a geological heartbeat. The most recent of these was the global calamity that claimed the dinosaurs and myriad other species around 66 million years ago. Growing numbers of scientists have asserted that our planet might soon see a sixth massive extinction — one driven by the escalating impacts of humanity. Others, such as the Swedish economist Bjørn Lomborg, have characterised such claims as ill-informed fearmongering. We argue emphatically that the jury is in and the debate is over: Earth's sixth great extinction has arrived

Structural Neuroimaging of Anorexia Nervosa: Future Directions in the Quest for Mechanisms Underlying Dynamic Alterations.

Anorexia nervosa (AN) is a serious eating disorder characterized by self-starvation and extreme weight loss. Pseudoatrophic brain changes are often readily visible in individual brain scans, and AN may be a valuable model disorder to study structural neuroplasticity. Structural magnetic resonance imaging studies have found reduced gray matter volume and cortical thinning in acutely underweight patients to normalize following successful treatment. However, some well-controlled studies have found regionally greater gray matter and persistence of structural alterations following long-term recovery. Findings from diffusion tensor imaging studies of white matter integrity and connectivity are also inconsistent. Furthermore, despite the severity of AN, the number of existing structural neuroimaging studies is still relatively low, and our knowledge of the underlying cellular and molecular mechanisms for macrostructural brain changes is rudimentary. We critically review the current state of structural neuroimaging in AN and discuss the potential neurobiological basis of structural brain alterations in the disorder, highlighting impediments to progress, recent developments, and promising future directions. In particular, we argue for the utility of more standardized data collection, adopting a connectomics approach to understanding brain network architecture, employing advanced magnetic resonance imaging methods that quantify biomarkers of brain tissue microstructure, integrating data from multiple imaging modalities, strategic longitudinal observation during weight restoration, and large-scale data pooling. Our overarching objective is to motivate carefully controlled research of brain structure in eating disorders, which will ultimately help predict therapeutic response and improve treatment

Circling the Drain: The Extinction Crisis and the Future of Humanity

Humanity has triggered the sixth mass extinction episode since the beginning of the Phanerozoic. The complexity of this extinction crisis is centered on the intersection of two complex adaptive systems: human culture and ecosystem functioning, although the significance of this intersection is not properly appreciated. Human beings are part of biodiversity and elements in a global ecosystem. Civilization, and perhaps even the fate of our species, is utterly dependent on that ecosystem’s proper functioning, which society is increasingly degrading. The crisis seems rooted in three factors. First, relatively few people globally are aware of its existence. Second, most people who are, and even many scientists, assume incorrectly that the problem is primarily one of the disappearance of species, when it is the existential threat of myriad population extinctions. Third, while concerned scientists know there are many individual and collective steps that must be taken to slow population extinction rates, some are not willing to advocate the one fundamental, necessary, ‘simple’ cure, that is, reducing the scale of the human enterprise. We argue that compassionate shrinkage of the human population by further encouraging lower birth rates while reducing both inequity and aggregate wasteful consumption—that is, an end to growth mania—will be required. This article is part of the theme issue ‘Ecological complexity and the biosphere: The next 30 years.