Numerous variations on structural motifs exist within pharmaceutical compounds that have entered the clinic. These variations have amounted over many decades based on years of drug development associated with screening natural products and de novo synthetic systems. Caged (or bridged) bicyclic structural elements offer a variety of diverse features, encompassing three-dimensional shape, and assorted pharmacokinetic properties. This review highlights approximately 20 all carbon cage containing pharmaceuticals, ranging in structure from bicyclo[2.2.1] through to adamantane, including some in the top-selling pharmaceutical bracket. Although, a wide variety of human diseases, illnesses and conditions are treated with drugs containing the bicyclic motif, a common feature is that many of these lipophilic systems display CNS and/or neurological activity. In addition, to an extensive overview of the history and biology associated with each drug, a survey of synthetic methods used to construct these entities is presented. An analysis section compares natural products to synthetics in drug discovery, and entertains the classical caged hydrocarbon systems potentially missing from the clinic. Lastly, this unprecedented review is highly pertinent at a time when big pharma is desperately trying to escape flatland drugs.
With 21 unknown stereocentres embedded in spatially separated stereoclusters, the cytotoxic polyketide hemicalide represents a seemingly intractible structural assignment problem. Herein, through the targeted synthesis of configurationally defined fragments, as...
The structural complexity and biological importance of macrolide natural products has inspired the development of innovative strategies for their chemical synthesis. With their dense stereochemical content, high level of oxygenation...
Herbal medicines, although significant components of health care for much of the global populace, are still far less stringently regulated than conventional pharmaceuticals. Safety and efficacy concerns arise because of the limited information regarding many of the phytochemicals present in herbal medicines. Chamaelirium luteum (false unicorn) is an indigenous American herb marketed for "women's issues". Recently, the potential bioactives, a new class of open-chain steroidal saponins, have been fully characterized and preliminary bioactivity assays have been performed. The present study utilized the Caco-2 cell monolayer model to evaluate metabolic vulnerability and potential bioavailability of eight saponins and sapogenins from false unicorn. No compound metabolism was detected in Caco-2 cell homogenate. One sapogenin, helogenin, exhibited low-to-moderate permeability across the monolayers. Three saponinschamaeliroside A, heloside A, and 6-dehydrochamaeliroside Awere found to have moderate permeability. Transport studies indicated active transport of these saponins. In contrast, all saponins with more than two sugar units exhibited low permeability.
The diverse and complex structures of polyketide natural products have stimulated the imagination of synthetic chemists for decades. Captivated by their often impressive biological activities and their dazzling array of stereochemically-rich motifs, we have been motivated to achieve their efficient and stereocontrolled total synthesis. This review captures snapshots from our thirty-year foray into the total synthesis of 18 polyketide natural products, detailing the unique challenges, discoveries and revelations made en route to eventual success. Notably, crucial to each of these campaigns was the judicious application of highly selective aldol reactions to iteratively configure the densely oxygenated stereoclusters that characterise this fascinating class of bioactive natural products.
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