This review focuses on all known natural products that contain a "heteroatom-rich" ring system, specifically a five-, six- or seven-membered ring that contains three or more heteroatoms. The ...isolation and biological activity of these natural products is discussed, along with the biosynthetic processes that Nature employs to assemble these rare heterocyclic frameworks.
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The biological activity and structural diversity of natural products are unsurpassed by any available synthetic screening libraries. As such, these privileged scaffolds serve as ...important, biologically prevalidated platforms for the design of compound libraries in the search for new drug candidates. Recent progress has focussed on improving the potency, selectivity and pharmacokinetics of bioactive natural products through structural modification, leading to the emergence of a number of drug-like lead compounds. Here, we review recent advances in the exploitation of terpenoid, polyketide, phenylpropanoid and alkaloid natural product scaffolds for inspiration in the design and development of important new drug candidates.
Cancer cells utilize the main de novo pathway and the alternative salvage pathway for deoxyribonucleotide biosynthesis to achieve adequate nucleotide pools. Deoxycytidine kinase is the rate-limiting ...enzyme of the salvage pathway and it has recently emerged as a target for anti-proliferative therapies for cancers where it is essential. Here, we present the development of a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations. This strategy allows an acceleration of the hit-to-lead process by gradually implementing key chemical modifications to increase affinity and activity. Our lead compound, OR0642, is more than 1000 times more potent than its initial parent compound, masitinib, previously identified from a drug repositioning approach. OR0642 in combination with a physiological inhibitor of the de novo pathway doubled the survival rate in a human T-cell acute lymphoblastic leukemia patient-derived xenograft mouse model, demonstrating the proof-of-concept of this drug design strategy.
A synthesis of putative bufopyramide has shown the structure assigned to the natural product to be incorrect. The spectroscopic data for the natural product bufopyramide matches that obtained from a ...synthetic sample of bufoserotonin C, confirming that the two natural products are not distinct, but instead the same compound.
The first total synthesis of the benzannulated 5,5-spiroketal natural products paeciloketal B and 1-
-paeciloketal B has been achieved in 10 linear steps employing a biomimetic spiroketalization. ...This approach also furnished the related natural product bysspectin A from the same putative biosynthetic precursor as the paeciloketals. Alternatively, bysspectin A could be accessed in only six steps using an improved route. This scalable and efficient synthesis affords insight into the biosynthesis of these natural products in nature.
A procedure that converts a series of structurally diverse, readily available indole derivatives to their corresponding indolequinones is described. The three-step route commences with an iridium ...catalyzed C-H borylation to give a 7-borylindole that upon oxidation-hydrolysis affords the 7-hydroxyindole. Subsequent oxidation provides the indolequinone.
Covering: 2000 to 2020. trans-Bicyclo4.4.0decane/decene (such as trans-decalin and trans-octalin)-containing natural products display a wide range of structural diversity and frequently exhibit ...potent and selective antibacterial activities. With one of the major factors in combatting antibiotic resistance being the discovery of novel scaffolds, the efficient construction of these natural products is an attractive pursuit in the development of novel antibiotics. This highlight aims to provide a critical analysis on how the presence of dense architectural and stereochemical complexity necessitated special strategies in the synthetic pursuits of these natural trans-bicyclo4.4.0decane/decene antibiotics.
alpha-heteroaryl acetaldehydes have become important building blocks in the synthesis of synthetic nucleosides. Novel organocatalytic cascades have enabled the rapid generation of nucleosides, which ...are valuable building blocks in the development of antisense oligonucleotides or as stand-alone antiviral and anticancer therapies, obviating the need for laborious synthetic routes relying on chiral pool starting materials and inefficient synthetic routes. This manuscript describes a robust and scalable protocol to alpha-heteroaryl acetaldehydes from readily available building blocks.
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