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Brodersen, Kai

doi:10.1017/cbo9781139027014.005

Cited by 25 publications

(3 citation statements)

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“…29 Characterized by four linearly fused sixmembered carbon rings, tetracyclines inhibit protein synthesis by binding to the 30S ribosomal subunit thereby preventing attachment of aminoacyl-tRNA to the ribosomal acceptor (A) site. 30 Like most β-lactam and macrolide antibiotics, nearly all tetracyclines approved for clinical use are derived via fermentation or through semisynthesis from fermentation products.…”

Section: Selected Examples Of Fully Synthetic Natural Product Analogsmentioning

confidence: 99%

Natural Products in the “Marketplace”: Interfacing Synthesis and Biology

Huffman

Shenvi

2019

J. Am. Chem. Soc.

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Drugs are discovered through the biological screening of collections of compounds, followed by optimization toward functional endpoints. The properties of screening collections are often balanced between diversity, physicochemical favorability, intrinsic complexity and synthetic tractability. 1 Whereas natural product (NP) collections excel in the first three attributes, NPs suffer a disadvantage on the last point. Academic total synthesis research has worked to solve this problem by devising syntheses of NP leads, diversifying late-stage intermediates or derivatizing the NP target. This work has led to the discovery of reaction mechanisms, the invention of new methods and the development of FDA-approved drugs. Few drugs, however, are themselves NPs; instead NP-analogs predominate. Here we highlight past examples of NP analog development and successful NP-derived drugs. More recently, chemists have explored how NP analogs alter the retrosynthetic analysis of complex scaffolds, merging structural design and synthetic design. This strategy maintains the intrinsic complexity of the NP but can alter the physicochemical properties of the scaffold, like core instability that renders the NP a poor chemotype. Focused libraries based on these syntheses may exclude the NP but maintain the molecular properties that distinguish NPspace from synthetic space, 2 properties that have statistical advantages in clinical progression. 3,4 Research that expedites synthetic access to NP-motifs can prevent homogeneity of chemical matter available for lead discovery. Easily accessed, focused libraries of NP scaffolds can fill empty but active gaps in screening sets and expand the molecular diversity of synthetic collections.

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Section: Selected Examples Of Fully Synthetic Natural Product Analogsmentioning

confidence: 99%

Natural Products in the “Marketplace”: Interfacing Synthesis and Biology

Huffman

Shenvi

2019

J. Am. Chem. Soc.

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“…3,4 Crystal structures of pactamycin bound to the 16S rRNA region of the ribosome illustrate that the two aromatic rings lie in the E-site of the 30S ribosome, acting as mRNA mimics to prevent initiation of protein biosynthesis. 5,6 The significant structural similarity between kingdoms at the pactamycin ribosomal binding site likely accounts for its broad and potent activity across Gram-positive and negative bacteria, as well as its antitumor activity. Unfortunately, pactamycin's broad activity is a double-edged sword, as it is also highly cytotoxic to healthy mammalian cells.…”

Section: Pactamycinmentioning

confidence: 99%

“…The tetracyclines inhibit protein translation by binding to the 30S ribosomal subunit to block aminoacylated tRNA from binding the ribosomal A-site. 5 Resistance to the tetracyclines is acquired via tet genes that encode for efflux pumps, ribosomal protection proteins, or tetracycline destructases. 51,52 Increasing acquisition of tet genes prompted new investigations into tetracycline derivatization, particularly at the C-9 position.…”

Section: Tetracyclinesmentioning

confidence: 99%

Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine

Yñigez-Gutierrez

Bachmann

2019

J. Med. Chem.

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Molecules isolated from natural sources including bacteria, fungi, and plants are a long-standing source of therapeutics that continue to add to our medicinal arsenal today. Despite their potency and prominence in the clinic, complex natural products often exhibit a number of liabilities that hinder their development as therapeutics, which may be partially responsible for the current trend away from natural product discovery, research, and development. However, advances in synthetic biology and organic synthesis have inspired a new generation of natural product chemists to tackle powerful undeveloped scaffolds. In this Perspective, we will present case studies demonstrating the historical and current focus on making targeted, but significant, changes to natural product scaffolds via biosynthetic gene cluster manipulation, total synthesis, semisynthesis, or a combination of these methods, with a focus on increasing activity, decreasing toxicity, or improving chemical and pharmacological properties.

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Between Greece and Babylonia

Stevens

2019

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Cartography

Cited by 25 publications

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Natural Products in the “Marketplace”: Interfacing Synthesis and Biology

Natural Products in the “Marketplace”: Interfacing Synthesis and Biology

Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine

Between Greece and Babylonia

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