Carbohydrate‐Based Therapeutics

Musser, John H.

doi:10.1002/0471266949.bmc026

Cited by 6 publications

(2 citation statements)

References 175 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We are, therefore, exploring the reduction in the number of aromatic side chains in order to identify and block potential oxidation sites . The use of carbohydrates as orally available therapeutics has been precedented. , …”

Section: Introductionmentioning

confidence: 99%

Effects of Heterocyclic Aromatic Substituents on Binding Affinities at Two Distinct Sites of Somatostatin Receptors. Correlation with the Electrostatic Potential of the Substituents

et al. 2003

View full text Add to dashboard Cite

In our continuing program exploring glucose-based peptidomimetics of somatostatin (SRIF-14), we sought to improve the water solubility of our glycosides. This led to insights into the nature of the ligand binding sites at the SRIF receptor. Replacement of the C4 benzyl substituent in glucoside (+)-2 with pyridinylmethyl or pyrazin-2-ylmethyl congeners increased water solubility and enhanced affinity for the human SRIF subtype receptor 4 (sst4). We attribute this effect to hydrogen bond formation. The pyridin-3-ylmethyl substituent at C4, when combined with the imidazol-4-ylmethyl group at C2, generated (-)-19, which has the highest affinity of a glucose-based peptidomimetic at a human SRIF receptor to date (K(i) 53 +/- 23 nM, n = 6 at sst4). The C4 heterocyclic congeners of glucosides bearing a 1-methoxy substituent rather than an indole side chain at the anomeric carbon, such as (+)-16, also provided information about the Trp(8) binding pocket. We correlated the SARs at both the C4 and the Trp(8) binding pockets with calculations of the electrostatic potentials of the diverse C4 aromatic substituents using Spartan 3-21G(*) MO analysis. These calculations provide an approximate analysis of a molecule's ability to interact within a receptor binding site. Our binding studies show that benzene and indole rings, but not pyridinylmethyl nor pyrazin-2-ylmethyl rings, can bind the hydrophobic Trp(8) binding pocket of sst4. The Spartan 3-21G(*) MO analysis reveals significant negative electrostatic potential in the region of the pi-clouds for the benzene and indole rings but not for the pyridinylmethyl or pyrazin-2-ylmethyl congeners. Our data further demonstrate that the replacement of benzene or indole side chains by heterocyclic aromatic rings typified by pyridine and pyrazine not only enhances water solubility and hydrogen bonding capacity as expected, but can also profoundly diminish the ability of the pi-cloud of the aromatic substituent to interact with side chains of an aromatic binding pocket such as that for Trp(8) of SRIF-14. Conversely, these calculations accommodate the experimental findings that pyrazin-2-ylmethyl and pyridinylmethyl substituents at C4- of C1-indole-substituted glycosides afford higher affinities at sst4 than the C4-benzyl group of (+)-2. This result is consistent with the high electron density in the plane of the heterocycle depicted in Figure 6 which can accept hydrogen bonds from the C4 binding pocket of the receptor. Unexpectedly, we found that the 2-fluoropyridin-5-ylmethyl analogue (+)-14 more closely resembles the binding affinity of (+)-8 than that of (+)-2, thus suggesting that (+)-14 represents a rare example of a carbon linked fluorine atom acting as a hydrogen bond acceptor. We attribute this result to the ability of the proton to bind the nitrogen and fluorine atoms simultaneously in a bifurcated arrangement. At the NK1 receptor of substance P (SP), the free hydroxyl at C4 optimizes affinity.

show abstract

Section: Introductionmentioning

confidence: 99%

Effects of Heterocyclic Aromatic Substituents on Binding Affinities at Two Distinct Sites of Somatostatin Receptors. Correlation with the Electrostatic Potential of the Substituents

et al. 2003

View full text Add to dashboard Cite

show abstract

“…1,12 In 1785, the English physician Withering published his observations on the use of the foxglove Digitalis purpurea for the treatment of dropsy, 13 and this eventually led to the isolation of the cardiotonic agent, digoxin. 14 Plants have a long history of use in the treatment of cancer, 15 though many of the claims for the efficacy of such treatments should be viewed with some skepticism because cancer, as a specific disease entity, is likely to be poorly defined in terms of folklore and traditional medicine. 16 Of the plant-derived anticancer drugs in clinical use, the best known are the so-called vinca alkaloids vinblastine and vincristine (FIG.…”

Section: Traditional Medicine and The Role Of Plants In Drug Discoverymentioning

confidence: 99%

Medicinals for the Millennia

Cragg

Newman

2001

Annals of the New York Academy of Sciences

115

View full text Add to dashboard Cite

Nature has been a source of medicinal agents for thousands of years, and an impressive number of modern drugs have been isolated from natural sources, many based on their use in traditional medicine. The use of herbal drugs is once more escalating in the form of complementary and alternative medicine. The past century, however, has seen an increasing role played by microorganisms in the production of the antibiotics and other drugs for the treatment of some serious diseases. With less than 1% of the microbial world currently known, advances in procedures for microbial cultivation and the extraction of nucleic acids from environmental samples from soil and marine habitats, and from symbiotic and endophytic microbes associated with terrestrial and marine macro-organisms, will provide access to a vast untapped reservoir of genetic and metabolic diversity. By use of combinatorial chemical and biosynthetic technology, novel natural product leads will be optimized on the basis of their biological activities to yield effective chemotherapeutic and other bioactive agents.

show abstract

A Migratory Ether Formation Route to Medium‐Sized Sugar Mimetics

Jiang

Fang

et al. 2016

Angewandte Chemie

View full text Add to dashboard Cite

Polyol-substituted cyclic ethers are fundamental building blocks of biomolecules.The position and stereochemistry of multiple hydroxy substituents of cyclic ethers play acentral role in their biological function. Current methods for the synthesis of such structures are limited to "naked" ring products with no or few substituents.Here we describe ageneral route to medium-sized polyol cyclic ethers using am igratory ether formation strategy.Incontrast to the common pathwayof direct opening of epoxides,M e 3 Al was found to promote an unprecedented ether addition reaction, opening aneighboring epoxide.T he resulting oxonium intermediate triggers a1 ,3methyl shift to yield 2-deoxyribital products.W hen the hemiacetal auxiliary is am onosaccharide,t he sugar ring is expanded by four atoms to give the corresponding 9-to 11membered analogues.T his method provides an entry into the untapped chemical space of medium-sized sugar mimetics. Scheme 1. Polyol cyclic ethers. Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under http://dx.

show abstract

Carbohydrate‐Based Therapeutics

Cited by 6 publications

References 175 publications

Effects of Heterocyclic Aromatic Substituents on Binding Affinities at Two Distinct Sites of Somatostatin Receptors. Correlation with the Electrostatic Potential of the Substituents

Effects of Heterocyclic Aromatic Substituents on Binding Affinities at Two Distinct Sites of Somatostatin Receptors. Correlation with the Electrostatic Potential of the Substituents

Medicinals for the Millennia

A Migratory Ether Formation Route to Medium‐Sized Sugar Mimetics

Contact Info

Product

Resources

About