Functionalized pyrrolidine inhibitors of human type II α-mannosidases as anti-cancer agents: Optimizing the fit to the active site

Fiaux, Hélène; Kuntz, D.A.; Hoffman, Daniela; Janzer, Robert C.; Gerber‐Lemaire, Sandrine; Rose, David R.; Juillerat‐Jeanneret, Lucienne

doi:10.1016/j.bmc.2008.06.021

Cited by 53 publications

(38 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[4,[13][14][15]18] Further, in a study of mannostatin analogues, interaction with the Arg876O appeared to be a key component. [19] In that study, removal of the thiomethyl group of mannostatin A (or a hydroxyl group in an analogue) to which Arg876O formed hydrogen bonds, resulted in a greater than 1000-fold reduction in inhibitor potency even though other interactions remained the same.…”

Section: The Aromatic C(5) Substituents Occupy Similar Positionsmentioning

confidence: 96%

See 1 more Smart Citation

Structural Investigation of the Binding of 5‐Substituted Swainsonine Analogues to Golgi α‐Mannosidase II

et al. 2010

Self Cite

View full text Add to dashboard Cite

Golgi alpha-mannosidase II (GMII) is a key enzyme in the N-glycosylation pathway and is a potential target for cancer chemotherapy. The natural product swainsonine is a potent inhibitor of GMII. In this paper we characterize the binding of 5alpha-substituted swainsonine analogues to the soluble catalytic domain of Drosophila GMII by X-ray crystallography. These inhibitors enjoy an advantage over previously reported GMII inhibitors in that they did not significantly decrease the inhibitory potential of the swainsonine head-group. The phenyl groups of these analogues occupy a portion of the binding site not previously seen to be populated with either substrate analogues or other inhibitors and they form novel hydrophobic interactions. They displace a well-organized water cluster, but the presence of a C(10) carbonyl allows the reestablishment of important hydrogen bonds. Already approximately tenfold more active against the Golgi enzyme than the lysosomal enzyme, these inhibitors offer the potential of being extended into the N-acetylglucosamine binding site of GMII for the creation of even more potent and selective GMII inhibitors.

show abstract

Section: The Aromatic C(5) Substituents Occupy Similar Positionsmentioning

confidence: 96%

“…[14] In the case of SK2, GHR, and LKS the addition of the phenyl moiety was markedly detrimental and reduced the inhibitory potency 7, 7.4, and 13-fold respectively in comparison to the parental compounds. [11][12][13] (There is no unsubstituted "parent" for GB6).…”

Section: The Aromatic C(5) Substituents Occupy Similar Positionsmentioning

confidence: 98%

Structural Investigation of the Binding of 5‐Substituted Swainsonine Analogues to Golgi α‐Mannosidase II

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover, the compound was found to be produced by endophytic isolates of Fusarium tricinctum recovered from Oxytropis kansuensis and O. deflexa in China [330]. The inhibitory properties on α-mannosidase have been exploited for the development of swainsonine as an anticancer drug, which has been impaired by reason of undesirable side effects [331,332]. Finally, it is interesting to note that plants of A. lentiginosus and Oxytropis sericea germinated from the embryo, which is not colonized by endophytes, were found to be fungus free and did not contain swainsonine [333].…”

Section: Other Alkaloidsmentioning

confidence: 99%

Plant Bioactive Metabolites and Drugs Produced by Endophytic Fungi of Spermatophyta

2015

View full text Add to dashboard Cite

Abstract:It is known that plant-based ethnomedicine represented the foundation of modern pharmacology and that many pharmaceuticals are derived from compounds occurring in plant extracts. This track still stimulates a worldwide investigational activity aimed at identifying novel bioactive products of plant origin. However, the discovery that endophytic fungi are able to produce many plant-derived drugs has disclosed new horizons for their availability and production on a large scale by the pharmaceutical industry. In fact, following the path traced by the blockbuster drug taxol, an increasing number of valuable compounds originally characterized as secondary metabolites of plant species belonging to the Spermatophyta have been reported as fermentation products of endophytic fungal strains. Aspects concerning sources and bioactive properties of these compounds are reviewed in this paper.

show abstract

“…183 Furthermore, a wide range of biological activities were also observed in compounds possessing a pyrrolidine motif which includes anti-cancer, 184 antifungal, 185 and antiviral properties. 186 Additionally, the family of pyrrolizidine alkaloids continues to provide novel structures with interesting and potentially valuable biological properties.…”

Section: Pyrrolidines and Pyrrolizidinesmentioning

confidence: 99%

Ninhydrin in synthesis of heterocyclic compounds

Ziarani¹,

Lashgari²,

Azimian³

et al. 2015

Arkivoc

View full text Add to dashboard Cite

Ninhydrin has been utilized in many heterocyclic preparations and considered as an important building block in organic synthesis. There is a wide range of reactions that include ninhydrin in the synthesis of heterocyclic compounds. This review highlights the advances in the use of ninhydrin as starting material in the synthesis of various organic compounds and drugs in a fully comprehensive way, from its first isolation in 1910 to the end of 2013. There is also a diversity of multi-component reactions of ninhydrin and we highlight the recent reports in this review.

show abstract

Functionalized pyrrolidine inhibitors of human type II α-mannosidases as anti-cancer agents: Optimizing the fit to the active site

Cited by 53 publications

References 52 publications

Structural Investigation of the Binding of 5‐Substituted Swainsonine Analogues to Golgi α‐Mannosidase II

Structural Investigation of the Binding of 5‐Substituted Swainsonine Analogues to Golgi α‐Mannosidase II

Plant Bioactive Metabolites and Drugs Produced by Endophytic Fungi of Spermatophyta

Ninhydrin in synthesis of heterocyclic compounds

Contact Info

Product

Resources

About