Synthesis of Bioreductive Esters from Fungal Compounds

Weerapreeyakul, Natthida; Anorach, Rutchayaporn; Khuansawad, Thidarut; Yenjai, Chavi; Isaka, Masahiko

doi:10.1248/cpb.55.930

Cited by 18 publications

(12 citation statements)

References 18 publications

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“…In the same way, the bisnaphtopyrone lichenicolin A isolated from an unidentified lichen-inhabiting fungus (He et al 2005) was active against Gram-positive bacteria, including strains of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Morever, the new bioactive structures of preussomerins produced by endolichenic fungi are considered as lead compounds to be optimized by chemists (Weerapreeyakul et al 2007). They were originally detected in the lichenicolous fungus Microsphaeropsis sp.…”

Section: Secondary Compounds From Microbial Associates Of Lichensmentioning

confidence: 99%

Bioactive lichen metabolites: alpine habitats as an untapped source

2010

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International audienceLichens are fungal and algal/cyanobacterial symbioses resulting in the production of specific metabolites. Some of these are forming an available biomass for phytochemical investigations, including the assessment of biological activities of the isolated compounds. The alpine or polar region are characterised by highly stressful environmental conditions for many organisms, but lichens are among the dominating organisms in these habitats. In the performant mutual protective system, lichen fungi often accumulate high amounts of metabolites with specific physicochemical properties (UV absorbents, hydrophobicity) which help the lichens to survive. Unique secondary metabolites and polysaccharides have been isolated and tested from these organisms. Even though this has been tested until now only with a low number of compounds so far, interesting activities have been recorded. We review here some of the antimicrobial, anti-inflammatory, antiproliferative and antioxidant activities properties described. Solutions with axenic biotechnological cultivation of each symbiotic partner and particularly the mycobiont to obtain the lichen secondary metabolites are challenging to overcome the limitations for the supply of these rare compounds. Additionally, these lichens appear to harbour a diversity of culturable microorganisms from which active compounds have also been isolated recently

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Section: Secondary Compounds From Microbial Associates Of Lichensmentioning

confidence: 99%

Bioactive lichen metabolites: alpine habitats as an untapped source

2010

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“…More recently, the "trimethyl lock" concept has been applied by Raines and co-workers to the design of latent fluorophores as labels/indicators for biochemical and biological research [95,96]. Last, but not least, a 2007 report by Weerapreeyakul et al describes "trimethyl lock" bioreductive prodrugs of fungal cytotoxic compounds aimed at cancer cells characterized by hypoxia and over-expression of reductases [97]. These two-step prodrugs were seen to be moderately to highly cytotoxic to cancer cells, while stable in the presence of esterases [97].…”

Section: Two-step Activationmentioning

confidence: 99%

“…Last, but not least, a 2007 report by Weerapreeyakul et al describes "trimethyl lock" bioreductive prodrugs of fungal cytotoxic compounds aimed at cancer cells characterized by hypoxia and over-expression of reductases [97]. These two-step prodrugs were seen to be moderately to highly cytotoxic to cancer cells, while stable in the presence of esterases [97]. From what is above described, two-step activation can be regarded as an ingenious way to deal with the undeniable relevance of enzyme bioconversion of prodrugs, even of those originally designed to be activated by strictly chemical intramolecular pathways.…”

Section: Two-step Activationmentioning

confidence: 99%

Cyclization-activated Prodrugs

2007

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Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter-and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.

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“…33–38 Importantly, the ability of NQO1 to reductively activate sophisticated quinone and quinoidal compounds makes it an ideal target for the development of antitumor compounds 39, 40 and prodrugs. 31, 41 However, the quantitative behavior of human NQO1 with structurally similar, simple quinones, or quinones that can be used as trigger groups for prodrugs and delivery vehicles, has to date not been assessed.…”

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confidence: 99%

Human NAD(P)H:Quinone Oxidoreductase Type I (hNQO1) Activation of Quinone Propionic Acid Trigger Groups

et al. 2012

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NAD(P)H:quinone oxidoreductase type I (NQO1) is a target enzyme for triggered delivery of drugs at inflamed tissue and tumor sites, particularly those that challenge traditional therapies. Prodrugs, macromolecules, and molecular assemblies possessing trigger groups that can be cleaved by environmental stimuli are vehicles with the potential to yield active drug only at prescribed sites. Furthermore, quinone propionic acids (QPAs) covalently attached to prodrugs or liposome surfaces can be removed by application of a reductive trigger stimulus, such as that from NQO1; their rates of reductive activation should be tunable via QPA structure. We explored in detail the recombinant human NAD(P)H:quinone oxidoreductase type I (rhNQO1)-catalyzed NADH reduction of a family of substituted QPAs and obtained high precision kinetic parameters. It is found that small changes in QPA structure—in particular, single atom and function group substitutions on the quinone ring at R1—lead to significant impacts on the Michaelis constant (Km), maximum velocity (Vmax), catalytic constant (kcat), and catalytic efficiency (kcat/Km). Molecular docking simulations demonstrate that alterations in QPA structure result in large changes in QPA alignment and placement with respect to the flavin isoalloxazine ring in the active site of rhNQO1; a qualitative relationship exists between the kinetic parameters and the depth of QPA penetration into the rhNQO1 active site. From a quantitative perspective, a very good correlation is observed between log(kcat/Km) and the molecular-docking-derived distance between flavin hydride donor site and quinone hydride acceptor site in the QPAs, an observation that is in agreement with developing theories. The comprehensive kinetic and molecular modeling knowledge obtained for the interaction of recombinant human NQO1 with the quinone propionic acid analogues provides insight into the design and implementation of the QPA trigger groups for drug delivery applications.

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Synthesis of Bioreductive Esters from Fungal Compounds

Cited by 18 publications

References 18 publications

Bioactive lichen metabolites: alpine habitats as an untapped source

Bioactive lichen metabolites: alpine habitats as an untapped source

Cyclization-activated Prodrugs

Human NAD(P)H:Quinone Oxidoreductase Type I (hNQO1) Activation of Quinone Propionic Acid Trigger Groups

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