Side chain azasteroids and thiasteroids as sterol methyltransferase inhibitors in ergosterol biosynthesis

Renard, Delphine; Perruchon, Johann; Giera, Martin; Müller, Jörg; Bracher, Franz

doi:10.1016/j.bmc.2009.09.037

Cited by 34 publications

(19 citation statements)

References 35 publications

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“…In analogy to the model reactions, an oil bath temperature of 165 C and 15 mol % of triflimide catalyst were required to enforce the rearrangement of 11a to episterone (12), at lower temperatures the desired product was not detectable. At the first glance the new CeC bond formation seemed to be successful, and a product having the same R f -value as ketosteroid 9a on TLC was isolated with 10% yield (Scheme 5).…”

Section: Resultsmentioning

confidence: 99%

Traceless bond construction via rearrangement of N-Boc-N-allylhydrazones giving 1,1-disubstituted olefins

Dittrich

Bracher

2015

Tetrahedron

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Section: Resultsmentioning

confidence: 99%

Traceless bond construction via rearrangement of N-Boc-N-allylhydrazones giving 1,1-disubstituted olefins

Dittrich

Bracher

2015

Tetrahedron

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“…Analysis of the changes in the sterol patterns upon incubation with potential antifungal compounds is a highly efficient method for identification of a defined target enzyme. To identify the target enzyme of EMC120B12, we analyzed the inhibitory effects of EMC120B12 on the distal ergosterol biosynthesis pathway, in which eight distinct enzymes are involved in the conversion of lanosterol to ergosterol (16,(30)(31)(32). Treatment with ergosterol biosynthesis inhibitors leads, depending on the target enzyme, to accumulation of typical ergosterol precursors, e.g., lanosterol (compound 1) (inhibition of C14-demethylase) and/or aberrantly formed sterols such as lichesterol (inhibition of sterol ⌬ 8/7 -isomerase) or 14-methylergosta-8,24(28)-dien-3␤,6␣-diol (compound 4; inhibition of C14-demethylase) (Fig.…”

Section: Resultsmentioning

confidence: 99%

An Antifungal Benzimidazole Derivative Inhibits Ergosterol Biosynthesis and Reveals Novel Sterols

Keller

Müller

Engelhardt

et al. 2015

Antimicrob Agents Chemother

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Fungal infections are a leading cause of morbidity and death for hospitalized patients, mainly because they remain difficult to diagnose and to treat. Diseases range from widespread superficial infections such as vulvovaginal infections to life-threatening systemic candidiasis. For systemic mycoses, only a restricted arsenal of antifungal agents is available. Commonly used classes of antifungal compounds include azoles, polyenes, and echinocandins. Due to emerging resistance to standard therapies, significant side effects, and high costs for several antifungals, there is a need for new antifungals in the clinic. In order to expand the arsenal of compounds with antifungal activity, we previously screened a compound library using a cell-based screening assay. A set of novel benzimidazole derivatives, including (S)-2-(1-aminoisobutyl)-1-(3-chlorobenzyl)benzimidazole (EMC120B12), showed high antifungal activity against several species of pathogenic yeasts, including Candida glabrata and Candida krusei (species that are highly resistant to antifungals). In this study, comparative analysis of EMC120B12 versus fluconazole and nocodazole, using transcriptional profiling and sterol analysis, strongly suggested that EMC120B12 targets Erg11p in the ergosterol biosynthesis pathway and not microtubules, like other benzimidazoles. In addition to the marker sterol 14-methylergosta-8,24(28)-dien-3␤,6␣-diol, indicating Erg11p inhibition, related sterols that were hitherto unknown accumulated in the cells during EMC120B12 treatment. The novel sterols have a 3␤,6␣-diol structure. In addition to the identification of novel sterols, this is the first time that a benzimidazole structure has been shown to result in a block of the ergosterol pathway.

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“…Indeed, novel and recently discovered pathways to ergosterol in the kinetoplastid protozoan Trypanosoma brucei and green algae Chlamydomonas reinhardtii are distinct from each other [5,6] and both of them are partly (T. brucei) or completely (C. reinhardtii) different from the fungal ergosterol biosynthesis pathway [7,8]. 24-SMT enzymes have also attracted considerable interest in drug design for treatment of disease since this class of catalyst is not synthesized by humans, yet they are important to many opportunistic pathogens and parasites responsible for human suffering [9][10][11][12]. 24-SMT enzymes have also attracted considerable interest in drug design for treatment of disease since this class of catalyst is not synthesized by humans, yet they are important to many opportunistic pathogens and parasites responsible for human suffering [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

C-24-methylation of 26-fluorocycloartenols by recombinant sterol C-24-methyltransferase from soybean: evidence for channel switching and its phylogenetic implications

Patkar

Haubrich

et al. 2013

Biochemical Journal

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The tightly coupled nature of the electrophilic alkylation reaction sequence catalysed by 24-SMT (sterol C-24-methyltransferase) of land plants and algae can be distinguished by the formation of cationic intermediates that yield phyla-specific product profiles. C-24-methylation of the cycloartenol substrate by the recombinant Glycine max (soybean) 24-SMT proceeds to a single product 24(28)-methylenecycloartanol, whereas the 24-SMT from green algae converts cycloartenol into two products cyclolaudenol [∆(25(27))-olefin] and 24(28)-methylenecycloartanol [(∆24(28))-olefin]. Substrate analogues that differed in the steric-electronic features at either end of the molecule, 26-homocycloartenol or 3β-fluorolanostadiene, were converted by G. max SMT into a single 24(28)-methylene product. Alternatively, incubation of the allylic 26-fluoro cyclosteroid with G. max SMT afforded a bound intermediate that converted in favour of the ∆(25(27))-olefin product via the cyclolaudenol cation formed initially during the C-24-methylation reaction. A portion of the 26-fluorocycloartenol substrate was also intercepted by the enzyme and the corresponding hydrolysis product identified by GC-MS as 26-fluoro-25-hydroxy-24-methylcycloartanol. Finally, the 26-fluorocycloartenols are competitive inhibitors for the methylation of cycloartenol and 26-monofluorocycloartenol generated timedependent inactivation kinetics exhibiting a kinact value of 0.12 min(-1). The ability of soybean 24-SMT to generate a 25-hydroxy alkylated sterol and fluorinated ∆(25(27))-olefins is consistent with our hypothesis that (i) achieving the cyclolaudenyl cation intermediate by electrophilic alkylation of cycloartenol is significant to the overall reaction rate, and (ii) the evolution of variant sterol C-24-methylation patterns is driven by competing reaction channels that have switched in algae from formation of primarily ∆(25(27)) products that convert into ergosterol to, in land plants, formation of ∆(24(28)) products that convert into sitosterol.

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Side chain azasteroids and thiasteroids as sterol methyltransferase inhibitors in ergosterol biosynthesis

Cited by 34 publications

References 35 publications

Traceless bond construction via rearrangement of N-Boc-N-allylhydrazones giving 1,1-disubstituted olefins

Traceless bond construction via rearrangement of N-Boc-N-allylhydrazones giving 1,1-disubstituted olefins

An Antifungal Benzimidazole Derivative Inhibits Ergosterol Biosynthesis and Reveals Novel Sterols

C-24-methylation of 26-fluorocycloartenols by recombinant sterol C-24-methyltransferase from soybean: evidence for channel switching and its phylogenetic implications

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