Synthesis of Rationally Designed Mechanism-Based Inactivators of the (S)-Adenosyl-L-methionine: Δ24(25)−Sterol Methyl Transferase

Jia, Zhonghua; Zhou, Wen; Guo, Dean; Nes, W. David

doi:10.1080/00397919608003800

Cited by 12 publications

(5 citation statements)

References 10 publications

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“…The source of sterol substrates evaluated in this study is described in our earlier papers ( 18 – 21 ). 24( R,S ),25-epiminolanosterol (EL) and 26,27-dehydrolanosterol were prepared as previously reported ( 30 , 31 ). Voriconazole was purchased from Sigma.…”

Section: Methodsmentioning

confidence: 99%

Sterol methyltransferase a target for anti-amoeba therapy: towards transition state analog and suicide substrate drug design

Kidane

Vanderloop

Zhou

et al. 2017

Journal of Lipid Research

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Ergosterol biosynthesis pathways essential to pathogenic protozoa growth and absent from the human host offer new chokepoint targets. Here, we present characterization and cell-based interference of Acanthamoeba spp sterol 24-/28-methylases (SMTs) that catalyze the committed step in C28- and C29-sterol synthesis. Intriguingly, our kinetic analyses suggest that 24-SMT prefers plant cycloartenol whereas 28-SMT prefers 24(28)-methylene lophenol in similar fashion to the substrate preferences of land plant SMT1 and SMT2. Transition state analog-24(R,S),25-epiminolanosterol (EL) and suicide substrate 26,27-dehydrolanosterol (DHL) differentially inhibited trophozoite growth with IC50 values of 7 nM and 6 µM, respectively, and EL yielded 20-fold higher activity than reference drug voriconazole. Against either SMT assayed with native substrate, EL exhibited tight binding ∼Ki 9 nM. Alternatively, DHL is methylated at C26 by 24-SMT that thereby, generates intermediates that complex and inactivate the enzyme, whereas DHL is not productively bound to 28-SMT. Steroidal inhibitors had no effect on human epithelial kidney cell growth or cholesterol biosynthesis at minimum amoebicidal concentrations. We hypothesize the selective inhibition of Acanthamoeba by steroidal inhibitors representing distinct chemotypes may be an efficient strategy for the development of promising compounds to combat amoeba diseases.

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Section: Methodsmentioning

confidence: 99%

Sterol methyltransferase a target for anti-amoeba therapy: towards transition state analog and suicide substrate drug design

Kidane

Vanderloop

Zhou

et al. 2017

Journal of Lipid Research

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“…The ⌬ 7 -sterol was chosen in preference to the ⌬ 8 -isomer because of well-known chemical diffi culties related to the ⌬ 8 -bond in steroid synthesis of potential mechanism-based inactivators ( 40 ). The preparation of the methylene cyclopropane ring structure is a modifi cation of our previous efforts to construct the sterol side chain bearing a terminal methylene cyclopropane group at C26/C27 ( 41,42 ). Cyclopropyltriphenylphosphium bromide (CPB) (368 mg) was added to anhydrous THF (20 ml) followed by drop-wise addition of n BuLi (1.6 M in hexanes, 0.6 ml) at 50°C under nitrogen protection.…”

Section: Synthesis Of Mcpmentioning

confidence: 99%

Structural complex of sterol 14α-demethylase (CYP51) with 14α-methylenecyclopropyl-Δ7-24, 25-dihydrolanosterol

Hargrove

Wawrzak

Liu

et al. 2012

Journal of Lipid Research

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“…The 26,27-dehydrosterols can be prepared in a few steps starting with the 3-acetylated sterol ( Figure 25 ). The 24–25 double bond of the corresponding sterol is transformed into an aldehyde by ozonolysis with a reductive workup [ 102 ]. The 26,27-cyclopropylidine moiety is installed via a Wittig reaction using the desired sterol aldehyde and the phosphorus ylide formed from cyclopropyltriphenylphosphonium bromide and butyllithium [ 102 ].…”

Section: 24-smt Inhibitorsmentioning

confidence: 99%

Synthesis and Biological Activity of Sterol 14α-Demethylase and Sterol C24-Methyltransferase Inhibitors

Leaver

2018

Molecules

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Sterol 14α-demethylase (SDM) is essential for sterol biosynthesis and is the primary molecular target for clinical and agricultural antifungals. SDM has been demonstrated to be a valid drug target for antiprotozoal therapies, and much research has been focused on using SDM inhibitors to treat neglected tropical diseases such as human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis. Sterol C24-methyltransferase (24-SMT) introduces the C24-methyl group of ergosterol and is an enzyme found in pathogenic fungi and protozoa but is absent from animals. This difference in sterol metabolism has the potential to be exploited in the development of selective drugs that specifically target 24-SMT of invasive fungi or protozoa without adversely affecting the human or animal host. The synthesis and biological activity of SDM and 24-SMT inhibitors are reviewed herein.

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Synthesis of Rationally Designed Mechanism-Based Inactivators of the (S)-Adenosyl-L-methionine: Δ²⁴(25)₋Sterol Methyl Transferase

Cited by 12 publications

References 10 publications

Sterol methyltransferase a target for anti-amoeba therapy: towards transition state analog and suicide substrate drug design

Sterol methyltransferase a target for anti-amoeba therapy: towards transition state analog and suicide substrate drug design

Structural complex of sterol 14α-demethylase (CYP51) with 14α-methylenecyclopropyl-Δ7-24, 25-dihydrolanosterol

Synthesis and Biological Activity of Sterol 14α-Demethylase and Sterol C24-Methyltransferase Inhibitors

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