Synthesis and bioactivities of steroid derivatives as antifungal agents

Chung, Sung‐Kee; Ryoo, Chung Hwan; Yang, Huan; Shim, Jeung‐Yeop; Kang, Myung Goo; Lee, Ki Wha; Kang, Heui Il

doi:10.1016/s0040-4020(98)01000-x

Cited by 32 publications

(17 citation statements)

References 35 publications

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“…The fungal ability to Cmethylate sterols is the only proven difference in sterol synthetic pathways between humans and opportunistic pathogens; as such, the SMT is considered to be a unique target for rational drug design (7)(8)(9). Cultures of Saccharomyces cereVisiae, Candida albicans, or Gibberella fujikori in the presence of SMT inhibitors such as 25-azalanosterol 5 result in the decreased production of ergosterol 4, the accumulation of zymosterol 2, and the inhibition of growth, supporting its identification as a critical step (Scheme 1) (10)(11)(12)(13)(14)(15).…”

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confidence: 96%

Sterol Methyltransferase: Functional Analysis of Highly Conserved Residues by Site-Directed Mutagenesis

et al. 2003

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Sterol methyltransferase (SMT), the enzyme from Saccharomyces cerevisiae that catalyzes the conversion of sterol acceptor in the presence of AdoMet to C-24 methylated sterol and AdoHcy, was analyzed for amino acid residues that contribute to C-methylation activity. Site-directed mutagenesis of nine aspartate or glutamate residues and four histidine residues to leucine (amino acids highly conserved in 16 different species) and expression of the resulting mutant proteins in Escherichia coli revealed that residues at H90, Asp125, Asp152, Glu195, and Asp276 are essential for catalytic activity. Each of the catalytically impaired mutants bound sterol, AdoMet, and 25-azalanosterol, a high energy intermediate analogue inhibitor of C-methylation activity. Changes in equilibrium binding and kinetic properties of the mutant enzymes indicated that residues required for catalytic activity are also involved in inhibitor binding. Analysis of the pH dependence of log kcat/Km for the wild-type SMT indicated a pH optimum for activity between 6 and 9. These results and data showing that only the mutant H90L binds sterol, AdoMet, and inhibitor to similar levels as the wild-type enzyme suggest that H90 may act as an acceptor in the coupled methylation-deprotonation reaction. Circular dichroism spectra and chromatographic information of the wild-type and mutant enzymes confirmed retention of the overall conformation of the enzyme during the various experiments. Taken together, our studies suggest that the SMT active center is composed of a set of acidic amino acids at positions 125, 152, 195, and 276, which contribute to initial binding of sterol and AdoMet and that the H90 residue functions subsequently in the reaction progress to promote product formation.

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confidence: 96%

Sterol Methyltransferase: Functional Analysis of Highly Conserved Residues by Site-Directed Mutagenesis

et al. 2003

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“…The synthesis of these key aldehydes has been described previously. 34,41 3b-Acetoxy-5a-lanosta-8,24-diene (2) was prepared using previously published procedures and was isolated along with 50% dihydrolanosterol impurity which could not be separated at this stage. 39 Epoxidation of the mixed lanosterol acetates (2) and dihydrolanosterol acetate (3b) under standard conditions using m-CPBA gave 24(R,S)-3b-acetoxy5a-24,25-epoxy-lanost-8-ene (4) in 75% yield and unreacted dihydrolanosterol which was removed following chromatography.…”

Section: Resultsmentioning

confidence: 99%

“…1 H and 13 C NMR spectra for all compounds synthesized were assigned based on correlation with published data and NMR studies on similar compounds. 34,41 The key compounds synthesized in this study are the novel 24-amino-25,26,27-trinorlanost-8-enes (8-13) derived from the 3b-acetoxy aldehyde (6) and those from 3b-hydroxy aldehyde (7) to give amines (14-19) produced directly from aldehydes (6) and (7) of >95% purity. The direct reductive amination of aldehydes (6) and (7) with various secondary and primary amines was successfully achieved using sodium triacetoxyborohydride in 1,2-dichloroethane 42 (Table 1), with selective, fast reactions and no aldehyde reductions detected.…”

Section: Resultsmentioning

confidence: 99%

“…Chung et al have described the antifungal activity of a variety of amine derivatives of lanosterol at the C-24 position. 34 The antifungal activities of these amines against Cryptococcus neoformans, a fungal strain considered to be important in connection with AIDS, was seen to improve along the order of ethyl, cyclohexyl, benzyl, methyl and primary amino derivatives. Chung reported anti-fungal activity in vitro but unfortunately this effect was not evident in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of novel 24-amino-25,26,27-trinorlanost-8-enes: Cytotoxic and apoptotic potential in U937 cells

O'Keeffe

Kenny

Brunton

et al. 2015

Bioorganic & Medicinal Chemistry

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“…The aldehyde (4) was then used as the synthetic precursor to prepare both campesterol (12) (Scheme 2) and brassicasterol (17) (Scheme 3) via strategies similar to those reported for the preparation of cholesterol and cholestadiene/cholestatriene derivatives [30][31][32][33][34]. Further experimental details related to the synthesis of the reactive intermediate (4) and its conversion to campersterol (12) and brassicasterol (17) are included in the Supplementary Materials section, please see S1: General experimental procedures and S2: Experimental details.…”

Section: Synthesis Of Campesterol and Brassicasterol Targetsmentioning

confidence: 99%

Phytosterol Recognition via Rationally Designed Molecularly Imprinted Polymers

Schwarz

Leung

Danylec

et al. 2018

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Abstract:Molecularly imprinted polymers (MIPs) prepared via a semi-covalent imprinting strategy using stigmasteryl methacrylate as a polymerisable template have been evaluated by static binding methods for their ability to selectively capture other valuable phytosterol targets, including campesterol and brassicasterol. Design criteria based on molecular modelling procedures and interaction energy calculations were employed to aid the selection of the co-monomer type, as well as the choice of co-monomer:template ratios for the formation of the pre-polymerisation complex. These novel hybrid semi-covalently imprinted polymers employed N,N -dimethylacryl-amide (N,N -DMAAM) as the functional co-monomer and displayed specific binding capacities in the range 5.2-5.9 mg sterol/g MIP resin. Their binding attributes and selectivities towards phytosterol compounds were significantly different to the corresponding MIPs prepared via non-covalent procedures or when compared to non-imprinted polymers. Cross-reactivity studies using stigmasterol, ergosterol, cholesterol, campesterol, and brassicasterol as single analytes revealed the importance of the A-ring C-3-β-hydroxyl group and the orientational preferences of the D-ring alkyl chain structures in their interaction in the templated cavity with the N,N -dimethylamide functional groups of the MIP. Finally, to obtain useful quantities of both campersterol and brassicasterol for these investigations, improved synthetic routes have been developed to permit the conversion of the more abundant, lower cost stigmasterol via a reactive aldehyde intermediate to these other sterols.

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Synthesis and bioactivities of steroid derivatives as antifungal agents

Cited by 32 publications

References 35 publications

Sterol Methyltransferase: Functional Analysis of Highly Conserved Residues by Site-Directed Mutagenesis

Sterol Methyltransferase: Functional Analysis of Highly Conserved Residues by Site-Directed Mutagenesis

Synthesis of novel 24-amino-25,26,27-trinorlanost-8-enes: Cytotoxic and apoptotic potential in U937 cells

Phytosterol Recognition via Rationally Designed Molecularly Imprinted Polymers

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