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1.
Famciclovir is the oral form of the potent antiherpesvirus agent, penciclovir. Hydrolysis of one of the acetyl ester groups of famciclovir creates a chiral centre leading to the possible formation of (R)- and (S)-enantiomers. During its conversion to penciclovir, famciclovir forms two chiral metabolites, namely monoacetyl-6-deoxy-penciclovir and monoacetyl-penciclovir. The absolute configuration and stereospecificity of the monoacetyl metabolites of famciclovir, produced in human intestinal wall extract, were determined using isotopically chiral famciclovir and 13C NMR spectroscopy of the isolated metabolites. 13C NMR showed that the esterase(s), in human intestinal wall extract, hydrolysed the acetyl group preferentially from the pro-(S)-acetoxymethyl group of famciclovir. The specificity of esterase action in forming monoacetyl-6-deoxy-penciclovir and monoacetyl-penciclovir was about 77 and 72%, respectively. © 1993 Wiley-Liss, Inc. 相似文献
2.
Anber F. Mohammed Graciela Andrei Alaa M. Hayallah Samia G. Abdel-Moty Robert Snoeck Claire Simons 《Bioorganic & medicinal chemistry》2019,27(6):1023-1033
A series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against herpes simplex virus 1 and 2 (HSV-1, HSV-2) and thymidine kinase deficient (ACV resistant) HSV-1. The tricyclic HBG derivatives were devoid of inhibitory activity however several of the tricyclic PCV derivatives showed promising antiviral activity, in particular 9g (R?=?4-MeO-C6H4) displayed good inhibitory activity (HSV-1 EC50 1.5?μM, HSV-2 EC50 0.8?μM) and retained inhibitory activity in HSV-1 TK? cells (EC50 0.8?μM). Computational docking experiments supported the biological data observed and this preliminary study provides useful data for further development of tricyclic acyclic nucleoside derivatives with improved lipophilicity and retention of activity in HSV-1 TK deficient strains. Also, the new tricyclic derivatives were evaluated against a broad range of other DNA and RNA viruses, but were found to be inactive at subtoxic concentrations. In addition, weak to moderate cytostatic effect was observed for the new compounds. 相似文献
3.
Fabio Dall'Olio Nadia Malagolini Gabriella Campadelli-Fiume Franca Serafini-Cessi 《Glycoconjugate journal》1986,3(1):71-84
The progeny of Herpes simplex virus type 1 (HSV-1) grown in ricin-resistant 14 cells (RicR14) lackingN-acetylglucosaminyltransferase I was released in the extracellular medium at a very low rate. By using a monoclonal antibody immobilized on Sepharose we purified from HSV-1-infected RicR14 cells a viral glycoprotein (gC), which carries bothN-andO-linked oligosaccharides. Glycopeptides obtained from [3H]mannoselabeled gC by Pronase digestion were entirely susceptible to endo--N-acetylglucosaminidase H, and the major oligosaccharide released was Man4GlcNAc. The accumulation of this high-mannose species was related to the enzymic defect of the host cells and to the long retention of the viral glycoprotein within the cells. The extent ofO-glycosylation evaluated in [14C]glucosamine-labeled gC from RicR14 cells as compared to that of gC from wild type cells did not appear to be significantly modified.Abbreviations Con A
concanavalin A
- BHK cells
baby hamster kidney cells
- HSV
Herpes simplex virus 相似文献
4.
Kern ER Palmer J Szczech G Painter G Hostetler KY 《Nucleosides, nucleotides & nucleic acids》2000,19(1-2):501-513
The purpose of these studies was to compare the efficacy of acyclovir monophosphate (ACVMP), acyclovir (ACV), or penciclovir (PCV) against HSV-1 in an orofacial infection of mice and against ACV sensitive and resistant genital HSV-2 infections of guinea pigs. Treatment was initiated 24, 48, or 72 hours post inoculation with 5% ACVMP, 5% ACV (Zovirax) or 1% PCV (Denavir). In all experiments, similar efficacy was obtained for ACVMP and ACV, whereas PCV was considerably less effective. 相似文献
5.
To assess the role of Fas in lesion development during genital HSV-2 infection, we used a well-established HSV-2 murine model applied to MRL-Faslpr/J (Fas−/−) and C3-Faslgld/J (FasL−/−) C57BL6 mice. In vitro infection of murine keratinocytes and epithelial cells was used to clarify molecular details of HSV-2 infection. Despite upregulation of Fas and FasL, HSV-2-infected keratinocytes and epithelial cells showed a moderate level of apoptosis due to upregulated expression of the anti-apoptotic factors Bcl-2, Akt kinase and NF-κB. Inflammatory lesions within the HSV-2-infected epithelium of C57BL6 mice consisted of infected cells upregulating Fas, FasL and Bcl-2, uninfected cells upregulating Fas and neutrophils expressing both Fas and FasL. Apoptosis was detected in HSV-2-infected cells and to even higher extent in non-infected cells surrounding HSV-2 infection sites. HSV-2 infection of Fas- and FasL-deficient mice led to increased apoptosis and stronger recruitment of neutrophils within the infection sites. We conclude that the Fas pathway participates in regulation of inflammatory response in the vaginal epithelium at the initial stage of HSV-2 infection. 相似文献
6.
Jrgen Hermansson Mrit Eriksson Olof Nyquist 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1984,336(1)
The direct resolution and quantitation of (R)- and (S)-disopyramide, isolated from human plasma, was accomplished using a chiral α1-acid glycoprotein column. A LiChrosorb RP-2 column (50 × 3.0 mm I.D.) was used as a precolumn. Phosphate buffer, pH 6.20, containing 2-propanol and N,N-dimethyloctylamine was used as mobile phase, expressed as the relative standard deviation, was 1.8% and 3.3% for (R)- and (S)-disopyramide, respectively, at a drug level of 0.5 μg/ml. In two subjects who received a single capsule of racemic disopyramide (150 mg), the plasma levels of the (R) isomer were about half those of the (S) isomer. The half-lives of (R)- and (S)-disopyramide were similar. 相似文献
7.
Characterization of herpes simplex viruses selected in culture for resistance to penciclovir or acyclovir 总被引:4,自引:0,他引:4
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Sarisky RT Quail MR Clark PE Nguyen TT Halsey WS Wittrock RJ O'Leary Bartus J Van Horn MM Sathe GM Van Horn S Kelly MD Bacon TH Leary JJ 《Journal of virology》2001,75(4):1761-1769
Penciclovir (PCV), an antiherpesvirus agent in the same class as acyclovir (ACV), is phosphorylated in herpes simplex virus (HSV)-infected cells by the viral thymidine kinase (TK). Resistance to ACV has been mapped to mutations within either the TK or the DNA polymerase gene. An identical activation pathway, the similarity in mode of action, and the invariant cross-resistance of TK-negative mutants argue that the mechanisms of resistance to PCV and ACV are likely to be analogous. A total of 48 HSV type 1 (HSV-1) and HSV-2 isolates were selected after passage in the presence of increasing concentrations of PCV or ACV in MRC-5 cells. Phenotypic analysis suggested these isolates were deficient in TK activity. Moreover, sequencing of the TK genes from ACV-selected mutants identified two homopolymeric G-C nucleotide stretches as putative hot spots, thereby confirming previous reports examining Acv(r) clinical isolates. Surprisingly, mutations identified in PCV-selected mutants were generally not in these regions but distributed throughout the TK gene and at similar frequencies of occurrence within A-T or G-C nucleotides, regardless of virus type. Furthermore, HSV-1 isolates selected in the presence of ACV commonly included frameshift mutations, while PCV-selected HSV-1 mutants contained mostly nonconservative amino acid changes. Data from this panel of laboratory isolates show that Pcv(r) mutants share cross-resistance and only limited sequence similarity with HSV mutants identified following ACV selection. Subtle differences between PCV and ACV in the interaction with viral TK or polymerase may account for the different spectra of genotypes observed for the two sets of mutants. 相似文献
8.
Yao Nie Hai Yan wang Na Xu Rong Xiao Zhi Hao sun 《Biocatalysis and Biotransformation》2013,31(3):210-219
An (R)-specific carbonyl reductase from Candida parapsilosis CCTCCM203011 (CprCR) was shown to catalyze the asymmetric reduction of 2-hydroxyacetophenone to (R)-1-phenyl-1,2-ethanediol (PED), which is a critical chiral building block in organic synthesis. The gene (rcr) encoding CprCR was cloned based on the amino acid sequences of tryptic fragments of the enzyme. Sequence analysis revealed that rcr is comprised of 1008 nucleotides encoding a 35 977 Da polypeptide, and shares similarity to proteins of the medium-chain dehydrogenase/reductase (MDR) superfamily. Recombinant rcr expressed in Escherichia coli showed a specific 2-hydroxyacetophenone-reducing activity. Using rcr expressing cells, (R)-PED was obtained by asymmetric reduction, which is complementary in enantiomeric configuration to (S)-PED obtained by using whole cells of C. parapsilosis. After optimization of reaction conditions, (R)-PED was produced at 95.5% enantiomeric excess with a yield of 92.6% when isopropanol was used for cofactor regeneration. 相似文献
9.
Esteban A. Ugliarolo Dolores Gagey Beatriz Lantaño Graciela Y. Moltrasio Rodolfo H. Campos Lucía V. Cavallaro Albertina G. Moglioni 《Bioorganic & medicinal chemistry》2012,20(19):5986-5991
New chiral purinyl and 8-azapurinyl carbanucleoside derivatives based on indanol were synthesized from commercial available (1S,2S)-trans-1-amino-2-indanol and (1R,2R)-trans-1-amino-2-indanol using a linear methodology. The antiviral activity and cytotoxicity of these compounds were evaluated against herpes simplex virus type 1 (HSV-1) in Vero cells, bovine viral diarrhea virus (BVDV) in Mardin-Darby bovine kidney (MDBK) cells and hepatitis B virus (HBV) in HepG2 2.2.15 cell line. Three compounds, showed an inhibition of the HBsAg levels similar to reference drug lamivudine. One chloropurinyl nucleoside, derived from the cis-1-amino-2-indanol, was cytotoxic on MDBK cells and it could be a lead for developing anticancer agents. 相似文献
10.
Akihisa Kato Shumpei Tsuda Zhuoming Liu Hiroko Kozuka-Hata Masaaki Oyama Yasushi Kawaguchi 《Journal of virology》2014,88(1):655-666
Us3 is a serine-threonine protein kinase encoded by herpes simplex virus 1 (HSV-1). In this study, a large-scale phosphoproteomic analysis of titanium dioxide affinity chromatography-enriched phosphopeptides from HSV-1-infected cells using high-accuracy mass spectrometry (MS) and subsequent analyses showed that Us3 phosphorylated HSV-1-encoded dUTPase (vdUTPase) at serine 187 (Ser-187) in HSV-1-infected cells. Thus, the following observations were made. (i) In in vitro kinase assays, Ser-187 in the vdUTPase domain was specifically phosphorylated by Us3. (ii) Phosphorylation of vdUTPase Ser-187 in HSV-1-infected cells was detected by phosphate-affinity polyacrylamide gel electrophoresis analyses and was dependent on the kinase activity of Us3. (iii) Replacement of Ser-187 with alanine (S187A) in vdUTPase and an amino acid substitution in Us3 that inactivated its kinase activity significantly downregulated the enzymatic activity of vdUTPase in HSV-1-infected cells, whereas a phosphomimetic substitution at vdUTPase Ser-187 restored the wild-type enzymatic activity of vdUTPase. (iv) The vdUTPase S187A mutation as well as the kinase-dead mutation in Us3 significantly reduced HSV-1 replication in human neuroblastoma SK-N-SH cells at a multiplicity of infection (MOI) of 5 but not at an MOI of 0.01, whereas the phosphomimetic substitution at vdUTPase Ser-187 restored the wild-type viral replication at an MOI of 5. In contrast, these mutations had no effect on HSV-1 replication in Vero and HEp-2 cells. Collectively, our results suggested that Us3 phosphorylation of vdUTPase Ser-187 promoted HSV-1 replication in a manner dependent on cell types and MOIs by regulating optimal enzymatic activity of vdUTPase. 相似文献
11.
《Bioscience, biotechnology, and biochemistry》2013,77(6):1354-1357
Stereoselective synthesis of a promising flower-inducing 9,10-ketol octadecadienoic acid (KODA) analog, (9R,12S,13R,15Z)-9-hydroxy-12,13-methylene-10-oxooctadec-15-enoic acid, was designed to obtain the desired stereoisomer via coupling between chiral sulfone and aldehyde segments. A known chiral cyclopropane derivative was converted to the sulfone segment via carbon-chain elongation and sulfonylation. Dec-9-en-1-ol was converted to the aldehyde segment, whose C-9 configuration was introduced by Sharpless asymmetric dihydroxylation. Coupling of the both segments and subsequent assembly gave the desired (9R,12S,13R,15Z)-analog. The (9S,12S,13R,15Z)-analog was also synthesized by using the enatiomeric aldehyde segment. This strategy made it possible to synthesize the remaining stereoisomeric analogs. 相似文献
12.
Chiral alcohols are useful as intermediates for the synthesis of drugs. In the production of chiral alcohols, microbial enzymes are promising since high optical purity is required. Under these conditions, the reaction by resting cells is more convenient and inexpensive than by an enzyme reaction. Chiral 1,2‐propanediol and 2,3‐butanediol were obtained using cells expressing the enzyme which demonstrated high stereospecificity. By means of recombinant cells expressing the glycerol dehydrogenase of Hansenula polymorpha DL‐1, the medium was enriched with (S)‐1,2‐propanediol (98 % enantiometric excess, e.e.) during a 24‐h incubation, whereas the (R)‐form was removed from 100 mM of the racemate (R:S = 1:1). For an asymmetric reduction, a recombinant was constructed which also expressed the glucose dehydrogenase gene of Bacillus subtilis origin as an NADH reproducer. In the resting cell reaction, the pH control at 7.5 promoted the conversion from ketone to alcohol. (2R,3R)‐2,3‐butanediol (e.e. > 99.9 %; 308 mM) was produced from 800 mM acetoin (R:S = 3:4); (R)‐1,2‐propanediol (e.e. > 99.9 %; 550 mM) from 800 mM acetol in a 33‐h incubation by the addition of glucose and ketone with pH control. In this reaction, (S)‐forms of both 2,3‐butanediol and 1,2‐propanediol were not produced. The pH control and feeding of the substrates were uncomplicated. The production process of the chiral alcohol by the recombinants which expresses glycerol dehydrogenase proved convenient. 相似文献
13.
Byung-Kwan Cho Ho Jung Cho Hyungdon Yun Byung-Gee Kim 《Journal of Molecular Catalysis .B, Enzymatic》2003,26(3-6):273
An efficient simultaneous synthesis of enantiopure (S)-amino acids and chiral (R)-amines was achieved using α/ω-aminotransferase (α/ω-AT) coupling reaction with two-liquid phase system. As, among the enzyme components in the α/ω-AT coupling reaction systems, only ω-AT is severely hampered by product inhibition by ketone product, the coupled reaction cannot be carried out above 60 mM substrates. To overcome this problem, a two-liquid phase reaction was chosen, where dioctylphthalate was selected as the solvent based upon biocompatibility, partition coefficient and effect on enzyme activity. Using 100 mM of substrates, the AroAT/ω-AT and the AlaAT/ω-AT coupling reactions asymmetrically synthesized (S)-phenylalanine and (S)-2-aminobutyrate with 93% (>99% eeS) and 95% (>99% eeS) of conversion yield, and resolved the racemic α-methylbenzylamine with 56% (95% eeR) and 54% (96% eeR) of conversion yield, respectively. Moreover, using 300 mM of 2-oxobutyrate and 300 mM of racemic α-methylbenzylamine as substrates, the coupling reactions yielded 276 mM of (S)-2-aminobutyrate (>99% ee) and 144 mM of (R)-α-methylbenzylamine (>96% ee) in 9 h. Here, most of the reactions take place in the aqueous phase, and acetophenone mainly moved to the organic phase according to its partition coefficient. 相似文献
14.
In this study, a standard strain of HSV-1 (strain SM44) was used to investigate the antiviral activity of the recombinant Cyanovirin-N (CV-N) against Herpes simplex virus type
1 (HSV-1) in vitro and in vivo. Cytopathic effect (CPE) and MTT assays were used to evaluate the effect of CV-N on HSV-1 in Vero cells. The number of copies
of HSV-DNA was detected by real-time fluorescence quantitative PCR (FQ-PCR). The results showed that CV-N had a low cytotoxicity
on Vero cells with a CC50 of 359.03±0.56 μg/mL, and that it could not directly inactivate HSV-1 infectivity. CV-N not only reduced the CPE of HSV-1
when added before or after viral infection, with a 50% inhibitory concentration (IC50) with 2.26 and 30.16μg/mL respectively, but it also decreased the copies of HSV-1 DNA in infected host cells. The encephalitis
model for HSV-1 infection was conducted in Kunming mice, and treated with three dosages of CV-N (0.5, 5 &; 10 mg/kg) which
was administered intraperitoneally at 2h, 3d, 5d, 7d post infection. The duration for the appearance of symptoms of encephalitis
and the survival days were recorded and brain tissue samples were obtained for pathological examination (HE staining). Compared
with the untreated control group, in the 5mg/kg CV-N and 10mg/kg CV-N treated groups, the mice suffered light symptoms and
the number of survival days were more than 9d and 14d respectively. HE staining also showed that in 5mg/kg CV-N and 10mg/kg
CV-N treated groups, the brain cells did not show visible changes, except for a slight inflammation. Our results demonstrated
that CV-N has pronounced antiviral activity against HSV-1 both in vitro and in vivo, and it would be a promising new candidate for anti-HSV therapeutics. 相似文献
15.
Kiril Chuchkov Radoslav Chayrov Anton Hinkov Daniel Todorov Kalina Shishkova Ivanka G. Stankova 《Nucleosides, nucleotides & nucleic acids》2020,39(7):979-990
АBSTRACTEsters of the antiherpetic drugs ganciclovir, penciclovir with the bile acids (cholic, chenodeoxycholic and deoxycholic) and amino acid esters of acyclovir were generated and evaluated for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The antiviral assays demonstrated that modified analogs of ACV and PCV are less active compared to the initial substances against HSV-1and HSV-2. CC50 for ganciclovir-deoxycholate corresponded to the CC50 of the other analogs and its activity is lower than ganciclovir. Obtained results show that tested modification do not improve bioavailability of nucleoside analogs in cells. 相似文献
16.
An asymmetric hydrogen-transfer biocatalyst consisting of mutated Rhodococcus phenylacetaldehyde reductase (PAR) or Leifsonia alcohol dehydrogenase (LSADH) was applied for some water-soluble ketone substrates. Among them, 4-hydroxy-2-butanone was
reduced to (S)/(R)-1,3-butanediol, a useful intermediate for pharmaceuticals, with a high yield and stereoselectivity. Intact Escherichia coli cells overexpressing mutated PAR (Sar268) or LSADH were directly immobilized with polyethyleneimine or 1,6-diaminehexane
and glutaraldehyde and evaluated in a batch reaction. This system produced (S)-1,3-butanediol [87% enantiomeric excess (e.e.)] with a space time yield (STY) of 12.5 mg h−1 ml−1 catalyst or (R)-1,3-butanediol (99% e.e.) with an STY of 60.3 mg h−1 ml−1 catalyst, respectively. The immobilized cells in a packed bed reactor continuously produced (R)-1,3-butanediol with a yield of 99% (about 49.5 g/l) from 5% (w/v) 4-hydroxy-2-butanoate over 500 h. 相似文献
17.
Tai-Shun Lin Shi-Ping Xu Mao-Chin Liu William R. Mancini 《Nucleosides, nucleotides & nucleic acids》2013,32(4):559-568
Abstract Optically pure (R)- and (S)-1-[[2-hydroxy-1-(aminomethyl) ethoxy]methyl]-5-benzyluracil [(R)-AHPBU and (S)-AHPBU, respectively], two potent uridine phosphorylase inhibitors, have been synthesized via multi-step syntheses starting from independent chiral compounds. The activity of (R)-AHPBU, (S)-AHPBU, and (R,S-AHPBU which have been previously synthesized, on the inhibition of uridine phosphorylase from Sarcoma-180 cells has been studied and compared. The K. values for (R,S)-, (R)- and (S)-AHPBU were determined to be 15·2.3, 17·2.7 and 16·2.0 nM, respectively. This indicates that (R) and (S) optical enantiomers have the same affinity for binding to uridine phosphorylase. These acyclic pyrimidine amino nucleoside analogues represent a new class of potent uridine phosphorylase inhibitors, which has a bulky hydrophobic substituent at the 5-position in the uracil base, yet has remarkably high water solubility. 相似文献
18.
《Bioscience, biotechnology, and biochemistry》2013,77(7):1640-1646
An (R)-1-phenyl-1,3-propanediol-producing enzyme was purified from Trichosporon fermentans AJ-5152. It was NADPH-dependent and converted 3-hydroxy-1-phenylpropane-1-one (HPPO) to (R)-1-phenyl-1,3-propanediol [(R)-PPD] with anti-Prelog’s specificity. It showed maximum activity at pH 7.0 and 40 °C. Its K m and V max values toward HPPO were 20.1 mM and 3.4 μmol min?1 mg protein?1 respectively. The relative molecular weight of the enzyme was estimated to be 68,000 on gel filtration and 32,000 on SDS-polyacrylamide gel electrophoresis. An (R)-PPD-producing reaction using the (R)-PPD-producing enzyme and an NADPH recycling system was carried out by successive feeding of HPPO. A total (R)-PPD yield of 8.9 g/l was produced in 16 h. The molar yield was 76%, and the optical purity of the (R)-PPD produced was over 99% e.e. 相似文献
19.
Martinelli E Tharinger H Frank I Arthos J Piatak M Lifson JD Blanchard J Gettie A Robbiani M 《PLoS pathogens》2011,7(6):e1002109
Herpes simplex virus type 2 (HSV-2) increases the risk of HIV-1 infection and, although several reports describe the interaction between these two viruses, the exact mechanism for this increased susceptibility remains unclear. Dendritic cells (DCs) at the site of entry of HSV-2 and HIV-1 contribute to viral spread in the mucosa. Specialized DCs present in the gut-associated lymphoid tissues produce retinoic acid (RA), an important immunomodulator, able to influence HIV-1 replication and a key mediator of integrin α4β7 on lymphocytes. α4β7 can be engaged by HIV-1 on the cell-surface and CD4+ T cells expressing high levels of this integrin (α4β7
high) are particularly susceptible to HIV-1 infection. Herein we provide in-vivo data in macaques showing an increased percentage of α4β7
high CD4+ T cells in rectal mucosa, iliac lymph nodes and blood within 6 days of rectal exposure to live (n = 11), but not UV-treated (n = 8), HSV-2. We found that CD11c+ DCs are a major target of HSV-2 infection in in-vitro exposed PBMCs. We determined that immature monocyte-derived DCs (moDCs) express aldehyde dehydrogenase ALDH1A1, an enzyme essential for RA production, which increases upon HSV-2 infection. Moreover, HSV-2-infected moDCs significantly increase α4β7 expression on CD4+ T lymphocytes and HIV-1 infection in DC-T cell mixtures in a RA-dependent manner. Thus, we propose that HSV-2 modulates its microenviroment, influencing DC function, increasing RA production capability and amplifying a α4β7
highCD4+ T cells. These factors may play a role in increasing the susceptibility to HIV-1. 相似文献
20.
Production of Lactobacillus kefir cells for asymmetric synthesis of a 3,5-dihydroxycarboxylate 总被引:1,自引:0,他引:1
Pfruender H Amidjojo M Hang F Weuster-Botz D 《Applied microbiology and biotechnology》2005,67(5):619-622
An efficient fedbatch process for the production of Lactobacillus kefir DSM 20587 cells was developed. An improvement in space time yield of 270% (3.7 gDCW l–1 day–1) and in final enzyme activity of 440% (9.1 U/ml) was achieved on a 150 l scale by controlling the oxygen transfer rate to 7–9 mmol l–1 h–1. The cells exhibited good and highly stereoselective reducing activities against tert-butyl 6-chloro-3,5-dioxohexanoate. tert-Butyl (3R,5S)-6-chloro-dihydroxyhexanoate, a chiral building block for HMG-CoA reductase inhibitor synthesis, was produced with 47.5% yield and >99% ee at C33 and C55 in a simple batch biotransformation process. 相似文献