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[ CAS No. 159351-69-6 ] {[proInfo.proName]}

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Andressa Santana?Santos ; Vinícius Alexandre Fiaia?Costa ; Vivianny Aparecida Queiroz?Freitas , et al. DOI: PubMed ID:

Abstract: Sporotrichosis is recognized as the predominant subcutaneous mycosis in South America, attributed to pathogenic species within the Sporothrix genus. Notably, in Brazil, Sporothrix brasiliensis emerges as the principal species, exhibiting significant sapronotic, zoonotic and enzootic epidemic potential. Consequently, the discovery of novel therapeutic agents for the treatment of sporotrichosis is imperative. The present study is dedicated to the repositioning of pharmaceuticals for sporotrichosis therapy. To achieve this goal, we designed a pipeline with the following steps: (a) compilation and preparation of Sporothrix genome data; (b) identification of orthologous proteins among the species; (c) identification of homologous proteins in publicly available drug-target databases; (d) selection of Sporothrix essential targets using validated genes from Saccharomyces cerevisiae; (e) molecular modeling studies; and (f) experimental validation of selected candidates. Based on this approach, we were able to prioritize eight drugs for in vitro experimental validation. Among the evaluated compounds, everolimus and bifonazole demonstrated minimum inhibitory concentration (MIC) values of 0.5 μg/mL and 4.0 μg/mL, respectively. Subsequently, molecular docking studies suggest that bifonazole and everolimus may target specific proteins within S. brasiliensis– namely, sterol 14-α-demethylase and serine/threonine-protein kinase TOR, respectively. These findings shed light on the potential binding affinities and binding modes of bifonazole and everolimus with their probable targets, providing a preliminary understanding of the antifungal mechanism of action of these compounds. In conclusion, our research advances the understanding of the therapeutic potential of bifonazole and everolimus, supporting their further investigation as antifungal agents for sporotrichosis in prospective hit-to-lead and preclinical investigations.

Keywords: Sporotrichosis ; Sporothrix brasiliensis ; Drug repurposing ; Structural bioinformatics ; Everolimus

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Leclercq, Gabrielle ; Haegel, Hélène ; Toso, Alberto , et al. DOI: PubMed ID:

Abstract: Background: T cell engaging therapies, like chimeric antigen receptor T cells and T cell bispecific antibodies (TCBs), efficiently redirect T cells towards tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing, a process that is accompanied by the release of cytokines. Despite their promising efficacy in the clinic, treatment with TCBs is associated with a risk of cytokine release syndrome (CRS). The aim of this study was to identify small molecules able to mitigate cytokine release while retaining T cell-mediated tumor killing. Methods: By screening a library of 52 Food and Drug Administration approved kinase inhibitors for their impact on T cell proliferation and cytokine release after CD3 stimulation, we identified mTOR, JAK and Src kinases inhibitors as potential candidates to modulate TCB-mediated cytokine release at pharmacologically active doses. Using an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the effects of mTOR, JAK and Src kinase inhibitors combined with 2+1 T cell bispecific antibodies (TCBs) including CEA-TCB and CD19-TCB on T cell activation, proliferation and target cell killing measured by flow cytometry and cytokine release measured by Luminex. The combination of mTOR, JAK and Src kinase inhibitors together with CD19-TCB was evaluated in vivo in non-tumor bearing stem cell humanized NSG mice in terms of B cell depletion and in a lymphoma patient-derived xenograft (PDX) model in humanized NSG mice in terms of antitumor efficacy. Results: The effect of Src inhibitors differed from those of mTOR and JAK inhibitors with the suppression of CD19-TCB-induced tumor cell lysis in vitro, whereas mTOR and JAK inhibitors primarily affected TCB-mediated cytokine release. Importantly, we confirmed in vivo that Src, JAK and mTOR inhibitors strongly reduced CD19-TCB-induced cytokine release. In humanized NSG mice, continuous treatment with a Src inhibitor prevented CD19-TCB-mediated B cell depletion in contrast to mTOR and JAK inhibitors, which retained CD19-TCB efficacy. Ultimately, transient treatment with Src, mTOR and JAK inhibitors minimally interfered with antitumor efficacy in a lymphoma PDX model. Conclusions: Taken together, these data support further evaluation of the use of Src, JAK and mTOR inhibitors as prophylactic treatment to prevent occurrence of CRS.

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Product Details of [ 159351-69-6 ]

CAS No. :159351-69-6 MDL No. :MFCD00929329
Formula : C53H83NO14 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 958.22 Pubchem ID :-
Synonyms :
RAD001;SDZ-RAD;Xience V.;Certican;Zortress;Brand name Afinitor;RAD 001.SDZ-RAD
Chemical Name :(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-3-((R)-1-((1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl)propan-2-yl)-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentaone

Safety of [ 159351-69-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 159351-69-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 159351-69-6 ]

[ 159351-69-6 ] Synthesis Path-Upstream   1~7

  • 1
  • [ 1314705-20-8 ]
  • [ 159351-69-6 ]
YieldReaction ConditionsOperation in experiment
15% With pyridine; hydrogen fluoride In tetrahydrofuran at 0 - 20℃; for 4 h; To a solution of intermediate 17 (280 mg. 0.23 mmol) in THF (10 mL) was added 2 mL HF in pyridine at 0 deg and stirred at rt for 4 hours. Then 20 ml water ws added and extracted with EtOAc (20 mL x 3). The combined organic layer was washed by 0.5N HCI saturated NaHCO3 and brine, dried over anhydrous Na2S04. After concentration the residue was purified with silica gel chromatography (30percent to 100 percent of EtOAc in petroleum ether as eluent) to give white solid which was further purified by prep-HPLC to give compound A15 (34 mg. 15percent) as a white solid.
15% With pyridine hydrogenfluoride In tetrahydrofuran at 0 - 20℃; for 4 h; To a solution of intermediate 17 (280 mg, 0.23 mmol) in THF (10 mL) was added 2 mL HF in pyridine at 0 deg and stirred at rt for 4 hours. Then, 20 mL water was added and extracted with EtOAc (20 mL×3). The combined organic layer was washed by 0.5N HCl, saturated NaHCO3 and brine, dried over anhydrous Na2SO4. After concentration, the residue was purified with silica gel chromatography (30percent to 100percent of EtOAc in petroleum ether as eluent) to give white solid which was further purified by prep-HPLC to give compound A15 (34 mg, 15percent) as a white solid. 1H NMR (300 MHz, CDCl3) δ6.40-6.00 (m, 5H), 5.53-5.25 (m, 4H), 4.83 (s, 1H), 4.13 (m, 1H): LCMS (m/z) ES? 957 (M?1)?.
6.81 g With pyridine hydrogenfluoride In tetrahydrofuran at 0 - 45℃; for 3.5 h; To a solution of 2-((tert-butyldiphenylsilyl)oxy)ethanol (13.1 g, 43.8 mmol) in toluene (51 g) was added N,N-Diisopropylpentan-3-amine (8.7 g, 50.3 mmol) The clear solution was then cooled to 0°C and trifluoromethanesulfonic acid anhydride (12.3 g, 43.8 mmol) was added dropwise such that the temperature was maintained between (-2°C - 2°C). Following the addition a further portion of toluene (5 g) was used for washing. After 1 .5 h N,N-Diisopropylpentan-3-amine (8.7 g, 50.3 mmol) was added followed by toluene (3 g) and Rapamycin (10.0 g, 10.9 mmol ) washing with toluene (18 g). The reaction was then heated to 40°C and allowed to stir at this temperature for 22.5 h at which point less than 5 Areapercent Rapamycin was remaining according to HPLC analysis. The reaction was cooled to ambient temperature and pyridine (1 .0 mL) was then added to quench the reaction which was stirred for a further 30 mins. The reaction was filtered and diluted with isopropyl acetate. The organic solution was washed with 1 M citric acid solution, 10percent sodium bicarbonate solution followed by water, dried (MgS04) and concentrated in vacuo. To the crude residue (35.6 g) was added THF (240 mL) and this solution was then added dropwise at 0 °C to a HF*pyridine solution (1 :1 , 38.1 g). The reaction was heated to 45 °C for 3.5 h then allowed to cool to ambient temperature and diluted with isopropylacetate (300 g). The reaction was then added slowly to an 8percent aqueous solution of sodium bicarbonate and further washed with isopropylacetate (250 g). The organic phase was then separated and washed with saturated aqueous sodium chloride solution, dried (MgS04) and concentrated in vacuo. The residue was diluted with isopropylacetate, BHT (0.2percent m/m) was added, and the yield of everolimus determined by HPLC analysis against an external standard (6.81 g, 65percent).
Reference： [1] Patent: WO2014/82286, 2014, A1, . Location in patent: Paragraph 50
[2] Patent: US2015/51242, 2015, A1, . Location in patent: Paragraph 0086
[3] Patent: WO2014/203185, 2014, A1, . Location in patent: Page/Page column 22; 23; 24; 26
[4] Patent: CN109206441, 2019, A, . Location in patent: Paragraph 0081; 0087; 0088; 0089
  • 2
  • [ 159351-68-5 ]
  • [ 159351-69-6 ]
YieldReaction ConditionsOperation in experiment
2.96 g With pyridine hydrogenfluoride In tetrahydrofuran at 0 - 45℃; for 1.5 h; To a solution of 2-((tert-butyldimethylsilyl)oxy)ethanol (8.04 g, 43.8 mmol ) in toluene (55 g) was added N,N-diisopropylethylamine (5.94 g, 45.9 mmol ) The clear solution was then cooled to 0°C and Trifluoromethanesulfonic acid anhydride (1 1 .97 g, 42.4 mmol) was added dropwise such that the temperature was maintained between (-2°C - 2°C). Following the addition a further portion of toluene (5 g) was used for washing. After 30 minutes N,N-Diisopropylpentan-3-amine (7.871 g, 45.9 mmol) was added followed by toluene (3 g) and Rapamycin (10.0 g, 10.9 mmol) washing with toluene (18.4 g). The reaction was then heated to 40 °C and allowed to stir at this temperature for 42 h at which point less than 5 Areapercent Rapamycin was remaining according to HPLC analysis. The reaction was cooled to ambient temperature and pyridine (2.6 g) was then added to quench the reaction which was stirred for a further 30 mins. The reaction was filtered and diluted with isopropyl acetate. The organic solution was washed with 1 M citric acid solution, 10percent sodium bicarbonate solution followed by water, dried (MgS04) and concentrated in vacuo. The residue was divided into two portions. To half of this crude residue (9.66 g) THF (100 ml_) was added and this solution was then added dropwise at 0 °C to a HF*pyridine solution (1 :1 , 17.7 g). A further portion of THF (20 ml_) was used for washing. The reaction was heated to 45 °C for 1 .5 h, then allowed to cool to ambient temperature and diluted with isopropylacetate (150 g). The reaction was then added slowly to an 8percent aqueous solution of sodium bicarbonate and further washed with isopropylacetate (250 g). The organic phase was then separated and washed with saturated aqueous sodium chloride solution, dried (MgS04) and concentrated in vacuo. The residue was diluted with isopropylacetate, butylhydroxytoluol (BHT; 0.2percent m/m) was added, and the yield of everolimus determined by HPLC analysis against an external standard (2.96 g, 57percent).
68 %Chromat. With hydrogenchloride; phosphoric acid; water In n-heptane; acetonitrile at 20℃; for 1 h; Example 2: Synthesis of 40-O-(2-hydroxy)ethyl-rapamycin (i.e. everolimus) The crude 40-O-[2-(f-butyldimethylsilyl)oxy]ethyl-rapamycin solution of Example 1 was evaporated to dryness under reduced pressure at 25-30° C. Subsequently, 66 ml of heptane were added to the residue, and the resulting mixture was evaporated to a volume of 40 ml. Then, 48 ml of a (80:20) (v/v) mixture of acetonitrile/water (pH = 1.7, adjusted with 75percent ortho-phosphoric acid) were added, and the pH of the resulting mixture was adjusted to 1 .8 with 1 N HCI solution. The resulted mixture was stirred for 1 hour at room temperature, and the lower layer containing everolimus was separated. The overall yield of everolimus as determined by HPLC using an external standard was 68percent (71 1 mg).
Reference： [1] Patent: WO2014/203185, 2014, A1, . Location in patent: Page/Page column 21; 22
[2] Patent: WO2016/20664, 2016, A1, . Location in patent: Page/Page column 22
[3] Patent: CN103848849, 2016, B, . Location in patent: Paragraph 0027; 0030; 0031
[4] Patent: WO2016/207205, 2016, A1, . Location in patent: Page/Page column 13
[5] Patent: CN109206441, 2019, A, . Location in patent: Paragraph 0077; 0078; 0081
  • 3
  • [ 75-21-8 ]
  • [ 53123-88-9 ]
  • [ 159351-69-6 ]
YieldReaction ConditionsOperation in experiment
6.9 g With trifluorormethanesulfonic acid In toluene at 70℃; for 8 h; Autoclave 9.14 g rapamycin (0.01mol), 11g ethylene oxide (0.25 mol), 0.1 g trifluoromethanesulfonic acid, 30mL toluene was added to the autoclave after mixing, Warmed to 70 ° C, Maintaining 1.0 MPa pressure, the reaction was stopped after 8 hours, cooled to room temperature,The solvent was recovered under reduced pressure and the residue was purified by silica gel column chromatography (200-300 mesh silica gel,Eluent: ethyl acetate: petroleum ether = 20: 1),7.7 g 97.95percent of everolimus was obtained, which was purified by HP-20 resin column chromatography (eluent: acetonitrile: water = 65:35) 6.9 g of everolimus was obtained as a white solid, HPLC purity:99.6percent, Isomer content:0.12percent. Molar yield:72.0percent
Reference： [1] Patent: CN104876944, 2017, B, . Location in patent: Paragraph 0035-0050
  • 4
  • [ 1392400-31-5 ]
  • [ 159351-69-6 ]
Reference： [1] Patent: WO2012/103959, 2012, A1, . Location in patent: Page/Page column 18
[2] Patent: CN106478663, 2017, A, . Location in patent: Paragraph 0023
  • 5
  • [ 107-21-1 ]
  • [ 53123-88-9 ]
  • [ 159351-69-6 ]
YieldReaction ConditionsOperation in experiment
5.7 kg
Stage #1: With trifluoroacetic anhydride In tetrahydrofuran at 10℃; for 1.5 h; Inert atmosphere; Large scale
Stage #2: With boron trifluoride diethyl etherate In tetrahydrofuran at 10℃; for 2 h; Large scale		 620g of ethylene glycol and 6L of tetrahydrofuran were added to the reaction flask,Mix well to mix.The reaction temperature was controlled at 10 .Under nitrogen protection,1.41L trifluoroacetic anhydride was slowly added dropwise,Dropping is completed,Reaction for 1.5 hours,The reaction solution.9.14 kg of rapamycin was dissolved in 54 L of tetrahydrofuran,Added to the reaction solution,The reaction temperature was controlled at 10 .Slowly add 13ml boron trifluoride diethyl ether solution. Bi completed,The reaction was stirred for 2 hours. After the reaction is completed,60L saturated aqueous sodium bicarbonate solution was added,Stir wellThen suction filtered,To the filtrate was added 30 L of ethyl acetate,Liquid separation,The organic phase is washed with pure water until nearly neutral.The organic phase was dried over 500 g of anhydrous sodium sulfate for 2 hours, filtered,Concentrated under reduced pressure to a solventless outflow,A thick liquid. Column chromatography,The eluent is petroleum ether:Ethyl acetate = 1: 6. The collected effluent was concentrated under reduced pressure to give 6.3 kg of yellow foamy solid,Yield 66percent.A mixture of 26.8 L of methanol and ethyl acetate (v / v = 1/3) was added to the above yellow foamy solid,Stirring to dissolve,The temperature was controlled at 25 for 30 minutes,13.4 L cyclohexane was added dropwise,Bi completed,The temperature was controlled at 12 for 2 hours,Cool the feed liquid to about 0 slowly stirring 3h,Suction filtration,Drying at room temperature under vacuum gave 5.7 kg of a white solid,HPLC and mass spectrometry determined that the white solid was everolimus,Purity 98.1percent.
Reference： [1] Patent: CN106146535, 2016, A, . Location in patent: Paragraph 0037; 0038; 0039; 0040; 0041; 0042; 0043-0056
  • 6
  • [ 53123-88-9 ]
  • [ 159351-69-6 ]
Reference： [1] Patent: WO2014/203185, 2014, A1,
[2] Patent: WO2016/20664, 2016, A1,
[3] Patent: CN105254646, 2016, A,
[4] Patent: CN105254646, 2016, A,
[5] Patent: CN105254646, 2016, A,
[6] Patent: CN105254646, 2016, A,
[7] Patent: WO2016/207205, 2016, A1,
[8] Patent: CN106146536, 2016, A,
  • 7
  • [ 331810-13-0 ]
  • [ 159351-69-6 ]
Reference： [1] Patent: CN106146536, 2016, A,
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