[ CAS No. 154447-36-6 ] {[proInfo.proName]}

Name: 154447-36-6|2-Morpholino-8-phenyl-4H-chromen-4-one|98%
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SKU: A133122
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Product Citations Expand+

Keratin 19 interacts with GSK3β to regulate its nuclear accumulation and degradation of cyclin D3

Sharma, Pooja ; Tiufekchiev, Sarah ; Lising, Victoria , et al. Mol. Biol. Cell,2021,32(21):ar21. DOI: 10.1091/mbc.e21-05-0255 PubMed ID: 34406791

Abstract: Cyclin D3 regulates the G1/S transition and is frequently overexpressed in several cancer types including breast cancer, where it promotes tumor progression. Here we show that a cytoskeletal protein keratin 19 (K19) phys. interacts with a serine/threonine kinase GSK3β and prevents GSK3β -dependent degradation of cyclin D3. The absence of K19 allowed active GSK3β to accumulate in the nucleus and degrade cyclin D3. Specifically, the head (H) domain of K19 was required to sustain inhibitory phosphorylation of GSK3βSer9, prevent nuclear accumulation of GSK3β,and maintain cyclin D3 levels and cell proliferation. K19 was found to interact with GSK3β and K19-GSK3β interaction was mapped out to require Ser10 and Ser35 residues on the H domain of K19. Unlike wildtype K19, S10A and S35A mutants failed to maintain total and nuclear cyclin D3 levels and induce cell proliferation. Finally, we show that the K19-GSK3β-cyclin D3 pathway affected sensitivity of cells toward inhibitors to cyclin-dependent kinase 4 and 6 (CDK4/6). Overall, these findings establish a role for K19 in the regulation of GSK3β-cyclin D3 pathway and demonstrate a potential strategy for overcoming resistance to CDK4/6 inhibitors.

Purchased from AmBeed: 154447-36-6

Regulation of Cell Cycle Progression by Keratin 19 in Breast Cancer Cells

Sharma, Pooja ; Catholic University of America,2021.

Abstract: Keratins are widely used as diagnostic markers to detect tumors in both primary and distal sites and to determine tumors’ tissue of origin in order to aid in treatment strategies. In this regard, K19 has been particularly useful because it is among the most sensitive diagnostic markers across a broad range of cancer types. K19 has also been shown to be one of the most reliable prognostic markers for multiple tumor types, including breast cancer where higher expression of K19 is correlated with worse patient survival. Despite the clinical data showing positive correlation between increased K19 expression and poor survival rates among patients of breast cancer types, the role of K19 in breast cancer remains unclear. To understand the role of K19 in breast cancer, we generated KRT19 knockout (KO) cell lines using MCF7 and MDA-MB-231 breast cancer cell lines. Using this system, we found that KRT19 KO cells exhibit reduced proliferation compared to parental control cells and uncovered a cell cycle promoting role of K19. We identified that K19 promotes proliferation of cancer cells by stabilizing a cell cycle regulator cyclin D3. However, how a cytoskeletal protein regulates levels of cyclin D3 remained unknown. It has been known that GSK3β play a crucial role in degrading cyclin D3 for proteasomal degradation. In our study in MCF7 cells, we identified GSK3β as a keratin-interacting protein and found that K19 suppressed GSK3β activity by inhibiting its nuclear accumulation. GSK3β-binding by K19 required serine 10 and 35 residue as K19 S10A or S35A mutation failed to protect cyclin D3 from protein degradation. Our results reveal a novel regulatory role of K19 on GSK3β localization and activity as a mechanism of how a cytoskeletal protein stabilizes a cell cycle regulator and promotes proper cell proliferation. In addition, we found that K19 expressing cells are more sensitive to cyclin dependent kinase (CDK) 4/6 inhibitors as compare to KRT19 KO cells. The sensitivity of KRT19 KO cells to CDK4/6 inhibitor was increased when cotreated with a GSK3β inhibitor, demonstrating that the K19-GSK3β axis plays a critical role in drug resistance. Given that K19 expression levels are frequently elevated in various cancers, K19 can be used to predict the efficacy of CDK4/6 inhibitors and patients may be cotreated with a GSK3β inhibitor to avoid drug resistance.

Purchased from AmBeed: 154447-36-6

Product Details of [ 154447-36-6 ]

CAS No. :	154447-36-6	MDL No. :	MFCD00270881
Formula :	C₁₉H₁₇NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CZQHHVNHHHRRDU-UHFFFAOYSA-N
M.W :	307.34	Pubchem ID :	3973
Synonyms :	SF 1101;NSC 697286	Chemical Name :	2-Morpholino-8-phenyl-4H-chromen-4-one

Calculated chemistry of [ 154447-36-6 ] Expand+

Physicochemical Properties

Num. heavy atoms :	23
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.21
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	93.65
TPSA :	42.68 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.95 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.9
Log Po/w (XLOGP3) :	3.13
Log Po/w (WLOGP) :	2.92
Log Po/w (MLOGP) :	2.18
Log Po/w (SILICOS-IT) :	3.91
Consensus Log Po/w :	3.01

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-4.1
Solubility :	0.0244 mg/ml ; 0.0000794 mol/l
Class :	Moderately soluble
Log S (Ali) :	-3.7
Solubility :	0.062 mg/ml ; 0.000202 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-6.3
Solubility :	0.000154 mg/ml ; 0.000000501 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.14

Safety of [ 154447-36-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 154447-36-6 ]

* 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 [ 154447-36-6 ]
Downstream synthetic route of [ 154447-36-6 ]

[ 154447-36-6 ] Synthesis Path-Upstream 1~18

1
[ 688745-45-1 ]
[ 154447-36-6 ]

Reference： [1] Angewandte Chemie - International Edition, 2014, vol. 53, # 34, p. 9026 - 9029[2] Angew. Chem., 2014, vol. 126, # 34, p. 9172 - 9175,4
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 2, p. 569 - 585
[4] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

2
[ 4906-69-8 ]
[ 154447-36-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 2, p. 569 - 585
[2] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

3
[ 98-80-6 ]
[ 351002-11-4 ]
[ 154447-36-6 ]

Reference： [1] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

4
[ 1696-20-4 ]
[ 154447-36-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 2, p. 569 - 585

5
[ 2411-83-8 ]
[ 154447-36-6 ]

Reference： [1] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

6
[ 303-38-8 ]
[ 154447-36-6 ]

Reference： [1] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

7
[ 877-22-5 ]
[ 154447-36-6 ]

Reference： [1] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

8
[ 6342-70-7 ]
[ 154447-36-6 ]

Reference： [1] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

9
[ 130766-15-3 ]
[ 154447-36-6 ]

Reference： [1] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

10
[ 351002-09-0 ]
[ 154447-36-6 ]

Reference： [1] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

11
[ 130735-95-4 ]
[ 154447-36-6 ]

Reference： [1] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

12
[ 688745-54-2 ]
[ 154447-36-6 ]

Reference： [1] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

13
[ 503469-17-8 ]
[ 154447-36-6 ]

Reference： [1] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

14
[ 304-06-3 ]
[ 154447-36-6 ]

Reference： [1] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

15
[ 90-43-7 ]
[ 154447-36-6 ]

Reference： [1] Angewandte Chemie - International Edition, 2014, vol. 53, # 34, p. 9026 - 9029[2] Angew. Chem., 2014, vol. 126, # 34, p. 9172 - 9175,4
[3] Angewandte Chemie - International Edition, 2014, vol. 53, # 34, p. 9026 - 9029[4] Angew. Chem., 2014, vol. 126, # 34, p. 9172 - 9175,4

16
[ 132939-03-8 ]
[ 154447-36-6 ]

17
[ 63992-45-0 ]
[ 154447-36-6 ]

Reference： [1] Angewandte Chemie - International Edition, 2014, vol. 53, # 34, p. 9026 - 9029[2] Angew. Chem., 2014, vol. 126, # 34, p. 9172 - 9175,4

18
[ 15159-40-7 ]
[ 21424-82-8 ]
[ 154447-36-6 ]

Reference： [1] Angewandte Chemie - International Edition, 2014, vol. 53, # 34, p. 9026 - 9029[2] Angew. Chem., 2014, vol. 126, # 34, p. 9172 - 9175,4

[ 154447-36-6 ] Synthesis Path-Downstream 1~43

1
[ 98-80-6 ]
[ 351002-11-4 ]
[ 154447-36-6 ]

Reference： [1]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

2
[ 688745-45-1 ]
[ 154447-36-6 ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 9026 - 9029
Angew. Chem.,2014,vol. 126,p. 9172 - 9175,4
[2]Journal of Medicinal Chemistry,2005,vol. 48,p. 569 - 585
[3]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

3
[ 1696-20-4 ]
[ 154447-36-6 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 569 - 585

4
[ 4906-69-8 ]
[ 154447-36-6 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 569 - 585
[2]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

5
[ 2411-83-8 ]
[ 154447-36-6 ]

Reference： [1]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

6
[ 303-38-8 ]
[ 154447-36-6 ]

Reference： [1]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

7
[ 877-22-5 ]
[ 154447-36-6 ]

Reference： [1]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

8
[ 6342-70-7 ]
[ 154447-36-6 ]

Reference： [1]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

9
[ 304-06-3 ]
[ 154447-36-6 ]

Reference： [1]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

10
[ 130766-15-3 ]
[ 154447-36-6 ]

Reference： [1]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

11
[ 351002-09-0 ]
[ 154447-36-6 ]

Reference： [1]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

12
[ 130735-95-4 ]
[ 154447-36-6 ]

Reference： [1]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

13
[ 688745-54-2 ]
[ 154447-36-6 ]

Reference： [1]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

14
[ 503469-17-8 ]
[ 154447-36-6 ]

Reference： [1]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

16
[ 29173-65-7 ]
[ 154447-36-6 ]
[ 778643-67-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; In acetonitrile; at 55℃; for 48.0h;	[0216] In order to prepare the 4-Isocyanatobenzyl quarternary salt of Compound 1101, a mixture of 300 mg Compound 1101, 450 mg sodiun iodide (3.0 equivalents) and 490 mg (3.0 equivalents) of 4-chloromethyl benzeneisocyanate was dissolved in 4.0 ML dry acetonitrile and heated oil in an oil bath at 65 C FOR 2 days. The LCMS indicated the reaction had gone to completion because of the absence of starting material (Compound 1101). The product was identified as a new peak with a retention time of 4.577 minutes, M+ = 439. Compound A044-80 is reacted with nucleophilic groups of various targeting agents to produce carbamate or urea linkages to the targeting agents by the methods of Examples utilizing compound 1105 and A040- 26.

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 90-91

17
[ 154447-36-6 ]
[ 74-88-4 ]
C₂₀H₂₀NO₃⁽¹⁺⁾*I^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[0146] Following the procedure of Scheme 3 the tertiary amine of LY294002 was quaternized using iodomethane or benzyl chlorides under forcing conditions to yield compounds A052-10 and Compound 13B. Example 56 describes the synthesis of methyl quaternary prodrug A052- 10. Example 57 describes the synthesis of a phthalimido quaternary prodrug A052-08. Example 58 describes the synthesis of a paracarboxy benzyl quaternary A044-78. [0199] [0215] describes the synthesis of a PARA-SCN-BENZYL quaternary prodrug A044-80

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 42-43

18
[ 100-44-7 ]
[ 154447-36-6 ]
C₂₆H₂₄NO₃⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[0146] Following the procedure of Scheme 3 the tertiary amine of LY294002 was quaternized using iodomethane or benzyl chlorides under forcing conditions to yield compounds A052-10 and Compound 13B. Example 56 describes the synthesis of methyl quaternary prodrug A052- 10. Example 57 describes the synthesis of a phthalimido quaternary prodrug A052-08. Example 58 describes the synthesis of a paracarboxy benzyl quaternary A044-78. [0199] [0215] describes the synthesis of a PARA-SCN-BENZYL quaternary prodrug A044-80

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 42-43

19
[ 590-97-6 ]
[ 154447-36-6 ]
[ 778643-68-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; In acetonitrile; at 20 - 65℃;	[0218] In order to prepare the acetoxymethyl quarternary salt of Compound 1101,1. 0 g Compound 1101 was dissolved in 10 ML dry acetonitrile in a glass vial, and 1.0 g bromomethyl acetate (2.0 equivalents) was added and allowed to stir at room temperature overnight. LCMS indicated presence of starting material, so the reaction was heated at 65 C in an oil bath for 8 hours. The mother liquors were decanted from the solid and the solids washed with a small amount of cold acetonitrile. The solid was dried in a vacuum dessicator overnight. The product was identified as 264 mg of a white solid with a retention time of 2.204 minutes, M+ = 380 which was 97% pure. This compound was found to have very high water solubility; a 32.5 millimolar solution of this compound in phosphate buffered saline was prepared, by dissolving 27 mg in 1. 865 mL of phosphate buffered saline with a resulting pH of around 4. A 50 uL aliquot of this solution (which contains 1.625 UMOLES of Compound 1101 as a prodrug) was injected in the tail vein of a nude mouse with no observable untoward effects illustrating the lack of toxicity for the prodrug form whereas injection of 1.04 UMOLES of Compound 1101 caused immediate death in three out of three mice. Additionally, 250 uL of this 32.5 mM solution of compound A040-70 was administered to a nude mouse by oral gavage. After 5,15, and 30 minutes 40 uL of mouse blood was obtained and analyzed by LC-MS (after extraction using acetonitrile) to demonstrate that combined blood levels of prodrug A040-70 and compound 1 were 1.8, 4.97, and 4.80 micromolar at the respective time points. This result demonstrates oral bioavailability of the active drug from the prodrug in vivo. The chloride salt is obtained by dissolving this compound A040-70 in a minimum amount of water and passing through an anion exchange resin bed such as Dowex 22 (chloride form) available from Aldrich and then washing with water and freeze-dry the combined eluant to give A solid possessing a chloride ion exchanged for the bromide ion.

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 92

20
[ 432037-43-9 ]
[ 154447-36-6 ]
C₂₄H₂₄NO₇⁽¹⁺⁾*I^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; In acetonitrile; for 16.0h;	0211] The 3 g of A047-71 from above were dissolved in 36 mL of acetonitrile and treated with 1.8 g of Compound 1101 and 1. 8 g of NaI and put on a heater with stirring for 16 hours. The reaction mix (including precipitate) was partitioned between water and methylene chloride and the methylene chloride layer was separated, washed with brine, dried over sodium sulfate and evaporated to give a dark oil. This oil was dissolved in 5 mL of acetonitrile and stored in the freezer for two days. The yellow precipitate that formed was then filtered and washed with 3 mL of acetonitrile and dried to give 2.8435 g OF >95% purity product assigned lot A046-67A, retention time 2.719 minutes, [M+] of 494 M/Z. All of this product was dissolved in 10 mL of thionyl chloride and heated to 65C for 4 hours. The excess thionyl chloride was removed under vacuum and the yellow oil dried under high vacuum to yield 1.9906g of the acid chloride (Compound 1111) as a yellow crunchy solid. This solid was used directly in subsequent reactions.

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 86-88

21
[ 432037-43-9 ]
[ 154447-36-6 ]
C₂₈H₃₂NO₇⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; In acetonitrile; at 65℃; for 4.0h;	[0148] LY294 002 (Compound 1) was dissolved in acetonitrile and then each of the chloromethyl esters (1-1.5 equiv) from Example 3 was added along with 1-2 equivalents of sodium iodide. At room temperature, the reaction proceeded only slowly with the CHLOROMETHYLESTERS to give very small amounts of the quaternized amine product along with the precipitation of sodium chloride. At 65C, the reaction proceeded to completion usually in in 4 hours. The reaction when complete (as judged by analysis by LC-MS) was filtered ; concentrated and then purified on reverse phase HPLC. The fractions were collected and lyophilized to give the desired products as fluffy powders. Examples prepared and purified in this manner are shown in the table below (the counter anions are not displayed but included chloride, iodide, acetate or mixtures thereof).

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 45

22
[ 18997-19-8 ]
[ 154447-36-6 ]
C₂₅H₂₈NO₅⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; In acetonitrile; at 55℃; for 2.0h;	[0217] In order to prepare the PIVALOYLMETHYL quarternary salt of Compound 1101,100 mg pivaloyl chloride (2.0 equivalents) was added dropwise to a mixture of 100 mg Compound 1101 and 100 mg sodium iodide (2.0 equivalents) in 2.0 ml dry acetonitrile. The mixture was heated on an oil bath at 65 C FOR 2 hours. The solids were filtered using a fritted plastic syringe fitted with a 2 micron filter. The compound was identified and isolated using preparative LCMS. A yellow solid with a retention time of 2. 735 minutes, M+ = 422 was obtained with a yield of 102.3 mg of 93.7% purity

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 45-47; 91

23
[ 778643-59-7 ]
[ 154447-36-6 ]
C₂₉H₂₉N₂O₅⁽¹⁺⁾*I^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21.5%	With sodium iodide; In acetonitrile; at 65℃;	[0206] In order to prepare the N-benzyl, N-methyl carbamoylmethyl quarternary salt of Compound 1101,0. 5 g of Compound 1101 and 0.5 g sodium iodide (20 equivalents) were dissolved in 5.0 ml dry acetonitrile in a glasss vial. The N-benzyl, N-methyl carbamoyl chloromethyl ester was added to the solution then placed on an oil bath at 65 C overnight. The product was identified by LCMS and purified by preparative LCMS to give 169.5 mg (21.5 % theoretical yield) of a solid assigned A044-52 with a retention time of 2.731 MINUTES,, M+ = 485 and 90% purity.

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 84

24
4-isothiocyanatophenyl acetic acid chloromethyl ester [ No CAS ]
[ 154447-36-6 ]
C₂₉H₂₅N₂O₅S⁽¹⁺⁾*I^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium iodide; In acetonitrile; at 65℃; for 5.0h;	[0204] In order to prepare the 4-isothiocyanato phenyl acetic acid quarternary salt derivative of Compound 1101, Compound 1101 (. 300g, 1.0 mmole) and. 582 g godium iodide (4 equivalents) were dissolved in 4.0 ml dry acetonitrile in a one dram vial. The 4-isothiocyanatophenyl acetic acid chloromethyl ester (compound A040-22) in 2.0 ml dry acetonitrile was added with stirring. The mixture was heated on a silicone oil bath at 65 C for five hours, monitoring the progress of the reaction by LCMS. When most of the Compound 1101 starting material was consumed the reaction mixture was purified using preparative LCMS retention time of 3.019 minutes, M+ =513. A yield of 194.1 mg of 94% pure product was obtained and identified by LCMS. Compound A040-26 is then reacted with nucleophile-bearing targeting agents as described by the methods disclosed in the examples utilizing compound 1105 to prepare useful targeted prodrugs.

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 83

25
[ 778643-69-9 ]
[ 154447-36-6 ]
C₃₀H₃₈NO₉⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With sodium iodide; In acetonitrile; at 65℃; for 5.0h;	0219] A 78 mg portion of compound 1 was dissolved in 2 mL of acetonitrile along with 76 mg of NaI and treated all at once with 144 mg of chloromethylester A029-62 and stirred at 65C for 5 hours. The reaction was purified by reverse phase LC-MS to give 72 mg (51% yield) of yellow solid A027-85 with a retention time of 2.30 minutes and characterized by having a mass spectrum showing M+=556 as expected for C30H38NO9. A small sample was introduced into phosphate buffer at pH= 7.4 followed by LC-MS over time whereupon a substantial portion of the prodrug converted back to compound 1 with an estimated half-life of conversion of about 3 hours.

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 93

26
C₉H₆INO₂S [ No CAS ]
[ 154447-36-6 ]
[ 778643-09-7 ]

Yield	Reaction Conditions	Operation in experiment
45%	In acetonitrile; at 20℃; for 46.0h;	[0227] A 184 mg portion of A014-48 prepared by the method of Example 20 was dissolved with 154 mg of Compound 1 in 12 mL of acetonitrile and stirred at room temperature. After 16 hours LC-MS indicated about 65% conversion to the desired quat compound so an addition 45 mg of the iodo compound was added and after an additional 22 hours the reaction had gone to 80 % completion so an additional 40 mg of iodo compound was added and allowed to stir and additional 24 hours. The solids were then centrifuged and wash with acetonitrile to give 282. 6 mg (45% yield) of the desired product in high purity characterized by a retention time OF 2. 89 minutes and showing the desired M+ of 499 for C28H23N205S AS COMPOUND COMPOUND 1105.

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 50; 98-99

27
[ 17564-64-6 ]
[ 154447-36-6 ]
[ 778643-65-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; In acetonitrile; at 55℃; for 96.0h;	[0214] In order to preparation the phthalimidomethyl quarternary salt of Compound 1101, a mixture of 100 mg Compound 1101 and 100 mg sodium iodide (2.0 equivalents) were dissolved in 3.0 ml dry acetonitrile. To the mixture was added 128 mg of chloromethylphthalimide and the vial was heated in an oil bath at 55 C for four days. The product was identified by LCMS as a new peak with RF= 3.984, M+ = 467

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 89

28
[ 99464-81-0 ]
[ 154447-36-6 ]
C₃₀H₃₀NO₅⁽¹⁺⁾*I^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.7%	With sodium iodide; In acetonitrile; at 65℃;	[0209] To 100 mg Compound 1101 and 100 MG NAI (20 equivalents) dissolved in 1.0 ml dry acetonitrile was added 107 mg (1.5 equivalents) of the BENZYL-L-CHLOROETHYL formate. The mixture was heated at 65 C overnight. The LCMS indicated the presence of starting material so an additional 107 mg (1.5 equivalents) of benzyl-1-chloroether formate was added and the heating continued another 24 hours. The LCMS identified a product which could be separated from starting material with slow gradient chromatography. The desired compound was isolated using preparative LCMS to give 13.7 mg (8.7 % theoretical yield) of a compound with a retention time of 4.690 minutes, M= + 488 in 98. 6% purity

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 85-86

29
[ 1642-81-5 ]
[ 154447-36-6 ]
[ 778643-66-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; In acetonitrile; at 65℃; for 336.0h;	[0215] In order to prepare the 4-CARBOXYBENZYL quarternary salt of Compound 1101, 300 mg Compound 1101,400 mg sodium iodide and 500 mg of chloromethyl benzoic acid were mixed in a glass vial and suspended in 4.0 ml dry acetonitrile. The reaction was heated on an oil bath at 65 C and monitored for two weeks by LCMS. The solution was filtered through a fritted plastic syringe that had been fitted with an additional 2 micron filter. The desired compound was isolated using preparative LCMC and had a retention time of 3.717 minutes, M+ = 442. A yield of 27.7 mg of 96% purity was obtained. The carboxlic acid group of compound A044-78 is converted to a reactive group by a) reaction with N-HYDROXYSUCCINIMIDE as described by the method in Example 31 to prepare the NHS active ester or b) conversion to the acid chloride as described by the method in Example 56. Either of these reactive groups are then reacted with the nucleophilic amine or alcohol groups of targeting agents using methods described in the previous Examples to give targeted prodrug conjugates.

Reference： [1]Patent: WO2004/89925,2004,A1 .Location in patent: Page 90

30
C₁₉H₁₉NO₄ [ No CAS ]
[ 154447-36-6 ]

Reference： [1]Organic Letters,2008,vol. 10,p. 3809 - 3812

31
[ 154447-36-6 ]
[ 1202494-01-6 ]

Reference： [1]Chemistry - A European Journal,2009,vol. 15,p. 11723 - 11729

32
[ 154447-36-6 ]
[ 1202494-02-7 ]

Reference： [1]Chemistry - A European Journal,2009,vol. 15,p. 11723 - 11729

33
[ 154447-36-6 ]
[ 1174428-87-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	With Lawessons reagent; In toluene; at 130℃; for 0.333333h;Sealed tube; Microwave irradiation;	A 2 mL conical microwave vial was charged with a magnetic stirring bar, 2-morpholino-8-phenyl-4H-chromen-4-one (LY294002) (150 mg, 488 mumol), Lawesson's reagent (118 mg, 293 mumol), and toluene (2 mL). The reaction mixture was sealed, and the reaction mixture was magnetically stirred and heated via microwave irradiation to 130 C. for 20 minutes. The final mixture was poured onto water (approximately 30 mL), extracted with dichloromethane (3×5 mL), the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Purification via column chromatography (silica gel; hexanes/ethyl acetate (1:1), then 100% ethyl acetate) afforded pure 2-morpholino-8-phenyl-4H-chromene-4-thione (68) (128 mg, 81% yield).

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 1922 - 1939
[2]Patent: US9550790,2017,B2 .Location in patent: Page/Page column 42; 43

34
[ 15159-40-7 ]
[ 21424-82-8 ]
[ 154447-36-6 ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 9026 - 9029
Angew. Chem.,2014,vol. 126,p. 9172 - 9175,4

35
[ 90-43-7 ]
[ 154447-36-6 ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 9026 - 9029
Angew. Chem.,2014,vol. 126,p. 9172 - 9175,4
[2]Angewandte Chemie - International Edition,2014,vol. 53,p. 9026 - 9029
Angew. Chem.,2014,vol. 126,p. 9172 - 9175,4

36
[ 132939-03-8 ]
[ 154447-36-6 ]

37
[ 63992-45-0 ]
[ 154447-36-6 ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 9026 - 9029
Angew. Chem.,2014,vol. 126,p. 9172 - 9175,4

38
[ 154447-36-6 ]
[ 1174428-97-7 ]

Yield	Reaction Conditions	Operation in experiment
2.06 g	With Dichloromethyl methyl ether; at 80℃; for 2.0h;Inert atmosphere;	A solution of 2-morpholino-8-phenyl-4H-chromen-4-one (LY294002) (1.50 g, 4.93 mmol) and dichloromethyl methyl ether (15 mL) was stirred and heated to 80 C. for 2 hours under argon. The mixture was cooled to room temperature, and then concentrated in vacuo to give 4-chloro-2-morpholino-8-phenylchromenylium chloride (78) (2.06 g, 5.73 mmol).

Reference： [1]Patent: US9550790,2017,B2 .Location in patent: Page/Page column 49

39
[ 154447-36-6 ]
[ 1174428-98-8 ]

Reference： [1]Patent: US9550790,2017,B2

40
[ 154447-36-6 ]
[ 1174428-99-9 ]

Reference： [1]Patent: US9550790,2017,B2

41
C₅₄H₈₄N₂O₁₃ [ No CAS ]
[ 154447-36-6 ]
C₇₃H₁₀₀N₃O₁₆⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzyl chloride; In acetonitrile; at 90℃; for 24.0h;	(1) 5g of LY294002 and 0.1g of benzyl chloride are mixed and dissolved in acetonitrile;(2) adding 10 g of a compound having the structure shown in Formula VII to the above solution;(3) The solution obtained in step (2) is placed in a reaction flask and heated at 90C for 24 hours;(4) After completion of the reaction, the heating was stopped to room temperature, and an ice bath was used to obtain a precipitate 3 as a compound.

Reference： [1]Patent: CN107759616,2018,A .Location in patent: Paragraph 0118-0126

42
C₅₂H₈₁NO₁₃ [ No CAS ]
[ 154447-36-6 ]
C₇₁H₉₇N₂O₁₆⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With methyl iodide; In 1-Propyl acetate; at 75℃; for 96.0h;	(1) 2g LY294002 and0.1g of iodomethane was mixed and dissolved in n-propyl acetate;(2) adding 10 g of rapamycin to the above solution;(3) The solution obtained in step (2) is placed in a reaction flask and heated at 75 C. for 4 days.(4) After the reaction is completed, stop heating to room temperature,Wash with saturated saline solution,Drying under reduced pressure to give a powderThe substance is Compound 1.

Reference： [1]Patent: CN107759616,2018,A .Location in patent: Paragraph 0102-0109

43
C₅₃H₈₁NO₁₄ [ No CAS ]
[ 154447-36-6 ]
C₇₂H₉₇N₂O₁₆⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzyl chloride; In acetonitrile; at 35℃; for 288.0h;	(1) 2g of LY294002 and 0.15g of benzyl chloride were mixed and dissolved in acetonitrile;(2) adding 12 g of a compound having the structure shown in Formula VI to the above solution;(3) The solution obtained in step (2) is placed in a reaction flask and heated at 35 C. for 12 days.(4) After the completion of the reaction, the heating was stopped to room temperature, and an ice bath was used to obtain a precipitate as Compound 2

Reference： [1]Patent: CN107759616,2018,A .Location in patent: Paragraph 0110-0117

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Precautionary Statements-General
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P101	If medical advice is needed,have product container or label at hand.
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Code	Phrase
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P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
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P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
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P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
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P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
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Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	Inquiry	{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price) ]}	{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate,item.pr_is_large_size_no_price) ]}	{[ item.pr_usastock ]}		{[ item.pr_chinastock ]}	{[ item.pr_remark ]}

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
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H228	Flammable solid
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H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 154447-36-6 ] {[proInfo.proName]}

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[ 154447-36-6 ] Synthesis Path-Upstream 1~18

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