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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Camptothecin (CPT), an alkaloid, is a DNA topoisomerase I (Topo I) inhibitor with an IC50 of 679 nM. It shows strong antineoplastic activity against colorectal, breast, lung, and ovarian cancers and modulates hypoxia-inducible factor-1α (HIF-1α) activity by altering microRNA (miRNA) expression patterns in human cancer cells.
Synonyms: Campathecin; CPT; (+)-Camptothecin
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Batch number can be found on the product's label following the word 'Batch'.
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CAS No. : | 7689-03-4 |
Formula : | C20H16N2O4 |
M.W : | 348.35 |
SMILES Code : | [C@@]5(C2=C(C(N1CC4=C(C1=C2)N=C3C=CC=CC3=C4)=O)COC5=O)(CC)O |
Synonyms : |
Campathecin; CPT; (+)-Camptothecin
|
MDL No. : | MFCD00081076 |
InChI Key : | VSJKWCGYPAHWDS-FQEVSTJZSA-N |
Pubchem ID : | 24360 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H301 |
Precautionary Statements: | P501-P270-P264-P301+P310+P330-P405 |
Class: | 6.1 |
UN#: | 1544 |
Packing Group: | Ⅲ |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.4% | With sulfuric acid; dihydrogen peroxide; acetic acid; at -5 - 5℃; for 0.166667h; | Adding 80 g of camptothecin, 840 g of glacial acetic acid and 368 g of concentrated sulfuric acid to a 5 L reactor, and then mechanically stirring, after total dissolution80 g of propionaldehyde was added, and 102 g of hydrogen peroxide was further added thereto, and the reaction was carried out at a temperature of -5 to 5 C for 10 minutes. Add 10 kg of purified water to the system and mix itCrystal 2h, suction filtration to obtain 72.5 g of 7-ethylcamptothecin, the yield was 95.4%. |
62% | FeSO4·7H2O 4.2g (15.1mmol) was added to a 500mL three-necked flask.Propylaldehyde 2.18mL (30.2mmol),120 mL of water, 105 mL of glacial acetic acid, 1.75 g (5 mmol) of camptothecin, and stirred.After cooling to 5 C, 30 mL of concentrated sulfuric acid was added to obtain a yellow transparent solution.1.86 mL (17.6 mmol) of 30% H 2 O 2 was added dropwise, and the reaction was carried out at 5 to 8 C for 15 min.Pour into 500 mL of ice water, adjust the pH to 8, and precipitate a large amount of yellow solid. filter,The filter cake was washed with a small amount of water to obtain 1.22 g of 7-ethylcamptothecin, yield: 62%. | |
Step - a:; Camptothecin (100 g) is taken in DM water (2000 ml), adding slowly concentrated sulfuric acid (1100 ml) at a temperature ranging between 45 - 55C, further maintaining the temperature around 60C for a period 2 hours to 4 hours, cooling the mixture to about minus 3C, adding propionaldehyde (48ml) and maintaining the temperature between 0 to 3C. Adding ferrous sulphate, hydrogen peroxide (130 ml), raising the temperature up to about 30C and maintaining for about 2 hours. Charging this mixture to a solution of aqueous sodium sulphate, extracting with chloroform (3x5 I), followed by washing the chloroform layer with water, separating chloroformlayer and removing completely chloroform under vacuum up to below 45C, obtaining a residue, treating it with dimethyl formamide (3900 ml) at a temperature ranging between 80 -100C, cooling to 0 to 5C, filtering, washing with methanol, drying to obtain the required product of 7-ethylcamptothecin (68g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.1% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h; | The mixture of camptothecin (30 mg, 0.086 mmol), 4-bromophenoxyacetic acid (41 mg, mmol), EDCI (60 mg, 0.31 mmol), DMAP (5 mg, 0.047 mmol) and dichloromethane (5 ml) was stirred in the room temperature for 20 h, then dichloromethane (20 ml) was added to the solution. Organic layer was washed with water (20 ml), saturated NaHCO3 aqueous solution (10 ml) and brine (20 ml), and then dried over MgSO4. After the solvent was removed under reduced pressure, the resulting solid was recrystallized from ethyl acetate to afford 42 mg camptothecin-20-O-bromophenoxyacetate, yield: 87.1%, mp 232-234 C. (dec.). The chemical structure analysis was performed by 1HNMR (CDCl3, 600 MHz): delta 8.67 (s, 1H, Ar-H), 8.26 (d, 1H, Ar-H), 8.10 (d, 1H, Ar-H), 7.90 (t, 1H, Ar-H), 7.73 (t, 1H, Ar-H), 7.43 (d, 2H, Ar-H), 7.23 (s, 1H, Ar-H), 6.97 (d, 2H, Ar-H), 5.53 (d, 1H, H17), 5.45 (d, 1H, H17), 5.31 (s, 2H, H5), 5.15, 5.00 (dd, 2H, OCH2CO), 2.08 (d, 2H, CH2), 1.02 (t, 3H, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With dmap; diisopropyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃; for 48h;Inert atmosphere; | General procedure: To a mixture of Biotin or 6-biotinylaminocaproic acid (0.3 mmol), camptothecin analogues (0.1 mmol) and DMF (2.5 mL) was added, 4-Dimethylaminopyridine (DMAP) (0.01 mmol) was added and N, N'-Diisopropylcarbodiimide) (DIC) (0.6 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 days under N2. Solvent were removed under a reduced. The residue was purified on a silica gel chromatography (CHCl3:CH3OH = 15:1?9:1) to afford the product Biotin-(20s)-camptothecin (11). Yellow amorphous powder, yield 60percent; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.0% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h; | The mixture of camptothecin (10 mg, 0.029 mmol), <strong>[1643-16-9]4-isopropylphenoxyacetic acid</strong> (8 mg, 0.42 mmol), EDCI (28 mg, 0.15 mmol), DMAP (2 mg, 0.02 mmol) and dichloromethane (3 ml) was stirred in the room temperature for 20 h, then dichloromethane (20 ml) was added to the solution. Organic layer was washed with water (20 ml), saturated NaHCO3 aqueous solution (10 ml) and brine (20 ml), and then dried over MgSO4. After the solvent was removed under reduced pressure, the resulting solid was separated by column chromatography (eluent: CHCl3:CH3OH 9:1) to afford 12 mg camptothecin-20-O-4-isopropylphenoxyacetate, yield: 80.0%, mp 208-210 C. The chemical structure analysis was performed by 1HNMR (CDCl3, 600 MHz): delta 8.42 (s, 1H, Ar-H), 8.23 (d, 1H, Ar-H), 7.98 (d, 1H, Ar-H), 7.85 (t, 1H, Ar-H), 7.69 (t, 1H, Ar-H), 7.10 (s, 2H, Ar-H), 6.84 (d, 2H, Ar-H), 5.63 (d, 1H, H17), 5.63 (d, 1H, H17), 5.25 (q, 2H, H5), 4.84 (q, 2H, OCH2CO), 2.72 (m, 1H, CHMe2), 2.21 (dm, 2H, CH2), 1.00 (m, 9H, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; dihydrogen peroxide; acetic acid; In water; | EXAMPLE 27 (Preparation of 7-ethylcamptothecin) Ferrous sulfate heptahydrate (350 mg, 1.25 m-mol) was dissolved in water (10 ml). Propionaldehyde (144 mg, 2.48 m-mol) was added to the solution and dissolved therein by addition of acetic acid (10 ml). Camptothecin (175 mg, 0.5 m-mol) was suspended in the solution and then dissolved therein by addition of concentrated sulfuric acid (2 ml) in small portions. To this solution was added dropwise under ice-cooling and agitation a 30percent aqueous solution of hydrogen peroxide (144 mg, 1.27 m-mol) in small portions. The agitation was continued for 15 minutes under ice-cooling. The reaction mixture was diluted with ice water (500 ml) and then extracted with chloroform (800 ml). The chloroform layer was dried with magnesium sulfate, filtered and evaporated until dryness under reduced pressure. The residue was subjected to column chromatography (chloroform) through silica gel (10 g) to effect separation and purification of the product whereby 105 mg (55.8percent) of the objective compound were obtained as light yellow white crystals. The analytical data of the resultant product were identical with those of the product obtained in Example 26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; dihydrogen peroxide; propionic acid; In water; | EXAMPLE 29 (Preparation of 7-ethylcamptothecin) Ferrous sulfate heptahydrate (1.20 g, 4.31 m-mol) and propionic acid was dissolved in water (15 ml). Camptothecin (300 mg, 0.862 m-mol) was suspended in the solution and dissolved therein by addition of concentrated sulfuric acid (6 ml) in small portions. To this solution was added dropwise under ice-cooling and agitation a 30percent aqueous solution of hydrogen peroxide (1 ml, 9.81 m-mol) in small portions over the period of about 10 minutes. After addition of the hydrogen peroxide, the agitation was continued for 16 hours at room temperature. The reaction mixture was diluted with ice water (300 ml) and extracted with chloroform (400 ml). The chloroform layer was dried with magnesium sulfate, filtered and evaporated until dryness under reduced pressure. The residue was subjected to column chromatography (chloroform) through silica gel (10 g) to effect separation and purification of the product whereby 73 mg (22.5 g) of the objective compound were obtained as a yellow white solid. The analytical data of this compound were identical with those of the compound obtained in Example 26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; dihydrogen peroxide; In water; | EXAMPLE 26 (Preparation of 7-ethylcamptothecin) In an aqueous solution of sulfuric acid (15 ml of concentrated sulfuric acid in 30 ml of water) were dissolved camptothecin (1.00 g, 2.87 m-mol), ferrous sulfate heptahydrate (5.60 g, 20.1 m-mol) and 1-propanol (6 ml, 86.1 m-mol). To this solution was added dropwise under ice-cooling and agitation a 30percent aqueous solution of hydrogen peroxide (2.1 ml, 20.1 m-mol) in small portions. After addition of the hydrogen peroxide, the agitation was continued for one hour at room temperature. The reaction was diluted with ice water (2 l) and extracted with chloroform (2.5 l). The chloroform layer was dried with anhydrous magnesium sulfate, filtered and evaporated until dryness under reduced pressure. The residue was subjected to column chromatography (chloroform) through silica gel (15 g) to effect separation and purification of the product which was then recrystallized from n-hexane-chloroform whereby 265 mg (25.3percent) of the objective compound were obtained as light yellow white needle crystals. M.P. 258°-261° C. IRnumaxKBr cm-1: 3370, 2920, 1750, 1650, 1600, 1460, 1150, 760. NMR (in DMSO-d6 -CDCl3) delta: 0.97(3H, t, J=7 Hz), 1.39(3H, t, J=7 Hz), 1.91(2H, q, J=7 Hz), 3.21(2H, q, J=7 Hz), 5.21(2H, s), 5.24(1H, d, J=16 Hz), 5.57 (1H, d, J=16 Hz), 7.49(1H, s), 7.44-8.21 (4H, m). MS m/e: 376.1399 [M+ ] (C22 H20 N2 O4 =376.1422). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; dihydrogen peroxide; acetic acid; In water; | EXAMPLE 28 (Preparation of 7-ethylcamptothecin) Ferrous sulfate heptahydrate (1.0 g, 3.59 m-mol) was dissolved in water (10 ml). Diethyl ketone (1.29 g, 15 m-mol) was added to this solution and acetic acid (6 ml) was then dissolved therein. Camptothecin (175 mg, 0.5 m-mol) was suspended in this solution and then dissolved by addition of concentrated sulfuric acid (2 ml). To this solution was then added dropwise under ice-cooling and agitation a 30percent aqueous solution of hydrogen peroxide (560 mg, 5 m-mol) in small portions. After addition of the hydrogen peroxide, the mixture was agitated for 48 hours at room temperature. The reaction mixture was diluted with ice water (500 ml) and extracted with chloroform (500 ml). The chloroform layer was dried with magnesium sulfate, filtered and evaporated until dryness under reduced pressure. The residue was subjected to column chromatography (chloroform) through silica gel (10 g) to effect separation of the product whereby 17 mg (13.8percent) of the objective compound and 61 mg of unreacted camptothecin were obtained. The analytical data of the resultant 7-ethylcamptothecin were identical with those of the compound obtained in Example 26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h; | General procedure: EDCI (383.4 mg, 2 mmol) and DMAP (36 mg, 0.34 mmol) were added to a solution with CPT (139.2 mg, 0.4 mmol) and N-(tert-butoxycarbonyl) glycine (140.1 mg, 0.8 mmol) in dichloromethane (15 mL) and stirred at room temperature for 2 h. Chloroform (35 mL) was subsequently added, and the organic phase was washed with water (50 mL) and saturated sodium bicarbonate aqueous solution (50 mL), and then dried using Mg2SO4 before evaporating to dryness. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Camptothecin 1.0g, 2.5 g of disulfide diacetic anhydride, 0.3 g of DMAP, 1.5 g of triethylamine, adding DMS0 as the reaction solvent, heating and refluxing reaction for 12 h; dilute hydrochloric acid washing three times, Dilute hydrochloric acid layer, take filter cake. Add I 1.2g, dissolved in 20mL trichloromethane, stirring at 25 C 3h, filtration. To the filtrate was added 3-dimethylamino-1,2-propanediol, 0.4 g of DBU, and heated to reflux for 24 h. The reaction solution was diluted with chloroform to 50mL, 1M hydrochloric acid washed three times, Na2S04 drying, rotary evaporation of dry solvent, the intermediate product UTLC detection reaction process (developing agent for methanol: dichloromethane / 1: 1, UV detection lambda254nm); The mass spectrum determines the product structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | General procedure: (Using the synthesis of the 3a as an example). Under the atmosphere of N2, to a suspension of Camptothecin (CPT, 323 mg, 0.93 mmol) and triphosgene (110 mg, 0.37 mmol) in CH2Cl2 (25 mL) was added a solution of DMAP (361 mg, 2.96 mmol) in CH2Cl2 (5 mL), after the addition, the reaction mixture was stirred 30 min. Then, a solution of monomethoxy M-PEG 7g (534 mg, 1.39 mmol) in CH2Cl2 (10 mL) was slowly added. The reaction mixture was stirred 16 h at rt, and concentrated under vacuum, the residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH = 10/1) to give 3a as yellow solid (385 mg, 55% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.2% | CPT and PTX prodrugs (ProCPT and ProPTX) were synthesized according the synthetic routes as shown in Fig. S5 and S6. Briefly, CPT (0.52g, 1.5mmol) and DMAP (4.3mmol) were suspended in dry DCM (15mL) under nitrogen atmosphere in a 150mL flask. Subsequently, triphosgene (0.15g, 0.5mmol) was added and the mixture was stirred for 30min at room temperature. 4-(Hydroxymethyl)phenylboronic acid pinacol ester (0.7g, 3mmol) in dry THF (10mL) was added dropwise via a constant pressure funnel. The reaction mixture was stirred overnight. After evaporating all the solvents, the crude product was purified by column chromatography using ethyl acetate as eluent (100percent EtOAc) to give CPT prodrug (ProCPT) as a pale yellow solid powder (0.45g, yield: 49.2percent). 1H NMR (400MHz, DMSO?d6) delta (ppm): 8.70 (s, 1H), 8.22 (d, J=8.5Hz, 1H), 8.15 (d, J=8.0Hz, 1H), 7.89 (t, J=7.1Hz, 1H), 7.74 (t, J=7.8Hz, 1H), 7.62 (d, J=7.9Hz, 2H), 7.35 (d, J=7.9Hz, 2H), 7.08 (s, 1H), 5.58?5.46 (m, 2H), 5.29 (s, 2H), 5.22 (s, 2H), 2.25?2.13 (m, 2H), 1.22 (d, J=8.4Hz, 12H), 0.93 (t, J=7.4Hz, 3H) (Fig. S7). 13C NMR (CDCl3) delta (ppm): 166.30, 156.26, 152.61, 151.29, 147.90, 145.44, 144.62, 136.34, 134.03, 130.13, 129.69, 128.75, 127.41, 127.15, 127.04, 126.00, 125.04, 119.29, 94.99, 82.78, 76.91, 76.21, 69.29, 66.05, 48.95, 30.91, 23.80, 6.62 (Fig. S8). ESI-MS: Calculated: [C34H33BN2O8+H]+ 609.46, found: [C34H33BN2O8+H]+ 609.24 (Fig. S11). According to the similar procedure, ProPTX was also synthesized. The characterizations were shown in Fig. S9, S10, and S12. |