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Synthesis of 2-oxoquinoline derivatives as dual pim and mTORC protein kinase inhibitors
Giri R. Gnawali ; Koichi Okumura ; Karolina Perez , et al. Med. Chem. Res.,2022,31(7):1154-1175. DOI: 10.1007/s00044-022-02904-z PubMed ID: 36389181
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Abstract: Compound VBT-5445 was identified as an inhibitor to block the association of Pim and the protein Enhancer of Decapping 3 (EDC3), a Pim substrate, which normally functions to enhance the decapping of messenger RNA (mRNA). It was also shown to inhibit both the Pim and mTORC protein kinases. The activity of this compound class can be fine-tuned by structural modification. A series of VBT analogs were designed, synthesized, and evaluated. These compounds decrease the growth of multiple cancer types, including pancreas, prostate, breast, lung, and leukemia. Notably, 6-methyl (GRG-1-31, 6d), 4-chloro (GRG-1-34, 6e), 4-Bromo (GRG-1-35, 6f), and phenylthio substituted (GRG-1-104, 6n) derivatives are highly potent at inhibiting tumor growth. The ability of these compounds to block cancer growth in vitro is highly correlated with their activity as mTORC inhibitors. The toxicity of GRG 1–34 is low in mice treated with twice-daily gavage for 30 days and did not induce weight loss. Pharmacokinetics of a single oral dose demonstrated a peak concentration at 0.5?h after gavage. In summary, further development of this compound class has the potential to inhibit important signaling pathways and impact cancer treatment.
Keywords: Quinoline derivatives ; Pim kinase ; Antitumor activity ; mTORC
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CAS No. : | 67938-76-5 | MDL No. : | MFCD10697658 |
Formula : | C6H7ClN2 | Boiling Point : | No data available |
Linear Structure Formula : | - | InChI Key : | KQJKUOYVWLBSDN-UHFFFAOYSA-N |
M.W : | 142.59 | Pubchem ID : | 21069929 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | |
Hazard Statements: | H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* 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 |
---|---|---|
51% | With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In ethanol; water; under 2068.65 Torr; for 2.0h; | A solution of 5-chloropicolinonitrile (3.8 g, 27.43 mmol), conc. HCl (3 mL) and 10percent Pd-C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2 h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4x25 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51percent yield). LCMS (M+H) calcd for C6H8ClN2: 143.04; found: 143.07. 1HNMR (500 MHz, CDCl3) ? ppm: 8.56-8.51 (1H, br d), 7.66-7.60 (1H, m), 7.28-7.14 (1H, m), 3.97 (2H, s), 1.72 (2H, s). |
51% | With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In ethanol; water; under 2068.65 Torr; for 2.0h; | A solution of 5-chloropicolinonitrile (3.8 g, 27.43 mmol), conc. HCl (3 mL) and 10percent Pd-C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2 h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4.x.25 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51percent yield). LCMS (M+H) calcd for C6H8ClN2: 143.04; found: 143.07. 1HNMR (500 MHz, CDCl3) delta ppm: 8.56-8.51 (1 H, br d), 7.66-7.60 (1 H, m), 7.28-7.14 (1 H, m), 3.97 (2H, s), 1.72 (2H, s). |
51% | With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In ethanol; water; under 2068.65 Torr; for 2.0h; | (5-Chloropyridin-2-yl)methanamine. A solution of 5-chloropicolinonitrile (3.8 g, 27.43 mmol), conc. HCl (3 mL) and 10percent Pd-C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2 h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4.x.25 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51percent yield). LCMS (M+H) calcd for C6H8ClN2: 143.04. found: 143.07. 1HNMR (500 MHz, CDCl3) delta ppm: 8.56-8.51 (1H, br d), 7.66-7.60 (1H, m), 7.28-7.14 (1H, m), 3.97 (2H, s), 1.72 (2H, s). |
51% | (5-Chloropyridin-2-yl)methanamine. A solution of 5-chloropicolinonitrile(3.8 g, 27.43 mmol), cone. HCl (3 mL) and 10percent Pd-C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4 X 25 mL). The combined CH2Cl2 layers were dried <n="142"/>(Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51percent yield). LCMS (M+H) calcd for C6H8ClN2: 143.04; found: 143.07. 1HNMR (500 MHz, CDCl3) delta ppm: 8.56-8.51 (IH, br d), 7.66-7.60 (IH, m), 7.28-7.14 (IH, m), 3.97 (2H, s), 1.72 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In methanol; dichloromethane; at 0 - 5℃; for 1.0h;Inert atmosphere; | The compound <strong>[67938-76-5]2-(aminomethyl)-5-chloropyridine</strong> (18 g, 0.13 mol, from Step D) was dissolved in dichioromethane (50 mL) and hydrochloric methanol solution (5 M, 50 mL) was added. After stirring for several min a white solid began to precipitate. The mixture was stirred for 1 h at 0-5 °C, and the solid was collected by filtration and the filtrate was evaporated in vacuo to give some off-white solid. The combined solid was washed with a small amount of cold DCM. The product was dried in vacuo to yield the indicated compound as the hydrochloric salt. -NMR (DMSO-de, 400 MHz) 6 8.70 (s, 3H), 8.62 (s5 1H), 8.0 (dd, 7=2.5, 6 Hz, 1H), 7.60 (d, J=8.5 Hz, lH), 4.15 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Diethyl (5-chloro-2-pyridyl) acetamidomalonate (70 g, 0.21 mol, Step C) was dissolved in 95percent ethanol (200 mL). To the stirred solution (2 °C) was added sodium hydroxide solution (105 mL, 8 N). After 2 hours, the mixture was cooled to 5 °C and acidified to pH 2 with hydrochloric acid (6 N, -40 mL). The ethanol was evaporated under reduced pressure to give a mixture containing some solid. The mixture was treated with hydrochloric acid (5 N, 150 mL) and heated to 80 °C for 4 hours, and then maintained at room temperature overnight. Sodium hydroxide solution (4 N) was slowly added to the mixture to adjust pH 10. The mixture was extracted with DCM (4 x 200 mL), the organic phases were combined, dried over anhydrous Na2S04, and filtered. The solvent was evaporated to give the indicated product as a pale yellow oil. | ||
Diethyl (5-chloro-2-pyridyl) acetamidomalonate (70 g, 0.21 mol) was dissolved in 95percent ethanol (200 mL). To the stirred solution (2 °C) was added sodium hydroxide solution (105 mL, 8 N). After 2h, the mixture was cooled to 5 °C and acidified to pH 2 with hydrochloric acid (6 N, ?40 mL). The ethanol was evaporated in vacuum to give a mixture containing some solid. The mixture was mixed with hydrochloric acid (5 N, 150 mL) and heated to 80 °C for 4 hr, and then maintained at room temperature overnight. Sodium hydroxide solution (4 N) was slowly added to the mixture to adjust pH 10. The mixture was extracted with DCM (4 x 200 mL), and then the combined organic phases were dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to give the indicated product as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 120℃; | General procedure: Example 6A (2 g, 6.35 mmol) and (4-fluorophenyl)methanamine (0.794 g, 6.35 mmol) in acetonitrile (10 ml) were stirred at 120 °C overnight. The reaction mixture was cooled, concentrated, taken into ethyl acetate and washed with saturated aqueous NaHC03 and brine. The combined aqueous layers were extracted twice with ethyl acetate. The combined organic extracts were dried (MgS04) and filtered. The filtrate was concentrated until solid material precipitated. The mixture was filtered to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In methanol; dichloromethane; at 0 - 5℃; | The compound <strong>[67938-76-5]2-(aminomethyl)-5-chloropyridine</strong> (18 g, 0.13 mol) was dissolved in dichloromethane (50 mL) and hydrochloric methanol solution (5 M, 50 mL) was added. After stirring for several min a white solid began to precipitate. The mixture was stirred for 1 h at 0-5 °C, and the solid was collected by filtration and the filtrate was evaporated in vacuo to give some off-white solid. The combined solid was washed with a small amount of cold DCM. The product was dried in vacuo to yield the indicated compound as the hydrochloric salt. 1H-NMR (d6-DMSO, 400 MHz) delta 8.70 (s, 3H), 8.62 (s, 1H), 8.0 (dd, J=2.5, 6 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 4.15 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16.0h;Inert atmosphere; | [000132] To a stirring solution of 30 (1 g, 3.30 mmol) in DMF (20 mL) under inert atmosphere were added EDCI.HC1 (945 g, 4.90 mmol), HOBt (668 mg, 4.95 mmol), ((5- chloropyridin-2-yl) methanamine 98 (470 mg, 3.30 mmol) and diisopropylethylamine (1.63 mL, 9.90 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2-3percent MeOH/ CH2CI2 to afford compound 99 (1.2 g, 85percent) as an off-white solid. TLC: 10percent MeOH/ CH2C12 (Rf. 0.5); 1H NMR (DMSO-6, 500 MHz): delta 9.37 (t, J= 5.8 Hz, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 8.01- 7.94 (m, 3H), 7.93-7.83 (m, 5H), 7.36 (d, J = 8.7 Hz, 1H), 4.55 (d, J = 6.1 Hz, 2H); (NMR shows DMF solvent) LC-MS: 50.51percent; 427.9 (M++l); (column; Ascentis Express C18, (50 chi 3.0 mm, 2.7 mupiiota); RT 2.09 min. 0.025percent Aq. TFA + 5percent ACN: ACN + 5percent 0.025percent Aq. TFA, 1.2 mL/min). |
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