Pharmaceutical combination for the treatment of melanoma
a technology of melanoma and combination drugs, applied in the field of drug combination, can solve the problems of poor response rate, poor overall survival, and ineffective treatment of metastatic melanoma
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reference example 1
(a) Preparation of (+)-trans-2-(2-chloro-4-trifluoromethylphenyl)-8-(2-hydroxy methyl-1-methyl pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one
[0204]To a solution of n-BuLi (15% solution in hexane, 2.2 mL, 5 mmol) in THF (10 mL), maintained at 0° C. under nitrogen atmosphere, hexamethyldisilazane (1.08 mL, 5.1 mmol) was added dropwise and stirred for 15 min. To this, a solution of (+)-trans-2-chloro-4-trifluoromethylbenzoic acid 2-(2-acetoxymethyl-1-methyl-pyrrolidin-3-yl)-6-acetyl-3,5-dimethoxyphenyl ester (1.44 g, 2.5 mmol) in THF (10 mL) was added dropwise, maintaining the temperature at 0° C. After the addition, the reaction was allowed to warm to room temperature and stirred for 2.5 h. The reaction mixture was acidified with dilute HCl, and basified with 10% sodium bicarbonate to pH 8 to 9. The aqueous layer was extracted with chloroform (3×25 mL). The organic layer was washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated unde...
reference example 2
(a) Preparation of (+)-trans-2-(2-chlorophenyl)-8-(2-hydroxymethyl-1-methyl pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one
[0210]Sodium hydride (50%, 0.54 g, 11.25 mmol) was added in portions to a solution of (−)-trans-1-[2-hydroxy-3-(2-hydroxymethyl-1-methyl pyrrolidin-3-yl)-4,6-dimethoxyphenyl)-ethanone (0.7 g, 2.2 mmol) in dry DMF (15 mL) at 0° C., under nitrogen atmosphere and with stirring. After 10 min., methyl 2-chlorobenzoate (1.15 g., 6.75 mmol) was added. The reaction mixture was stirred at 25° C. for 2 h. Methanol was added carefully below 20° C. The reaction mixture was poured over crushed ice (300 g), acidified with 1:1 HCl (pH 2) and extracted using EtOAc (2×100 mL). The aqueous layer was basified using a saturated Na2CO3 (pH 10) and extracted using CHCl3 (3×200 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated. To the residue, conc. HCl (25 mL) was added and stirred at room temperature for 2 h. The reaction mixture was poured over crushed ice (300 g) a...
example 1
I. In Vitro Study Involving Use of Combination of Compound a (CDK Inhibitor, Also Referred to as Voruciclib) and Vemurafenib (BRAFV600E Inhibitor) in BRAFV600E Mutated Melanoma Cell Lines
Objective:
[0216]To study the effect of the combination of compound A (CDK inhibitor, also referred to as voruciclib) and vemurafenib (BRAFV600E inhibitor) on the cell cycle and apoptosis in BRAFV600E mutated melanoma cell lines.
Materials and Methods:
Cell Lines
[0217]G361 and SK-MEL3 melanoma cell lines obtained from ATCC (American Type Culture Collection), USA, were used in this study. G361 is vemurafenib sensitive cell line while SK-MEL3 is vemurafenib resistant cell line. Both the cell lines are BRAFV600E mutated.
A. Analysis of Cell Cycle Distribution Using Flow Cytometry:
[0218]The G361 / SK-MEL3 melanoma cells were seeded in 25 mm3 tissue culture flasks. After 24 h, G361 cells were treated with: i) compound A (1 μM); ii) vemurafenib (1 μM); and iii) compound A (1 μM) and vemurafenib (1 μM) together ...
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