Abstract: Triphenylphosphonium (TPP+) compounds like mito-metformin (MMe) target cancer cells by exploiting their hyperpolarized mitochondrial membrane potential. Here, we present a protocol for synthesizing TPP+ analogs with selectivity for mammalian cancer cells, reduced toxicity, and quantifiability using fluorine-19 NMR (19F-NMR). We describe steps for treating mammalian cells with mitochondria-targeted compounds, treating and preparing mouse tissue with these compounds, and 19F-NMR detection of MMe analogs in cells and tissue. TPP+-conjugated metformin analogs include para-methoxy (pMeO-MMe) and para-trifluoromethyl MMe (pCF3-MMe) and meta-trifluoromethyl MMe (mCF3-MMe).
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ethyl 2-guanidino-5-thiazolylcarboxylate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; acetone;
(A) Ethyl 2-Guanidino-5-thiazolecarboxylate Hydrochloride A solution of amidinothiourea (117 g; 0.99 mole) and ethyl chloro-alpha-formylacetate (150 g; 1.0 mole) in 3.5 liters of absolute ethanol was stirred at ambient temperature for 18 hours and then heated at reflux temperature for 1 hour. At this time additional ethyl chloro-alpha-formylacetate (20.0 g; 0.13 mole) was added and 1 hour later another 20.0 g of ethyl chloro-alpha-formylacetate was added. After 2 hours of additional heating at reflux temperature, the reaction mixture was evaporated under reduced pressure and the residue triturated with 1.5 liters of acetone and filtered to give 103 g of product. Recrystallization from 2-propanol yielded the title compound, mp 204-206. Anal. Calcd for C7 H11 ClN4 O2 S: C, 33.53; H, 4.43; N, 22.35; Cl, 14.14; S, 12.79. Found: C, 33.38; H, 4.40; N, 22.54; Cl, 13.97; S, 12.92.
2-guanidino-4-(3-aminophenyl)-5-methylthiazole dihydrochloride[ No CAS ]
[ 2114-02-5 ]
[ 17408-16-1 ]
[ 72801-94-6 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogen bromide; bromine; In ethanol; chloroform; acetic acid;
The 2-guanidino-4-(3-aminophenyl)-5-methylthiazole dihydrochloride used as starting material may be prepared as follows: To a stirred mixture of <strong>[17408-16-1]m-nitropropiophenone</strong> (3.6 g.) in chloroform (50 ml.) was added 3 drops of a solution of hydrogen bromide in acetic acid (45% w/v). Bromine (3.2 g.) in chloroform (10 ml.) was then added dropwise. After addition the mixture was stirred until colourless, evaporated to dryness, the residue dissolved in ethanol (50 ml.) and this solution added to amidinothiourea (2.4 g.) in ethanol (150 ml.) at reflux. The mixture was heated under reflux for 30 minutes and then evaporated to approximately 50 ml. On standing overnight at room temperature a crystalline solid was produced. This was filtered off, washed with ethanol and air-dried to give 6.05 g. of 2-guanidino-4-(3-nitrophenyl)-5-methylthiazole hydrobromide, m.p. 217-222 C.
2-guanidino-4-(3-amino4-fluorophenyl)thiazole[ No CAS ]
[ 72802-25-6 ]
[ 2114-02-5 ]
[ 72802-26-7 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogen bromide; bromine; In ethanol; chloroform; acetic acid;
The 2-guanidino-4-(3-amino-4-fluorophenyl)thiazole used as starting material may be prepared as follows: To a solution of <strong>[72802-25-6]3-fluoro-4-nitroacetophenone</strong> (6 g.) in chloroform (40 ml.) was added 2 drops of hydrogen bromide in acetic acid (45% w/v) followed by bromine (1.75 ml.) added dropwise. After the bromine colour had disappeared the clear yellow solution was evaporated to dryness and the residue, dissolved in hot ethanol (40 ml.), was added to amidinothiourea (4.0 g.) in ethanol (100 ml.) under reflux. The mixture was heated under reflux for 15 minutes and then cooled to room temperature. The crystalline solid was filtered off to give 8.8 g. of 2-guanidino4-(3-fluoro-4-nitrophenyl)thiazole hydrobromide, m.p. 248-252 C.
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