Method for chemical synthesis of antrocin and use thereof for suppressing non-small cell lung cancer
The present invention provides a method for preparing antrocin of pharmaceutically acceptable salts thereof via a series of gold-catalyzed cyclization to construct the (6-6-5) tricyclic core frame. The present invention also provides a use of a composition in preparing drugs for suppressing growth of non-small cell lung cancer cells, wherein the composition comprises an effective amount of antrocin or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
1. A method for preparing antrocin, comprising the steps of:
(a) reacting Compound A
with sulfide and haloalkane in the presence of a base to produce an intermediate; and
(b) reacting the intermediate with a free radical initiator and a free radical source to form antrocin.
2. The method of claim 1 , wherein the base is sodium bis(trimethylsily)pamide, the sulfide is carbon disulfide, the haloalkane is iodomethane, the free radical initiator is azo-bis-isobutyronitrile, and the free radical source is tri-n-butyltin hydride.
3. The method of claim 1 , wherein the Compound A is produced by reacting Compound B
with an acid via a reducing agent.
4. The method of claim 3 , wherein the reducing agent is an alkali metal, and the acid is hydrochloric acid.
5. The method of claim 3 , wherein the Compound B is produced by reacting Compound C
with alcohol in an organic solvent in the presence of gold compound and silver salt as catalysts.
6. The method of claim 5 , wherein the gold compound is a gold compound (IPr)AuCl having the following structure:
7. The method of claim 5 , wherein the silver salt is AgSbF6, and the organic solvent is dichloromethane.
8. The method of claim 5 , wherein the Compound C is produced by reacting Compound D
with a first-step oxidizing agent and then reacting with a second-step oxidizing agent in a cosolvent.
9. The method of claim 8 , wherein the first-step oxidizing agent is (2,2,6,6-tetramethylpiperidin-1-yl)oxy free radical and iodobenzene diacetate, the second-step oxidizing agent is sodium chlorite, and the cosolvent is t-butanol and an aqueous phosphate buffer solution of pH 6.8.
10. The method of claim 8 , wherein the Compound D is produced by reacting Compound E
with a base in a solvent.
11. The method of claim 10 , wherein the base is potassium hydroxide and the solvent is a mixed solvent of methanol, tetrahydrofuran and water.
12. The method of claim 10 , wherein the Compound E is produced by reacting Compound F
with a reducing agent.
13. The method of claim 12 , wherein the reducing agent is lithium aluminum hydride.
14. The method of claim 12 , wherein the Compound F is produced by reacting Compound G
with hypervalent iodine compound under the effect of a fluorine source.
15. The method of claim 14 , wherein the hypervalent iodine compound is a compound having the following structure:
16. The method of claim 14 , wherein the fluorine source is tetra-n-butylammonium fluoride in tetrahydrofuran solution.
17. The method of claim 14 , wherein Compound G is produced by reacting Compound H
with a Grignard reagent under the effect of a copper reagent.
18. The method of claim 17 , wherein the Grignard reagent is prepared by a bromide having the following structure:
19. The method of claim 17 , wherein the cooper reagent is cuprous bromide-dimethyl sulfide complex.