Hydrocarbyl Tin Complex with Antitumor Activity and Preparation Method Thereof

Abstract

Hydrocarbyl tin complexs of alkynyl phosphonic acid with antitumor activity and their preparation method are provided in present invention. Tests are conducted to evaluate activity, showing that the provided complexs have much stronger activity than cisplatin, especially for human colon cancer. The provided hydrocarbyl tin complexs can be potential candidate as a clinical antitumor drug.

Claims

1. A hydrocarbyl tin complex with antitumor activity, characterized by having the following structure: ##STR00008## wherein, R.sub.1 is selected from the group consisting of n-butyl, t-butyl, phenyl, benzyl, p-chlorobenzyl and dimethylbenzyl; ##STR00009## and R.sub.2 is a randomly substituted alkyl, aryl and heteroaryl; n is an integer from 2.

2. The hydrocarbyl tin complex according to claim 1, wherein, R.sub.2 is a randomly substituted C1-C4 alkyl, C6-C10 aryl and C6-C10 heteroaryl.

3. The hydrocarbyl tin complex according to claim 1, wherein, R.sub.2 is a randomly substituted phenyl.

4. The hydrocarbyl tin complex according to claim 1, wherein, R.sub.2 is randomly substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-C8 alkyl, C1-C8 alkoxy, nitryl, cyano group, and trifluoromethyl.

5. The hydrocarbyl tin complex according to claim 1, wherein, R.sub.2 is randomly substituted by 1 to 5 substituents selected from C1-C8 alkoxy, trifluoromethyl.

6. The hydrocarbyl tin complex according to claim 1, wherein, R.sub.2 is randomly substituted by 1 to 5 substituents selected from methoxyl, trifluoromethyl.

7. The hydrocarbyl tin complex according to claim 3, wherein, R.sub.2 is randomly substituted by 1 to 5 substituents selected from methoxyl, trifluoromethyl.

8. The hydrocarbyl tin complex according to claim 7, wherein, R.sub.1 is selected from n-butyl and benzyl.

9. A preparation method of a hydrocarbyl tin complex, wherein, the hydrocarbyl tin complex having the following structure: ##STR00010## wherein, R.sub.1 is selected from the group consisting of n-butyl, t-butyl, phenyl, benzyl, p-chlorobenzyl and dimethylbenzyl; ##STR00011## and R.sub.2 is a randomly substituted alkyl, aryl and heteroaryl; n is an integer from 2; the method comprises: in a round-bottom flask, adding tin chloride substituted with R.sub.1 and organic solvent, dissolving the tin chloride substituted with R.sub.1 completely with stirring, and adding acetylenyl phosphate monosodium substituted with R.sub.2, performing an reaction under stirring, then cooling and filtering, concentrating the filtrate under reduced pressure, adding an appropriate amount of petroleum ether into the concentrated filtrate, filtering and performing vacuum concentration to obtain a product.

10. The preparation method of a hydrocarbyl tin complex according to claim 9, characterized in that, the hydrocarbyl tin complex of alkynyl phosphonic acid according to claim 1, wherein, R.sub.2 is a randomly substituted C1-C4 alkyl, C6-C10 aryl and C6-C10 heteroaryl.

11. The preparation method of a hydrocarbyl tin complex according to claim 9, characterized in that, R.sub.2 is a randomly substituted phenyl.

12. The preparation method of a hydrocarbyl tin complex according to claim 9, wherein, R.sub.2 is randomly substituted by 1 to 5 substituents selected from C1-C8 alkoxy, trifluoromethyl.

13. The preparation method of a hydrocarbyl tin complex according to claim 9, wherein, R.sub.2 is randomly substituted by 1 to 5 substituents selected from methoxyl, trifluoromethyl.

14. The preparation method of a hydrocarbyl tin complex according to claim 9, wherein, R.sub.1 is selected from n-butyl and benzyl.

15. The preparation method of a hydrocarbyl tin complex according to claim 10, wherein, R.sub.1 is selected from n-butyl and benzyl.

16. The preparation method of a hydrocarbyl tin complex according to claim 11, wherein, R.sub.1 is selected from n-butyl and benzyl.

17. The preparation method of a hydrocarbyl tin complex according to claim 12, wherein, R.sub.1 is selected from n-butyl and benzyl.

18. The preparation method of a hydrocarbyl tin complex according to claim 9, wherein, R.sub.1 is n-butyl and R.sub.2 is a phenyl substituted by trifluoromethyl; the method comprises: in a round-bottom flask, adding tri-n-butyl tin chloride and anhydrous methanol, dissolving the tri-n-butyl tin chloride completely with stirring, adding (3-trifluoromethyl phenyl) acetylenyl phosphate monosodium, performing an reaction under reflux with stirring for 4.5 hours, then cooling and filtering, concentrating the filtrate under reduced pressure, adding an appropriate amount of petroleum ether into the concentrated filtrate, filtering and performing vacuum concentration to obtain a product.

19. A preparation method of a hydrocarbyl tin complex, wherein, the hydrocarbyl tin complex having the following structure: ##STR00012## wherein, R.sub.1 is n-butyl, ##STR00013## n is an integer from 2; the method comprises: in a round-bottom flask, adding tri-n-butyl tin chloride and organic solvent, dissolving the tri-n-butyl tin chloride completely with stirring, and adding (4-methoxyphenyl) acetylenyl phosphate monosodium, performing an reaction under stirring, then cooling and filtering, concentrating the filtrate under reduced pressure, adding an appropriate amount of petroleum ether into the concentrated filtrate, filtering and performing vacuum concentration to obtain a product.

20. The preparation method of a hydrocarbyl tin complex according to claim 19, characterized in that the method comprises: in a 100 ml round-bottom flask, adding 3 mmol of tri-n-butyl tin chloride and 20 ml of anhydrous methanol, dissolving the tri-n-butyl tin chloride completely with stirring, adding 3.2 mmol of (4-methoxyphenyl) acetylenyl phosphate monosodium, performing an reaction under reflux with stirring for 4.5 hours, then cooling and filtering, concentrating the filtrate under reduced pressure, adding an appropriate amount of petroleum ether into the concentrated filtrate, filtering and performing vacuum concentration to obtain a product.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0015] In order to make the purpose, technical solution and advantages of the present invention clearer, the representative embodiments of the present invention will be described in detail below, but the present invention is not limited thereto.

[0016] The present invention provides a hydrocarbyl tin complex with antitumor activity, having the following structure:

##STR00003##

[0017] wherein, R.sub.1 is selected from n-butyl, t-butyl, phenyl, benzyl, p-chlorobenzyl and dimethylbenzyl;

##STR00004##

and R.sub.2 is a randomly substituted alkyl, aryl and heteroaryl; n is an integer from 2.

[0018] In some embodiments, R.sub.1 can be n-butyl, t-butyl, phenyl, benzyl; R.sub.2 can be a randomly substituted alkyl, aryl and heteroaryl. R.sub.2 can be randomly substituted by 1 to 5 substituents selected from the group consisting of halogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, nitryl, cyano group, and trifluoromethyl. More specifically, R.sub.2 can be randomly substituted by 1 to 5 substituents selected from the group consisting of halogen, such as F, Cl, Br, I; a C.sub.1-C.sub.8 alkyl, such as methyl, ethyl, propyl, t-butyl; a C.sub.1-C.sub.8 alkoxy, such as methoxy, ethoxy, propoxy, t-butoxy; nitryl, cyano group, trifluoromethyl.

[0019] In other embodiments, R.sub.1 can be n-butyl, benzyl; R.sub.2 can be a randomly substituted alkyl, aryl and heteroaryl. R.sub.2 can be randomly substituted by 1 to 5 substituents selected from the group consisting of halogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, nitryl, cyano group, and trifluoromethyl. Among them, halogen can be F, Cl, Br, I; C.sub.1-C.sub.8 alkyl can be methyl, ethyl, propyl, t-butyl, C.sub.1-C.sub.8 alkoxy can be methoxy, ethoxy, propoxy, t-butoxy.

[0020] In other embodiments, R.sub.2 can be C.sub.1-C.sub.4 alkyl, C.sub.6-C.sub.10 aryl and C.sub.6-C.sub.10 heteroaryl randomly substituted by 1 to 5 substituents selected from methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, propoxy, tert-butylene, nitryl, cyano group, trifluoromethyl.

[0021] More preferably, R.sub.2 is a phenyl randomly substituted by 1 to 5 substituents selected from methyl, methoxy, nitryl, cyano group, trifluoromethyl.

[0022] More preferably, R.sub.2 is a phenyl randomly substituted by 1 to 5 substituents selected from methoxyl and trifluoromethyl.

[0023] In other embodiments, R.sub.1 can be n-butyl, t-butyl, phenyl, benzyl; R.sub.2 can be C.sub.1-C.sub.4 alkyl, C.sub.6-C.sub.10 aryl and C.sub.6-C.sub.10 heteroaryl randomly substituted by 1 to 5 substituents selected from methyl, methoxyl, nitryl, cyano group, trifluoromethyl.

[0024] In other embodiments, R.sub.1 can be n-butyl, benzyl; R.sub.2 can be phenyl randomly substituted by 1 to 5 substituents selected from methoxyl and trifluoromethyl.

[0025] Moreover, the present invention also provides a preparation method of a hydrocarbyl tin complex, the hydrocarbyl tin complex has the following structure:

##STR00005##

[0026] wherein, R.sub.1 is selected from n-butyl, t-butyl, phenyl, benzyl, p-chlorobenzyl and dimethylbenzyl;

##STR00006##

and R.sub.2 is a randomly substituted alkyl, aryl and heteroaryl; n is an integer from 2.

[0027] the method comprises the following steps:

[0028] in a round-bottom flask, adding tin chloride substituted with R.sub.1 and organic solvent were added, the tin chloride substituted with R.sub.1 was completely dissolved with stirring, then acetylenyl phosphate monosodium substituted with R.sub.2 was added. Reaction was performed under stirring, then the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and an appropriate amount of petroleum ether was added into the concentrated filtrate, after filtering, vacuum concentration was performed to obtain a product.

[0029] In some embodiments, R.sub.1 of the hydrocarbyl tin complex prepared by the method can be n-butyl, t-butyl, phenyl, benzyl; R.sub.2 can be a randomly substituted alkyl, aryl and heteroaryl. R.sub.2 can be randomly substituted by 1 to 5 substituents selected from the group consisting of halogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, nitryl, cyano group, and trifluoromethyl. Among them, halogen can be F, Cl, Br, I; C.sub.1-C.sub.8 alkyl can be methyl, ethyl, propyl, t-butyl, C.sub.1-C.sub.8 alkoxy can be methoxy, ethoxy, propoxy, t-butoxy.

[0030] In other embodiments, R.sub.2 can be C.sub.1-C.sub.4 alkyl, C.sub.6-C.sub.10 aryl and C.sub.6-C.sub.10 heteroaryl randomly substituted by 1 to 5 substituents selected from methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, propoxy, tert-butylene, nitryl, cyano group, trifluoromethyl.

[0031] More preferably, R.sub.1 can be n-butyl, benzyl; R.sub.2 can be phenyl randomly substituted by 1 to 5 substituents selected from methoxyl and trifluoromethyl.

Embodiment 1: The Synthesis of Tri-n-butyltin (IV) (4-methoxyphenyl) Acetylenyl Phosphonic Acid Derivatives

[0032] ##STR00007##

[0033] The structural formula of the product is shown as above:

[0034] In a 100 ml round-bottom flask, 3 mmol of tri-n-butyl tin chloride and 20 ml of anhydrous methanol were added. The tri-n-butyl tin chloride was completely dissolved with stirring. After that, 3.2 mmol of (4-methoxyphenyl) acetylenyl phosphate monosodium was added. Reaction of the mixture in the flask was held for 4.5 hours under reflux with stirring, then cooled and the filtrate of the reaction solution was concentrated under reduced pressure. An appropriate amount of petroleum ether was added into the concentrated filtrate. After filtering, vacuum concentration was performed to obtain the product, wherein the yield is 87%.

[0035] Element Analysis Data: Anal. Calcd. For C.sub.21H.sub.35O.sub.4PSn (%): C, 53.33, H, 7.04, Sn, 23.69; Found (%): C, 53.37, H, 7.06, Sn, 23.73. Nuclear Magnetic Resonance Spectroscopy Data (.sup.1H NMR/): 0.79-0.83 (9H), 1.24-2.03 (18H), 3.42-4.02 (3H), 7.33-7.90 (4H).

Embodiment 2: The Synthesis of Tri-n-butyltin (IV) (3-Trifluoromethyl Phenyl) Acetylenyl Phosphonic Acid Derivatives

[0036] In a round-bottom flask, tri-n-butyl tin chloride and anhydrous methanol were added. The tri-n-butyl tin chloride was completely dissolved with stirring. After that, (3-trifluoromethyl phenyl) acetylenyl phosphate monosodium was added, Reaction of the mixture in the flask was held for 4.5 hours under reflux with stirring, then cooled and the filtrate of the reaction solution was concentrated under reduced pressure. An appropriate amount of petroleum ether was added into the concentrated filtrate. After filtering, vacuum concentration was performed to obtain the product.

Embodiment 3: Antitumor Activity Test of the Compounds

[0037] The compound produced in embodiment 1 is named as Compound 1, and the compound produced in embodiment 2 is named as Compound 2.

[0038] MCF-7, HT-29, A549 and HepG2 cells are got from American Tissue Culture Collection, which are cultured with the culture medium containing 10% bovine fetal serum in a CO.sub.2-containing incubator at 37 C. The MTT method is used to detect cell proliferation and growth inhibition. The number of experimental cells is adjusted to obtain the absorbance at 570 nm, 6 concentrations are set for the compound test solution (0.1 nmol/L10 mol/L). The cells are treated for 72 hours. At least 3 parallel experiments and 3 repeated experiments are conducted for each concentration. The IC.sub.50 value is determined by statistical analysis.

[0039] The inventors of this application make appropriate structural improvement and screening from existing hydrocarbyl tin complex of alkynyl phosphonic acid on the basis of existing literature, so as to explore new antitumor drugs. According to the preliminary biological activity test, it shows that this kind of hydrocarbyl tin complex of alkynyl phosphonic acid do possess antitumor activity. Among them, several specially-structured complexes especially show excellent activity.

[0040] Taking cisplatin as the contrast, the in-vitro growth inhibitory activity of Compound 1 and Compound 2 on tumor cells are tested, including MCF7 (human breast cancer cells), HT-29 (human colon cancer cells), A549 (human lung cancer cells) and HepG2 (liver cancer cells). The results are shown in the table below. It is found that the compounds show stronger antitumor activity than cisplatin, especially for the inhibition of HT-29, and can be used as candidate anticancer compounds.

TABLE-US-00001 TABLE 1 IC.sub.50 Value (mol/L) Compound MCF7 HT-29 A549 HepG2 1 0.853 0.065 0.243 0.329 2 1.732 0.962 0.274 0.872 Cisplatin 43 35 1.3 17