Ethoxy diphenyl ethane derivative and preparation method and application thereof

Abstract

The invention discloses an ethoxy diphenylethane derivative and a preparation method and application thereof. The 4, position of a B aromatic ring of phenylethane is chemically modified by an ethoxyl group, and simultaneously, a hydroxyl group at the 3, position of the B aromatic ring of the phenylethane is modified into water-soluble pro-drugs such as phosphate and the like, and likewise, an amino acid side chain is introduced into an amino group at the 3, position to form an amino acid amide water-soluble pre-drug having a structure as shown by a structural formula (I). An ethoxy phenylethane derivative and a pre-drug thereof have strong capacity of inhibiting tubulin aggregation, have obvious targeted destructive functions to tumor vessels, selectively cause the tumor vessels to have dysfunctions and structural damages, induce the apoptosis of vascular endothelial cells so that tumor cells lose the support of nutrition and oxygen gas, and give play to the functions of killing and wounding the tumor cells or inhibiting the tumor metastasis.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to the synthesis of diphenylethane derivative anticancer drugs. Background technique [0002] A new class of tubulin depolymerization factors discovered in recent years can close blood vessels at a dose lower than the MTD (Expert Opin Investig Drugs. 2004 Sep; 13(9) 1171-82). LoicVincent et al. mentioned a new class of tubulin depolymerization factors with similar properties in 2005. As vascular target factors (VTAs), they can destroy the tubulin skeleton. Literature data show that vascular target factors can selectively induce tumor blood vessels. decline, in part through the VE-cadherin signaling pathway. These tubulin-depolymerizing factors selectively destroy tumor blood vessels and prevent neovascularization without affecting normal vasculature. At the same time, it can inhibit the polymerization of tubulin, selectively cause the dysfunction and structure destruction of tumor bl...

AI Technical Summary

Problems solved by technology

Due to the existence of cis-trans isomerization reactions, the trans structure has no drug effect and will also bring certain toxic and side effects, so the separation and purification process requires high requirements, and it needs to go through column chromatography. The loss of raw materials is large, the process cost is high, and the yield is low. At the same time, the stilbene compounds should be transformed into the trans structure by ultraviolet light, and they need to be stored at low temperature and protected from light, which makes the stilbene compounds bring great difficulties in preservation and practical application.

[0005] Patent literature (Cushman, Mark et al., Synthesis and evaluation of analogs of (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethane aspotential cytotoxic and antimitotic agents, Journal of Medicinal Chemistry, 1992, Vol .35, No.12, 2293-306) discloses a compound, namely (Z)-1-(3,4,5-trimethoxy)phenyl-2-(4'-ethoxy)phenyl Ethylene, but there is no -OH, -NH2 and other substituent groups at the 3' position, which cannot form a synergistic active target, and the anticancer drug effect gradually decreases with the 4' position from 4'-methoxy, ethoxy, propoxy... ; And U.S. Patent SU6054598 discloses a kind of synthetic method that 2-methoxyestradiol is transformed into 2-ethoxyestradiol, and the in vitro antitumor activity of 2-ethoxyestradiol is better than 2-methoxyestradiol Estradiol is increased by 1000 times; we have found through research that ethoxydiphenylethane derivatives, 4'-ethoxy and 3'-hydroxyl, amino also have a synergistic effect, which can significantly improve the anti-cancer effect, but 4 'After modified with propoxy group, its anti-cancer effect is obviously greatly reduced

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