CYTIDINE DERIVATIVE DIMERS AND APPLICATIONS THEREOF

摘要

The present disclosure provides cytidine derivative dimers, salts and compositions of the cytidine derivative dimers, and methods of making and using the cytidine derivative dimers that are useful for treating a neoplasm in mammalian subjects. A cytidine derivative dimer may have the following general formula (I):;;By molecularly designing such cytidine-based compounds, the disclosed cytidine-based derivative dimers/salts show significant inhibiting effects on HCT-116 human colon cancer cells, and exhibit strong growth inhibiting effects on HCT-116 human colon cancer xenografts grown in nude mice. The disclosed cytidine derivative dimers/salts provide high anti-tumor activity with low toxicity and are useful for treating cancers.

主权项

1. A cytidine derivative dimer of formula (I), wherein: R1 is C1-C10 alkyl, C1-C10 substituted alkyl, —(CH2)n-Ph, or substituted —(CH2)n-Ph, n being an integer from 0 to 10, and Ph being phenyl; a carbon chain of the C1-C10 substituted alkyl is independently substituted by a substituent selected from the group consisting of halogen, cyano group, nitryl group, amino group, hydroxyl group, carboxyl group, and a combination thereof; and a carbon chain or a phenyl ring of the substituted —(CH2)n-Ph is independently substituted by a substituent selected from the group consisting of halogen, cyano group, nitryl group, amino group, hydroxyl group, carboxyl group, and a combination thereof; wherein: R2 is C1-C10 alkyl, C1-C10 substituted alkyl, —(CH2)n-Ph, or substituted —(CH2)n-Ph, n being an integer from 0 to 10, and Ph being phenyl; a carbon chain of the C1-C10 substituted alkyl is independently substituted by a substituent selected from the group consisting of halogen, cyano group, nitryl group, amino group, hydroxyl group, carboxyl group, and a combination thereof; and a carbon chain or a phenyl ring of the substituted —(CH2)n-Ph is independently substituted by a substituent selected from the group consisting of halogen, cyano group, nitryl group, amino group, hydroxyl group, carboxyl group, and a combination thereof; and wherein: R3 is hydrogen, alkoxycarbonyl or substituted alkoxycarbonyl, wherein a substituent of the substituted alkoxycarbonyl is selected from the group consisting of halogen, cyano group, nitryl group, amino group, hydroxyl group, carboxyl group and a combination thereof; R4 is hydrogen, alkoxycarbonyl or substituted alkoxycarbonyl, wherein a substituent of the substituted alkoxycarbonyl is selected from the group consisting of halogen, cyano group, nitryl group, amino group, hydroxyl group, carboxyl group and a combination thereof; and R5 is —(CH2)n-, n being an integer from 1 to 15; or substituted —(CH2)n- with a substituent on a carbon chain thereof, n being an integer from 1 to 15, and the substituent being selected from the group consisting of phenyl group, substituted phenyl group, cyano group, nitryl group, amino group, hydroxyl group, carboxyl group, and a combination thereof; or —(CH2)n-X1—X2—, X1 being O or S, X2 being —(CH2)n-Ph, pyrimidyl, pyranyl, imidazolyl, pyrazinyl, or pyridyl, and n being an integer from 0 to 3.