Derivatives of propane diyl dicinnamate
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Publication Number
US-9061993-B2
Publication Date
2015-06-23
Expiration Date
Abstract
The present invention provides a method for treating a cancer in a subject involving administering to the subject a compound of formula (II) or (II′): wherein R1, R2, R3, R4, R5, R6 and R7 are independently H, OH, alkoxy or alkylcarbonyloxy, or a pharmaceutically acceptable salt thereof. Also provided is a compound of formula (II) or (II)′, wherein R1 and R2 are independently OH, alkoxy or alkylcarbonyloxy, R3 and R4 are independently H, OH, alkoxy or alkylcarbonyloxy, R6 is H, alkoxy or alkylcarbonyloxy, R5 is H, OH or alkylcarbonyloxy, R6 is H or alkoxy, and R7 is H, or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to propane diyl dicinnamate derivatives as anticancer agents, including cancer-treatment compositions and pharmaceutical compositions. The compounds are defined by formula (I)/(I′), (II)/(II′), and related subformulas, with variable substituents R1–R6 or R7 defining chemical substitution patterns, together with pharmaceutically acceptable salt forms and pharmaceutically acceptable diluent or carrier.
The problem addressed is the need for cancer treatment by compounds that act in cancer cells, including limitations of conventional anticancer therapies due to toxicity. The disclosed approach provides methods for inducing apoptosis of cancer cells in a subject by administering an effective amount of a compound of formula (Ia)/(Ia′), (Ic)/(Ic′), or (II)/(II′), or a pharmaceutically acceptable salt thereof, with explicit exclusions of particular E-isomer compounds from the (II)/(II′) set.
The document further supports the invention by describing defined embodiments of the compound families, including subformulas (Ia)–(Id)/(Ie)/(If)/(Ig)/(Ih)/(Ii)/(Ij) and corresponding primes, and an intermediate glycidyl cinnamate derivative-type compound. It also provides example preparation pathways for compounds of formula (II)/(II′) from cinnamic acid derivatives and glycidyl cinnamates, and includes non-limiting example compounds such as (Id), (Id′), (Ie), (IIb), (IIc), and (Ie′).
In vitro anticancer activity is reported, including testing on B-16 melanoma cells and multiple human carcinoma cell lines versus normal fibroblasts. The text also references multiple cancer types including lung, breast, colon, prostate, ovarian, skin, and leukemia.
Claims Coverage
The provided material contains three independent claims, each directed to inducing apoptosis of cancer cells in a subject by administering an effective amount of specified formula compounds or pharmaceutically acceptable salts. Across the independent claims, the inventive features primarily differ in the structural substituent definitions for R1, R2, R4, and additional constraints or exclusions for the covered compound classes.
Substituent-limited apoptosis in formula (Ia) compounds
Administering to a subject in need thereof an effective amount of a compound of formula (Ia) or (Ia′) (or a pharmaceutically acceptable salt), wherein R1 and R2 are independently OH, alkoxy or alkylcarbonyloxy, R4 is OH, and R6 is H, alkoxy or alkylcarbonyloxy.
Substituent-limited apoptosis in formula (Ic) compounds
Administering to a subject in need thereof an effective amount of a compound of formula (Ic) or (Ic′) (or a pharmaceutically acceptable salt), wherein R1 and R2 are independently OH, alkoxy or alkylcarbonyloxy and R4 is OH.
Excluded-compound apoptosis in formula (II) compounds with matched R1/R2
Administering to a subject in need thereof an effective amount of a compound of formula (II) or (II′) (or a pharmaceutically acceptable salt), wherein R4 is OH; R1 and R2 are both OH or both alkoxy; and R6 and R7 are independently H, OH, alkoxy or alkylcarbonyloxy, provided that the compound is other than (2E,2′E)-2-acetoxypropane-1,3-diyl bis(3-(4-hydroxyphenyl)acrylate) and (E)-2-acetoxy-3-(((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)propyl 3-(4-hydroxyphenyl)acrylate.
Across the independent claims, the coverage centers on inducing apoptosis of cancer cells in a subject via administration of effective amounts of specific dicinnamate derivative formula compounds (Ia/Ia′, Ic/Ic′, II/II′) or pharmaceutically acceptable salts, with substituent-based limitations and, for formula (II)/(II′), explicit exclusion of two particular dicinnamate examples.
Stated Advantages
Induces apoptosis of cancer cells in a subject.
Provides compounds with in vitro anticancer activity, including EC50/IC50 reporting across multiple human carcinoma cell lines versus normal fibroblasts.
Higher selectivity/safety for compounds (Ib)/(Ie)/(Id) relative to paclitaxel, based on therapeutic index calculations.
Observation of membrane blebbing morphology in HCT116 cells consistent with apoptosis over time after treatment with compounds (IIb)/(Ie)/(Id).
Documented Applications
Method for inducing apoptosis of cancer cells in a subject by administering an effective amount of a compound of formula (Ia)/(Ia′), (Ic)/(Ic′), or (II)/(II′), or a pharmaceutically acceptable salt thereof.
In vitro anticancer activity testing in B-16 melanoma cells and multiple human carcinoma cell lines (GM9503, GM8399, MCF-7, A549, HCT116, SKOV-3, MDAY-D2, PC-3) versus normal fibroblasts, including reported EC50 and IC50 values and cases with NE.
In-vitro inhibition of multiple human carcinoma cell lines (A549, MCF-7, HCT116, PC-3, SKOV-3) by compounds (IIb)/(Ie)/(Id) compared with paclitaxel.
Assessment of therapeutic index and toxicity in normal human fibroblast cells (GM9503, GM8399) for selectivity/safety comparisons versus paclitaxel.
Apoptosis-related cell-death observation in HCT116 cells treated with compounds (IIb)/(Ie)/(Id), based on membrane blebbing morphology over time.
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