Platinum Compounds with Malonic Acid Derivatives for Cancer Treatment

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Solution Overview

Problem

Current platinum antitumor drugs suffer from high toxicity, poor solubility, and a limited anticancer spectrum, leading to significant side effects and drug resistance, necessitating the development of new compounds with improved aqueous solubility and reduced toxicity.

Innovation Solution

The development of platinum compounds with a malonic acid derivative leaving group containing amino and alkylamino radicals, which enhance aqueous solubility and reduce toxicity, including specific compounds such as [2-(2-methylamino ethyl)-malonato] [cis-diamine] platinum (II) and [2-(2-dimethylamino ethyl)-malonato] [cis-diamine] platinum (II), along with their pharmaceutical acceptable salts, solvates, racemates, and geometric isomers.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If traditional platinum antitumor drugs (cisplatin, carboplatin) are used, then antitumor activity is achieved, but aqueous solubility remains poor and toxicity is high

Engineering Contradiction:

Improveaqueous solubilityVSAvoidtoxicity

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of platinum compounds, specifically replacing traditional leaving groups (chloride, carboxylate) with malonic acid derivative leaving groups containing amino and alkylamino radicals. This structural parameter change fundamentally alters the compound's properties, achieving both improved aqueous solubility (up to 100 times higher than cisplatin) and reduced toxicity while maintaining antitumor activity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite molecular structures by combining platinum center with malonic acid derivative ligands containing amino and alkylamino radicals. This composite approach integrates multiple functional groups (platinum coordination sphere, malonic acid backbone, amino/alkylamino substituents) into a single molecule, achieving synergistic effects of enhanced solubility, reduced toxicity, and maintained anticancer activity

Inventive Principle:

Principle #40Composite materials

2Reliability

If platinum antitumor drugs are administered, then cell proliferation is inhibited, but severe side effects occur including bone marrow suppression and nephrotoxicity

Engineering Contradiction:

Improveantitumor efficacyVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent modifies molecular parameters by introducing amino and alkylamino radicals into the malonic acid derivative leaving group. These parameter changes result in compounds that maintain DNA-binding capability (antitumor efficacy) while reducing interaction with toxic targets, thereby lowering side effects such as bone marrow suppression and nephrotoxicity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention converts the traditionally harmful property of high reactivity (which causes toxicity) into a beneficial feature by designing malonic acid derivative leaving groups that are sufficiently reactive to bind tumor cell DNA but less reactive toward normal tissues. The amino and alkylamino radicals modulate the reactivity profile, allowing selective cytotoxicity against cancer cells while sparing healthy tissues

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Adaptability or versatility

If existing platinum compounds are used, then treatment is effective, but drug resistance develops and anticancer spectrum is limited

Engineering Contradiction:

Improveanticancer spectrumVSAvoiddrug resistance

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent employs parameter changes by varying the amino and alkylamino substituents on the malonic acid derivative leaving group. This creates a series of analogs with different steric and electronic properties, enabling the development of compounds that can overcome drug resistance mechanisms and expand anticancer spectrum to include platinum-resistant tumor types

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The malonic acid derivative leaving group structure serves multiple functions: it provides improved solubility, maintains DNA-binding capability, reduces toxicity, and offers structural versatility for creating analogs with different activities. This multi-functionality allows a single core structure to address multiple therapeutic needs and overcome limitations of traditional platinum drugs

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentEP2740738B1Platinum compounds for treating cell proliferative disease, preparation methods and uses thereof

Publication Date: 2018.03.28 BEIJING FSWELCOME TECH DEV

AI summary

Disclosed are a class of platinum compounds with a leaving group of malonic acid derivatives containing amino and alkylamino, their pharmaceutically acceptable salts, their preparation methods and pharmaceutical composites comprising them. Disclosed also are for the uses of the compounds in the treatment of cell proliferative diseases, particularly for the treatment of cancers. The present platinum compounds have high water solubility and low toxicity.