Acylfulvene Analog Structure Modification for Reduced Toxicity
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Solution Overview
Problem
There is a need for chemotherapeutic agents that effectively inhibit cancer cell growth, particularly solid tumor growth, with an adequate therapeutic index for in vivo treatment, and can overcome drug resistance mechanisms.
Innovation Solution
Development of acylfulvene analogs, modified with hydroxyurea or its derivatives, which have a specific chemical formula and are effective as antineoplastic agents, either alone or in combination with other anti-cancer agents, to inhibit cancer cell growth and treat various types of cancers, including solid tumors and hematologic malignancies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If illudin S and M are used as chemotherapeutic agents, then anti-tumor activity is achieved, but therapeutic index is poor
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of illudin S and M through systematic substitution at specific positions (C-6, C-7, C-8) with various functional groups including hydroxyurea derivatives. These structural modifications alter the pharmacological properties to reduce toxicity while preserving anti-tumor activity, as evidenced by compounds like irofulven showing improved therapeutic index compared to parent compounds
Solution Approach 2:
The patent creates composite chemical structures by combining the fulvene core of illudin with hydroxyurea moieties and other functional groups. This composite approach integrates multiple pharmacophores into single molecules, achieving both anti-tumor efficacy and reduced toxicity through the synergistic effects of different structural components
2Reliability
If irofulven is used to treat cancer, then clinical activity with acceptable safety profile is achieved, but drug resistance mechanisms limit efficacy
Solution Approach 1:
The patent continues the parameter changes approach by further modifying irofulven's structure through substitutions at positions 6, 7, and 8 with diverse functional groups. These modifications create analogs that maintain the core anti-tumor mechanism while evading common resistance pathways including multidrug resistance phenotype, anti-apoptotic bcl-2 overexpression, and p53/p21 mutations
3Reliability
If higher doses of chemotherapeutic agents are administered, then anti-tumor efficacy is improved, but toxicity increases
Solution Approach 1:
The patent resolves this contradiction through parameter changes by designing analogs with modified chemical structures that shift the dose-response curve. The structural modifications at C-6, C-7, and C-8 positions create compounds with improved therapeutic windows, allowing effective anti-tumor doses with reduced toxic side effects compared to parent compounds
Data Source
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AI summary
Acylfulvene analogs, which inhibit tumor growth, especially solid tumor growth, and which have an adequate therapeutic index to be effective for in vivo treatment are provided herein. The compounds described herein are useful as anti-neoplastic agents, i.e., to inhibit tumor cell growth in vitro or in vivo, in mammalian hosts, such as humans or animals, e.g., domestic animals, and are effective against solid tumors, hematologic malignancies and multi-drug resistant cancers/tumors. The present compounds can be used alone or they can be used in combination with one or more anti-cancer or anti-tumor agents.