Anticancer agents; topoisomerase inhibitors
Inventors
Cushman, Mark S. • Morrell, Andrew E. • Pommier, Yves G.
Assignees
Purdue Research Foundation • National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-7495100-B2
Publication Date
2009-02-24
Expiration Date
2025-05-09
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Indenoisoquinolines and dihydroindenoisoquinolines are described. In particular, such compounds possessing one or more electron withdrawing substituents are described. The in vitro anticancer activities of these molecules tested in the National Cancer Institute's screen of 55 cell lines is described. The compounds tested for topoisomerase I (top1) inhibition is described.
Core Innovation
The invention relates to cytotoxic indenoisoquinolines and dihydroindenoisoquinolines, particularly those substituted with one or more electron withdrawing substituents or nitrogen-containing groups. These compounds are effective topoisomerase I (top1) inhibitors that intercalate between DNA bases at the enzyme's cleavage site, poisoning top1 by preventing religation of the DNA backbone. This mechanism is similar to camptothecin and its derivatives but involves a novel class of non-camptothecin top1 inhibitors.
The invention provides novel processes for synthesizing these indenoisoquinolines and dihydroindenoisoquinolines. Notably, it includes methods such as cyclizing precursors with phosphorus pentoxide in aprotic solvents or activating carboxylic acid derivatives followed by Lewis acid-induced cyclization. The resulting compounds can be substituted with electron withdrawing groups like nitro or nitrogen containing groups such as amino derivatives. The document also describes novel dihydroindenoisoquinolines and explores variations in substitution to potentiate cytotoxicity and top1 inhibition.
The background highlights a problem that existing synthetic efforts focused largely on modulating lactam nitrogen substituents without fully exploring electron withdrawing or nitrogen containing groups on other parts of the molecule. Moreover, previous attempts at ring closure and oxidation to prepare the compounds often yielded poor results or complex mixtures. The invention aims to overcome these synthetic challenges by providing improved methods for preparing substituted indenoisoquinolines and dihydroindenoisoquinolines with enhanced anticancer activity and top1 inhibitory effects.
Claims Coverage
The patent includes multiple independent claims covering novel processes for preparing dihydroindenoisoquinolones and compounds with specific substituents, highlighting inventive methods and compound compositions.
Process for preparing dihydroindenoisoquinolones by cyclization with phosphorus pentoxide
A method comprising cyclizing a precursor compound using phosphorus pentoxide in an aprotic solvent to form dihydroindenoisoquinolones, where the precursor contains substituents such as nitro groups on RA or RB positions.
Use of aprotic solvents in cyclization step
In the cyclizing process, employing aprotic solvents selected from chlorinated solvents, carbon disulfide, aromatic solvents, ether solvents, ester solvents, nitrile solvents, polar aprotic solvents, or their combinations, including specifically chlorinated aprotic solvents.
Compounds of formula with electron withdrawing or nitrogen-containing substituents
Indenoisoquinoline or dihydroindenoisoquinoline compounds substituted on RA or RB positions with nitrogen-containing substituents such as nitro or optionally substituted amino groups, or electron withdrawing substituents.
Process involving activation of carboxylic acid followed by Lewis acid cyclization
A process including activating a carboxylic acid derivative using a carboxylic acid activating reagent and cyclizing the activated species with a Lewis acid to form indenoisoquinolines or dihydroindenoisoquinolines.
The inventive features collectively establish novel synthetic routes for preparing substituted dihydroindenoisoquinolines and indenoisoquinolines, focusing on improved cyclization conditions, solvent choices, and compound substitution patterns to optimize anticancer activity and topoisomerase I inhibition.
Stated Advantages
Improved yields and purity of dihydroindenoisoquinolines using P2O5 cyclization compared to previous methods like thionyl chloride or Eaton's reagent.
Compounds with nitro substituents exhibit enhanced cytotoxicity and topoisomerase I inhibition compared to unsubstituted or electron-rich analogues.
Processes allow preparation of a wide variety of substituted indenoisoquinolines and dihydroindenoisoquinolines, enhancing structural diversity and potential activity.
Documented Applications
Use as anticancer agents effective in inhibiting topoisomerase I by poisoning the enzyme via intercalation into DNA.
Evaluation of anticancer activity in vitro against a wide panel of 55 human cancer cell lines as part of the National Cancer Institute screen.
Interested in licensing this patent?