41234-71-3

Upstream product

• 23428-82-2 2-(1,4-dioxa-7-aza-spiro[4.4]nonane-7-carbonyl)-benzoic acid methyl ester 
• 6295-21-2 3-chloro-1(3H)-isobenzofuranone 
• 176-33-0 1,4-dioxa-6-azaspiro[4.4]nonane 
• 16859-59-9 3-hydroxy-1(3H)-isobenzofuranone 
• 14891-11-3 N-ethoxycarbonyl-3-pyrrolidinone ethylene ketal 
• 4397-55-1 phthalic monoacid monomethyl ester chloride 
• 23428-86-6 7-(2-hydroxymethyl-benzoyl)-1,4-dioxa-7-aza-spiro[4.4]nonane 

Relevant academic research and scientific papers

OXOBENZINDOLIZINOQUINOLINES AND USES THEREOF

The synthesis of aromathecins, substituted 12H-5,l la-diazadibenzo[b,h]fluoren- 11 -ones is described. Use of these cytotoxic compounds and pharmaceutical compositions containing them for the treatment of cancer is described. Two novel processes for the synthesis of this system and a series of 14-substituted aromathecins as novel cytotoxic, topoisomerase I poisons are described.

Design, synthesis, and biological evaluation of 14-substituted aromathecins as topoisomerase I inhibitors

The aromathecin or "rosettacin" class of topoisomerase I (top1) inhibitors is effectively a "composite" of the natural products camptothecin and luotonin A and the synthetic indenoisoquinolines. The aromathecins have aroused considerable interest following the isolation and total synthesis of 22-hydroxyacuminatine, a rare cytotoxic natural product containing the 12H-5,11a-diazadibenzo[b,h]fluoren-11-one system. We have developed two novel syntheses of this system and prepared a series of 14-substituted aromathecins as novel antiproliferative topoisomerase I poisons. These inhibitors are proposed to act via an intercalation and "poisoning" mechanism identical to camptothecin and the indenoisoquinolines. Many of these compounds possess greater antiproliferative activity and anti-top 1 activity than the parent unsubstituted compound (rosettacin) and previously synthesized aromathecins, as well as greater top1 inhibitory activity than 22-hydroxyacuminatine. In addition to potentially aiding solubility and localization to the DNA-enzyme complex, nitrogenous substituents located at the 14-position of the aromathecin system have been proposed to project into the major groove of the top1-DNA complex and hydrogen-bond to major-groove amino acids, thereby stabilizing the ternary complex.