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—The design, synthesis and evaluation of a pentacyclic scaffold, CWO-324 to mimic saframycin A is described. CWO-324 isreadily synthesized in five steps from 1,4-diacetyl-piperazine-2,5-dione and 2,5-dimethoxybenzaldehyde. CWO-324 was found to scissionDNA, binds to bases 69–83(5 0 -GCAGTCAGG CACCGT-3 ) of Hind III/Rsa I from plasmid pBR322 DNA in a foot-printing study andpossesses anti-tumor activity.q 2003 Elsevier Ltd. All rights reserved. 1. IntroductionSaframycins, 1 natural antiproliferative agents with a novelmolecular architecture containing two units of 7-methoxy-6-methyl-1,2,3,4-isoquinoline-5,8-dione connected throughthe fifth ring to give the central piperazine ring, and bearinga methylene group substituted with a pyruvamide group hasbeen an attractive target for total synthesis 2a–g due to bothits structural complexity and excellent biological activity.The promising clinical efficacy of members of this series forthe treatment of solid tumors has recently led to thepreparation of a large number of diverse analogs withamendable structural modifications devoted to exploringvariation in the nature of the side chains. |
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