Document Detail


Semi-synthetic mithramycin SA derivatives with improved anticancer activity.
MedLine Citation:
PMID:  23331575     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mithramycin (MTM) is a potent anti-cancer agent that has recently garnered renewed attention. This manuscript describes the design and development of mithramycin derivatives through a combinational approach of biosynthetic analogue generation followed by synthetic manipulation for further derivatization. Mithramycin SA is a previously discovered analogue produced by the M7W1 mutant strain alongside the improved mithramycin analogues mithramycin SK and mithramycin SDK. Mithramycin SA shows decreased anti-cancer activity compared to mithramycin and has a shorter, two carbon aglycon side chain that is terminated in a carboxylic acid. The aglycon side chain is responsible for an interaction with the DNA-phosphate backbone as mithramycin interacts with its target DNA. It was therefore decided to further functionalize this side chain through reactions with the terminal carboxylic acid in an effort to enhance the interaction with the DNA phosphate backbone and improve the anti-cancer activity. This side chain was modified with a variety of molecules increasing the anti-cancer activity to a comparable level to mithramycin SK. This work shows the ability to transform the previously useless mithramycin SA into a valuable molecule and opens the door to further functionalization and semi-synthetic modification for the development of molecules with increased specificity and/or drug formulation.
Authors:
Daniel Scott; Jhong-Min Chen; Younsoo Bae; Jürgen Rohr
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-04-04
Journal Detail:
Title:  Chemical biology & drug design     Volume:  81     ISSN:  1747-0285     ISO Abbreviation:  Chem Biol Drug Des     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-24     Completed Date:  2013-11-01     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  101262549     Medline TA:  Chem Biol Drug Des     Country:  England    
Other Details:
Languages:  eng     Pagination:  615-24     Citation Subset:  IM    
Copyright Information:
© 2013 John Wiley & Sons A/S.
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic* / chemistry,  pharmacology
Cell Line, Tumor
DNA, Neoplasm / chemistry*,  metabolism
Drug Screening Assays, Antitumor / methods
Humans
Neoplasms / chemistry,  drug therapy*,  metabolism
Plicamycin* / analogs & derivatives,  chemistry,  pharmacology
Grant Support
ID/Acronym/Agency:
5R25CA153954/CA/NCI NIH HHS; CA 091901/CA/NCI NIH HHS; R01 CA091901/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/DNA, Neoplasm; NIJ123W41V/Plicamycin
Comments/Corrections

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