title: Semi-synthetic mithramycin SA derivatives with improved anticancer activity.
abstract: 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: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536-0596, USA.
authors: Daniel
authors: D
authors: Scott
authors: Jhong-Min
authors: JM
authors: Chen
authors: Younsoo
authors: Y
authors: Bae
authors: Jürgen
authors: J
authors: Rohr
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism; D008926:Plicamycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D008926:Plicamycin