Semi-synthetic mithramycin SA derivatives with improved anticancer activity

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Pharmacology

Background:

• Mithramycin (MTM) is a potent anti-cancer agent with renewed research interest.
• Biosynthetic and synthetic approaches are key for developing novel MTM derivatives.
• Mithramycin SA, a MTM analogue, exhibits reduced anti-cancer activity due to a shorter aglycon side chain.

Purpose of the Study:

• To design and develop novel mithramycin derivatives with enhanced anti-cancer activity.
• To investigate the functionalization of the mithramycin SA side chain for improved DNA interaction.
• To explore semi-synthetic modifications for increased specificity and drug formulation.

Main Methods:

• Combinational approach: biosynthetic analogue generation followed by synthetic manipulation.
• Production of mithramycin SA, mithramycin SK, and mithramycin SDK using M7W1 mutant strain.
• Functionalization of the carboxylic acid terminal on the mithramycin SA side chain.

Main Results:

• Modification of the mithramycin SA side chain increased anti-cancer activity.
• Enhanced activity reached levels comparable to mithramycin SK.
• Demonstrated the potential to transform mithramycin SA into a valuable therapeutic molecule.

Conclusions:

• Semi-synthetic modification of mithramycin SA significantly enhances its anti-cancer properties.
• The functionalized side chain improves interaction with the DNA phosphate backbone.
• This strategy opens avenues for developing MTM derivatives with improved specificity and drug formulations.