Synthesis of novel geldanamycin derivatives

The toxicity associated with the geldanamycin family of benzoquinone ansamycins when used as heat shock protein-90 inhibitor molecular therapeutics is ameliorated by substitution at the 19-position. The resulting 19-substituted derivatives have greater potential for success in oncology clinical trials and for other medicinal purposes such as the treatment of neurodegenerative conditions. Having overcome hurdles associated with the sensitivity and complexity of these molecules, through a variety of synthetic approaches, the synthesis of a series of 19-substituted geldanamycin derivatives is reported herein using optimised Stille and Suzuki coupling reactions. Further compounds were accessible via copper-mediated coupling and nucleophilic addition reactions The new compounds are of significant medicinal interest, in view of their significantly reduced toxicity previously observed for this class of substrate compared to their 19-unsubstituted counterparts that have been evaluated in the clinic. (C) 2021 Elsevier Ltd. All rights reserved.

Automated summary

This paper reports the synthesis of a series of 19-substituted geldanamycin derivatives using optimized synthetic methods. These new compounds are of significant medicinal interest due to their significantly reduced toxicity compared to the unsubstituted counterparts previously evaluated in clinical trials.