Directed Biosynthesis of Iso-aclacinomycins with Improved Anticancer Activity

Abstract

A four-enzyme catalyzed hydroxy regioisomerization of anthracycline was integrated into the biosynthetic pathway of aclacinomycin A (ALM-A), to generate a series of iso-ALMs via directed combinatorial biosynthesis combined with precursor-directed mutasynthesis. Most of the newly acquired iso-ALMs exhibit obviously (1–5-fold) improved antitumor activity. Therefore, we not only developed iso-ALMs with potential as clinical drugs but also demonstrated the utility of this tailoring tool for modification of anthracycline antibiotics in drug discovery and development.

Rethinking Biosynthesis of Aclacinomycin A

“…11-hydroxyaclacinomycin A could be produced by transforming S. galilaeus ATCC 31133 with doxorubicin resistance genes drrA and drrB , as well as the aklavinone 11-hydroxylase-coding gene dnrF from the doxorubicin producer [ 192 ]. Moreover, the isomerization of the ACM-A hydroxyl region in S. galilaeus mutants led to the production of iso-aclacinomycins, which showed enhanced (1~5 folds) anticancer activity relative to ACM-A [ 193 ]. Overall, a lot of approaches could be developed to overproduce ACM-A and its analogues.…”

Anthracyclines: biosynthesis, engineering and clinical applications

“…S. galilaeus producing 5 and other aclacinomycins has been an ideal host for the generation of hybrid anthracyclines, since the aclacinomycin BGC does not harbor any native aglycone modification genes. 215 This has allowed modification of substituents at R 1 , R 4 , R 9 , R 10 and R 11 of the aklavinone aglycone by cloning different combinations of tailoring genes from the rhodomycin, 216,217 nogalamycin, 114,218,219 daunorubicin 220–222 and kosinostatin 223 pathways (Fig. 15).…”