Aureolic acid-type anticancer agents, such as mithramycin (MTM) or chromomycin (CMM), are potent anticancer drugs with a unique mode-of-action. They inhibit the growth of cancer cells by cross-linking GC-rich DNA thereby shutting down specificity-protein (Sp)-dependent pathways towards various proto-oncogenes including c-myc and c-src, the latter being associated with the unique hypocalcemic activity found for these drugs. Particularly, MTM is important, and has become a popular biochemical tool to study Sp-dependent signal transduction pathways, but due to its toxic side effects is rarely used as anticancer agent, except for the treatment of tumor hypercalcemia refractory to other chemotherapy. However, MTM was recently identified as a potential lead drug against neurological diseases, arthritis, and for the treatment of hematologic disorders. All these new applications require only very small, less toxic concentrations of the drug, although the mode-of- action in these contexts remains obscure. MTM's biosynthesis has been studied intensely during the previous funding period of this research project, and consequently pursued combinatorial biosynthetic efforts revealed various biosynthetic intermediates and new MTM-analogues. Two of these analogues, MTM SK and MTM SDK, showed a much better anticancer activity profile with a greatly improved therapeutic index than MTM itself. These new drugs deserve further investigations. During the previous biosynthetic studies biosynthetic intriguing and interesting key enzymes were discovered, which need to be further investigated, particularly oxygenase MtmOIV, Ketoreductase MtmW, glycosyltransferases MtmGIV, MtmGIII, MtmGII, MtmGI, and other, early acting post-polyketide synthase tailoring oxygenases and reductases. The goal is to understand the role and mechanisms of these enzymes in the MTM biosynthesis, and to optimize them for the engineering of novel MTM derivatives. It is planned to (a) further investigate unclear biosynthetic steps and mechanisms of the MTM and CMM pathways and to generate new MTM analogues applying combinatorial biosynthesis, (b) to analyze intriguing oxygenases and reductases, (c) to investigate and improve the substrate specificity of glycosyltransferases, (d) to study in vitro and in vivo MTM SK, MTM SDK and other promising MTM analogues developed during the project.

Public Health Relevance

The proposed work aims to develop and refine a new generation of aureolic acid type natural product analogues with significantly diminished toxicity that will be useful mainly as anticancer drugs, but also as drugs to treat neurological diseases, arthritis and hematologic disorders. To enable the production of these fine-tuned drugs through combinatorial biosynthesis, in-depth research of the biosynthetic machinery including key enzymes will be explored.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fu, Yali
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Schools of Pharmacy
United States
Zip Code
de Medeiros, Aliandra G; Savi, Daiani C; Mitra, Prithiba et al. (2018) Bioprospecting of Diaporthe terebinthifolii LGMF907 for antimicrobial compounds. Folia Microbiol (Praha) 63:499-505
Savi, Daiani C; Shaaban, Khaled A; Gos, Francielly Maria Wilke Ramos et al. (2018) Phaeophleospora vochysiae Savi & Glienke sp. nov. Isolated from Vochysia divergens Found in the Pantanal, Brazil, Produces Bioactive Secondary Metabolites. Sci Rep 8:3122
Gao, Guixi; Liu, Xiangyang; Xu, Min et al. (2017) Formation of an Angular Aromatic Polyketide from a Linear Anthrene Precursor via Oxidative Rearrangement. Cell Chem Biol 24:881-891.e4
Goswami, Anwesha; Liu, Xiaodong; Cai, Wenlong et al. (2017) Evidence that oxidative dephosphorylation by the nonheme Fe(II), ?-ketoglutarate:UMP oxygenase occurs by stereospecific hydroxylation. FEBS Lett 591:468-478
Salem, Shaimaa M; Weidenbach, Stevi; Rohr, J├╝rgen (2017) Two Cooperative Glycosyltransferases Are Responsible for the Sugar Diversity of Saquayamycins Isolated from Streptomyces sp. KY 40-1. ACS Chem Biol 12:2529-2534
Panchuk, Rostyslav R; Lehka, Lilya V; Terenzi, Alessio et al. (2017) Rapid generation of hydrogen peroxide contributes to the complex cell death induction by the angucycline antibiotic landomycin E. Free Radic Biol Med 106:134-147
Wang, Guojun; Chen, Jing; Zhu, Haining et al. (2017) One-Pot Enzymatic Total Synthesis of Presteffimycinone, an Early Intermediate of the Anthracycline Antibiotic Steffimycin Biosynthesis. Org Lett 19:540-543
Hou, Caixia; Weidenbach, Stevi; Cano, Kristin E et al. (2016) Structures of mithramycin analogues bound to DNA and implications for targeting transcription factor FLI1. Nucleic Acids Res 44:8990-9004
Pahari, Pallab; Saikia, Ujwal Pratim; Das, Trinath Prasad et al. (2016) Synthesis of Psoralidin derivatives and their anticancer activity: First synthesis of Lespeflorin I1. Tetrahedron 72:3324-3334
Jackson, David R; Yu, Xia; Wang, Guojung et al. (2016) Insights into Complex Oxidation during BE-7585A Biosynthesis: Structural Determination and Analysis of the Polyketide Monooxygenase BexE. ACS Chem Biol 11:1137-47

Showing the most recent 10 out of 65 publications