Anthracyclines are considered to be some of the most effective anticancer drugs ever developed, either used as single agents or in combination therapy. Several natural and semi-synthetic anthracycline compounds are clinically used as the front-line anticancer drugs. Daunorubicin (DNR) and idarubicin are primarily used in leukemia and lymphoma, whereas doxorubicin (DOX) and epirubicin have broader anticancer activities against leukemia, lymphomas, and a variety of solid tumors including breast cancers, small cell lung cancers, cervical, as well as head and neck cancers. Despite the widespread use in cancer therapy, drug resistance and cardiotoxicity are the two major limitations for anthracycline drugs. Over the past 30 years, search for new anthracyclines to overcome these limitations has never ceased. We have been systematically altering the structure of the carbohydrate portion of anthracyclines. Recently, we made our major breakthrough: we discovered that by simply converting the 3'-amino group (-NH2) on daunosamine in daunorubicin into an azido (-N3) group with one organic transformation, the resulted 3'-azido daunorubicin (ADNR) confers both activity against drug-resistant cancers and much lower toxicity in mice. The Ohio State University has submitted a patent application for such a seemingly simple, but very effective modification of a clinically important drug. To further enhance the activity of ADNR, we connected a second 2,6-dideoxysugar to the first 3'-azido daunosamine in ADNR, the resulting disaccharide anthracyclines have an enhanced efficacy towards anthracycline-resistant cancer cells and different selectivity against topoisomerase 2 (Top2) and Top1 targets. All of these observations prompt us to make a central hypothesis for this proposed research program: The structures of the second or third sugar on the established pharmacophore of 3'-azidodaunorubicin (ADNR) or its analogs can enhance anthracycline activity and overcome drug resistance with much lower cardiac toxicity by presenting an essential binding motif to the DNA-topoisomerase-drug ternary complex. Based on this hypothesis, a structure-based approach is proposed to investigate interaction and selectivity of designed anthracyclines in DNA-drug complex (as in the first step of drug action) and in Top-DNA-drug complex (as in the next step of drug action). The program will focus on three closely related and synergistic aims.
Aim I. Establishment of a platform for molecular modeling and screening of anthracycline drugs. The platform consists of two levels of modeling. A simpler binary DNA-drug complex model will be used for initial structural screening for a possible di- &trisaccharide anthracyclines and their O- or N-substituted analogs. Both NMR and X-ray crystallography will be used to validate the DNA-drug complex model. At the next more challenging level, molecular modeling and virtual drug screening will be performed on both Top2-DNA-drug and Top1-DNA-drug complex models. Insightful understanding from these models will be tested with new synthetic anthracyclines and with a series of biological and mechanistic approaches in Aim III.
Aim II. Synthesis of di- or trisaccharide anthracyclines. A selective subset of an uncommon sugar library will be synthesized using our established convergent approaches. Then both chemical and enzymatic approaches will be further developed to transfer these uncommon sugars to aglycones for the preparation of di- &trisaccharide anthracyclines.
Aim III. Biological and mechanistic investigation of the new synthetic anthracyclines. The molecular mechanisms of Top2 &Top1 poisoning will be clarified experimentally. Activities of the drug to drug-resistant leukemia and breast cancers will be investigated both in vitro &in vivo. Cardiac toxicity and pharmacokinetics will be studied on xenograft mice models. In summary, for the very first time, this program will combine molecular modeling and experimental validation to develop a new approach for designing carbohydrate-modified anthracyclines. The success of such a platform will accelerate new drug discovery in the field of anticancer drug involving DNA-enzyme-drug complex. This research program should produce new generations of preclinical anthracycline drug candidates.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA118208-04S1
Application #
7900642
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Ogunbiyi, Peter
Project Start
2006-08-01
Project End
2010-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$55,871
Indirect Cost
Name
Ohio State University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Yu, Shuwen; Zhang, Guisheng; Zhang, Wenpeng et al. (2012) Synthesis and biological activities of a 3'-azido analogue of Doxorubicin against drug-resistant cancer cells. Int J Mol Sci 13:3671-84
Salama, Samir A; Snapka, Robert M (2012) Amino acid chloramine damage to proliferating cell nuclear antigen in mammalian cells. In Vivo 26:501-17
Guan, Wanyi; Ban, Lan; Cai, Li et al. (2011) Combining carbochips and mass spectrometry to study the donor specificity for the Neisseria meningitidis ?1,3-N-acetylglucosaminyltransferase LgtA. Bioorg Med Chem Lett 21:5025-8
Zhao, Guohui; Guan, Wanyi; Cai, Li et al. (2010) Enzymatic route to preparative-scale synthesis of UDP-GlcNAc/GalNAc, their analogues and GDP-fucose. Nat Protoc 5:636-46
Woodward, Robert; Yi, Wen; Li, Lei et al. (2010) In vitro bacterial polysaccharide biosynthesis: defining the functions of Wzy and Wzz. Nat Chem Biol 6:418-23
Han, Weiqing; Li, Lei; Pettit, Nicholas et al. (2010) In vitro reconstitution of Escherichia coli O86 O antigen repeating unit. Methods Mol Biol 600:93-110
Zhao, Ran; Hammitt, Richard; Thummel, Randolph P et al. (2009) Nuclear targets of photodynamic tridentate ruthenium complexes. Dalton Trans :10926-31
Cai, Li; Guan, Wanyi; Kitaoka, Motomitsu et al. (2009) A chemoenzymatic route to N-acetylglucosamine-1-phosphate analogues: substrate specificity investigations of N-acetylhexosamine 1-kinase. Chem Commun (Camb) :2944-6
Xia, Chengfeng; Zhang, Wenpeng; Zhang, Yalong et al. (2009) The roles of 3' and 4' hydroxy groups in alpha-galactosylceramide stimulation of invariant natural killer T cells. ChemMedChem 4:1810-5
Cai, Li; Guan, Wanyi; Wang, Wenjun et al. (2009) Substrate specificity of N-acetylhexosamine kinase towards N-acetylgalactosamine derivatives. Bioorg Med Chem Lett 19:5433-5

Showing the most recent 10 out of 11 publications