This is a scientific account of how anthracyclines interact with cancer cells (biology section), and a summary of anthracycline synthesis (chemistry section).
Consider a portion of the very long DNA double helix, which comprises the genetic material used in cell replication:
Here is a DNA Watson-Crick base-pair interaction, where the bases form the coloured bands in the structure above:
This diagram shows part of the DNA, whereby adenine (A) is hydrogen bonded to thiamine (T) and cytosine (C) is hydrogen bonded to guanine (G). The bond angles and lengths are approximate to show clarity of diagram. More about the structure of DNA is reviewed1 below.
The structure of an anticancer chemotherapeutic agent, idarubicin (1), for the treatment of cancer, such as leukaemia is shown above. The ring-D is on the far left and the ring-A is on the far right of the structure. It is a member of the class of natural molecules called anthracyclines2, which were originally discovered from bacterial sources (Streptomyces) several decades ago.
Biosynthetically, the anthracyclinones (and hence anthracyclines) are derived initially from acetate and proprionate units to undergo an aldol condensation to afford a polyketide intermediate which is further transformed by the enzymes in Steptomyces to doxorubicin as shown in the following scheme:
Interestingly, L-Daunosamine (the sugar moiety in the parent anticancer anthracyclines) has been synthesised from a D-mannose sugar:
Clickhere to download a zip file (5.80Kb). Key: Carbon atom=grey ball, hydrogen=light blue, nitrogen=dark blue and oxygen=red.
Daunorubicin and doxorubicin (adriamycin) are still in use. However, most chemotherapeutic drugs have unpleasant side effects and are often administered with other agents. For a general medical site, including links to cancer treatments, click here.
P-glycoprotein was purified in 1979, and strong evidence in support of its role in pleiotropic drug resistance3 came in 1982. MDR-1 is the gene required for it's synthesis and is a target in chemotherapy. MRP is another protein involved in drug resistance. Preliminary phase I/II data were encouraging, showing that Incel (biricodar dicitrate, VX-710) could restore or enhance the activity of the anticancer agent doxorubicin in small-cell lung cancer (STS) patients who had documented aggressive disease, and who had intrinsic or acquired resistance to doxorubicin. Doxorubicin is the standard chemotherapy for this disease, accounting for up to one quarter of newly diagnosed lung cancers. Approximately 70% of patients do not respond to initial chemotherapy, relapse is frequent, and the five-year survival rate for patients who are refractory to chemotherapy is a low 10-30%. Cisplatin with the drug etoposide are alternatively used in the treatment and 36% can survive one year.
Mitosis is the process by which dividing cells control the separation of genetic material accurately into the two resulting daughter cells. Genes controlling mitosis in cancer and other proliferating cells are also the focus of cancer research. Proteins produced by gene targets interact with and regulate many aspects of the mitotic process, many interact with the mitotic spindle, which is the target of paclitaxel, the world's largest-selling cancer drug. These genes encode for many different classes of proteins such as enzymes, structural and scaffolding proteins, thereby increasing the likelihood of identifying new cancer targets amenable to small molecule drug development. The p53 gene found on chromosome 17, is a tumor-suppressor gene. In the cell, the p53 protein binds DNA at specific locations and stimulates another gene to produce a protein called p21. In turn, p21 suppresses a division-stimulating protein (cdk2) to prevent the cell from passing through to the next stage of cell division. When p53 is mutant and can no longer bind DNA effectively, the p21 protein is not available to act as the “stop signal” for cell division. Thus cells may divide uncontrollably and form tumors. The p53 gene plays a key role in the pathogenesis or etiology of human cancers and clearly is an important component in a network of events that culminate in tumor formation. Mutations in p53 are found in most tumor types.
A recent (2002) article4 studied using anthracyclines (doxorubicin, epirubicin) with the more recently discovered taxanes (docetaxel [Taxotere], paclitaxel [Taxol]) which are in phase III clinical trials might be more effective in treatment of advanced metastatic breast cancer than used on their own. Further steps toward optimising the treatment schedules will include combining chemotherapy with the therapeutic principles of very different modes of action, such as target-specific antibodies against cell surface receptors of growth factors or inhibitors of tyrosine kinases in pathways of signal transduction. Genetic factors would be included in breast cancer studies. See also a related article.
Anthracyclines
intercalate with nucleolar DNA (to form a sandwich, where the drug is
the filling in the sandwich and the base pairs are the bread) to form
a stabilised interaction, which is reversible. The DNA base pairs
buckle in order to accept the molecule; the aromatic D-ring enters
first (at the major groove) and the substituted A-ring is at the
minor groove. The antracycline is
at right angles to the direction of the DNA bases. The amino-sugar
attached to the A-ring form further H-bonding with the DNA molecule
including bonding via water molecules. There is considered to be
P-bonding above and below the aromatic rings in the
complex.
Nogalamycin, with its ring-D bicyclic sugar substituent actually intercalates with nucleic acids, and the DNA bases buckle evenmore. This has been proved by X-ray analysis of drug-DNA hexamers5.
Another mode of action2 of anthracyclines is via free radicles which attack the DNA backbone. Oxygen is required to initialize this. Anthracyclines do not appear to form covalent bonds with DNA, although in the presence of formaldehyde this can occur.
Anthracyclines attack fast growing heart tissue, mucal (e.g. loss of hair) and light intestine, resulting in their side effects. However, if administered in controlled doses, fatal heart cardiomyopathy is uncommon. For a mutagenic cancer, it is better to give the drug a chance, before it gets too late to treat it! Unrelated to the anthracyclines, Taxol6 (e.g. tamoxifen) and dynemycin agents are becoming more popular too in the search of a cure for cancer. The are several families of different molecules that are used in hospitals, in addition to those mentioned above, and with different modes of action.
Numerous laboratory synthetic endeavours have been devised by chemists and the drugs are now commercially available. Stoodley's group7 at the University of Manchester (formerly UMIST), England has developed a stereoselective route to (1); however this molecule did not contain the aminosugar on ring-A (there are methods to attach it2).
Interestingly and unique to Stoodley's group, a D-glucose based diene (a modified Danishefsky's diene) set up the stereochemistry in the molecule. Continuing with this methodology, myself8, I have tried to synthesise modified anthracyclines, although the projects are uncomplete and difficult, though providing interesting chemistry:-
Finally, to see my Résumé see below:
Recent trends in antitumor anthracycline development by Claude Monneret.
Click here to see a photo image of myself with Prof. Stoodley on the occasion of my BSc Graduation at UMIST, 1990 or same the image with moving inset.
REFERENCES
1. J. D. Watson, F. H. Crick, Nature, 1953, 171, 737. E. T. Kool, J. C. Morales and K. M. Guckian, "Mimicking the Structure and Function of DNA: Insights into DNA Stability and Replication", Angew. Chem. Int. Ed., 2000, 39, 991. See also The wang group.
2. F. Arcamone, "Doxorubicin
Anticancer Antibiotics", Academic Press, New York, 1981. See also pdf file. Review: C. Monneret, "Recent Developments in the field of antitumour anthracyclines", European Journal of Medicinal Chemistry, 2001, 36, 483. For an article about cancer research read "The Cancer Revolution", Simon Garfield Ed., The Observer Magazine Life, 9th December 2001, pp. 17-24, The Observer Newspaper, London. life@observer.co.uk. 3. See Nature Biotechnology 17, 94-95 (1999) or click here or pdf file.
4. K. Friedrichs et al., "Combination of taxanes and anthracyclines in first-line
chemotherapy of metastatic breast cancer: an interim report. European Journal of Cancer, 2002, 38, 1730. 5. C. A. Frederick, L. D. Williams,
G. Ughetto, G. A. Van der Marel, J. H. Van Boom and A. H. -J. Wang,
Biochemistry, 1990, 29, 2538.
6. K. C. Nicolaou, Z. Yang, J. J.
Liu, H. Veno, P. G. Nantermet, R. K. Guy, C. F. Claiborne, J. Renaud,
E. A. Couladouros, K. Paulvannan and E. J. Sorensen, Nature, 1994,
367, 630. 7. R. C. Gupta, D. A. Jackson and R.
J. Stoodley, Tetrahedron,
1984, 40, 4657; (+)-daunomycinone: R. C. Gupta, C. M. Raynor, A. M. Z. Slawin, D. J. Williams and R. J. Stoodley, J. Chem. Soc., Perkin Trans 1., 1988, 1773. Email Prof. Richard Stoodley
8. J. P. Miller and R. J. Stoodley,
"Asymmetric Synthesis of Anticancer Anthracyclines", Ph.D. Thesis, University of Manchester, 1994.
