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Intercalation between Anthracyclines and DNA

First of all, consider the 3-D structure of a DNA fragment (including a solvated magnesium ion), determined by X-ray crystallography:

DNA: (5'-D(CpCpApApCpIpTpTpGpG)-3'), Trigonal Form

Alternative DNA Fragments: B-DNA fragment 1, B-DNA fragment 1 view 2.


The primary mode of action of daunomycin (1) and adriamycin (2) is believed to be their reversible binding to nucleolar DNA which causes inhibition of the replication process1 and thence death. Numerous biochemical studies including evidence from NMR spectroscopic and X-ray crystallographic studies have shown that daunomycin and adriamycin intercalate into the B-form of the DNA double stranded helix with guanine-cytosine d(CpG) site-specific interactions2. The base pairs above and below the drug 'buckle' in conformation to afford a distorted DNA helix thereby preventing association with the DNA helicase, DNA topoisomerase3 and polymerase families of enzymes to initiate DNA replication for RNA synthesis, protein formation and thereby cell division.

i. DNA-Daunomycin Complex

Daunomycin-DNA complex

As a result of intercalation with daunomycin4, the GC and CG base pairs 'buckle' by ca. 9o and 15o respectively to prevent excessive van der Waal's contacts. Also, the base pairs separate from a nominal distance of 3.4 Å to 6.8 Å when accommodating the drug and these distortions lead to a total DNA unwinding angle of ca. 8o (5.2 measured from solution studies6) and a distortion of the tertiary structure of the helix, although it is still closer to the B-DNA conformation. Several factors play a role in the stabilisation of the drug-DNA complex. The anthracycline is stabilised by electrostatic hydrogen bond and stacking π-bond interactions between the electron-deficient quinone-based chromophore and the electron-rich purine-pyrimidine bases. Hydrogen bonds play an important part in the stabilisation of the complex assisted by way of several water molecules and a solvated sodium cation. Indeed, an anthracycline lacking the hydroxyl group at C-9 on the right side of the ring-A is devoid of anticancer activity. Also, the hydrogen atom of the charged amino group is hydrogen bonded to O-2 of the thiamine base (T10) and two water molecules. Replacing the C-13 hydrogen atom with the hydroxyl group as for adriamycin (2), this created7 additional hydrogen bonded interactions involving solvent media around the substituent. As this study5 included the charged aliphatic-amino spermine molecules close to the intercalation site, an important change in the bonding interaction of spermine and the complex was observed between daunomycin and adriamycin.

ii. Unplanar chromphore-DNA complex

The dumbbell shaped anthracycline nogalamycin (3)7 was found to form a stable intercalative complex with DNA as revealed by X-ray7 and NMR spectroscopic8 studies. To accommodate intercalation of the nogalamycin chromophore, the DNA helix must 'open up', by transiently melting to allow entry of the bulky bicyclic amino sugar attached to ring-D. The DNA helix then elongates, translocating the base pairs in the approximate direction of the helical axis9. In another study10, a buckle of -25.4o in the C11-G2 base pair was observed. This would shed some light on the possibility of the target ring-D modified anthracycline (4) (R=H) intercalating with DNA and thereby test anticancer activity and intercalation theory. However, anthracyclines are also known11 to be enzymatically reduced to a radical species that form hydroxyl radicals (in the presence of molecular oxygen) to cause strand breaks in DNA and thereby cause inhibition of the replication process.

The antitumour ene-diyne antibiotics such as Dynemycin (5)12 are known to inhibit cell replication by interfering with mitosis by causing single strand breaks in the DNA during spindle formation, by way of cyclisation of the ene-diyne bridge to a benzene biradical. On the basis of this, adriamycin bearing the bridge on the A-ring could possess enhanced anticancer effectiveness by intercalating with DNA and causing single strand breaks by forming the benzene biradical, in situ. The benzene species is shown below; the radicals seen as yellow dots. The synthesis of such a compound would indeed be a highly challenging synthetic endeavour in the laboratory!

Other classes of anticancer drug-DNA interactions have been studied. For example, the image below represents the crystal structure of a double-stranded DNA decamer containing a cisplatin [Pt(NH3)2] interstrand cross-link adduct13. Advances in other small molecule DNA-intercalators (including anthracyclines) was recently reviewed14.

(5'-D(CpCpTpCpGpCpTpCpTpC)-3, 5'-D(GpApGpApGpCpGpApGpG)-3');

1. S. Neidle, Prog. Med. Chem., 1979, 16, 151-221. F. Yang, S.S. Teves, C. J. Kemp and S. Henikoff, Doxorubicin, DNA torsion, and chromatin dynamics, Biochim. Biophys. Acta, 2014, 1845, 84-89.
2. J. B. Chaires, J. E. Herrera and M. Waring, Biochemistry, 1990, 29, 2538-2549.
3. G. Capanico and F. Zunino, "Molecular basis of Specificty in Nucleic Acid-Drug Interactions", eds B. Pullman and J. Jortner, Kluwer Academic Publishers, Netherlands, 1990, pp. 167-176; M. Dugnet, C. Lavenot, F. Harper, G. Mirambeau and A. -M. de Recondo, Nucleic Acids Research, 1983, 11, 1059-1075. Henry Sobell's website discusses drug-DNA intercalation further.
4. A. H. -J. Wang, G. Ughetto, G. J. Quigley and A. Rich, Biochemistry, 1987, 26, 1152-1163; Protein Data Bank Daunomycin-d(CGATCG) Fragment
5. C. A. Frederick, L. D. Williams, G. Ughetto, G. A. van der Marel. J. H. van Boom, A. Rich and A. H. -J. Wang, Biochemistry, 1990, 29, 2538-2549.
6.A. Di Marco and F. Arcamone, Arzneim-Forsch. (Drug Res.), 1975, 25, 368-375. 7.C. K. Smith, G. J. Davies, E. J. Dodson and M. H. Moore, Biochemistry, 1995, 34, 415-425.
8. M. S. Searle, J. G. Hall, W. A. Denny and L. P. Wakelin, Biochemistry, 1988, 27, 4340-4349.
9. M. Egli, L. D. Williams, C. A Frederick and A. Rich. Biochemistry, 1991, 30, 1364-1372.
10. Y. -C. Liaw, Y. -G. Gao, H. Robinson, G. A. van der Marel, J. H. van Boom and A. H. -J. Wang, Biochemistry, 1989, 28, 9913-9918.
11. F. Arcamone, Doxorubicin (Medicinal chemistry, a series of monographs volume 17), Academic Press, London, 1981. ISBN 0-12-059280-0.
12. K. C. Nicolaou and W. -M. Dai, Angew. Chem. Int. Ed. Engl., 1991, 30, 1387-1416; R. L. Halcomb, S. H. Boyer and S. J. Danishefsky, Angew. Chem. Int. Ed. Engl., 1992, 31, 338-340.
13. F. Coste, J. M. Malinge, L. Serre, W. Shepard, M. Roth, M. Leng and C. Zelwer, "Crystal structure of a double-stranded DNA containing a cisplatin interstrand cross-link at 1.63 A resolution: hydration at the platinated site", Nucleic Acids Res., 1999, 27, 1837-1846.
14. A. Rescifina, C. Zagni, M.G. Varrica, V. Pistarà, A. Corsaro, Recent Advances in Small Organic Molecules as DNA Intercalating Agents: Synthesis, Activity, and Modeling, Eur. J. Med. Chem., 2014, 74, 95–115.
15. A. Dautant, B. Langlois d`Estaintot, B. Gallois, T. Brown, W. N. Hunter, Nucleic Acids Res. 1995, 23, 1710-1716. See image below, Idarubicin-D(CGATCG) complex.
16. Idarubicin (4-demethoxydaunomycin) also forms an intercalation complex with DNA. S. Charak and R. Mehrotra, Int. J. Biological Macromolecules, 2013, 60, 213-218.

This scientific information is also available at: doi:10.7910/DVN/26948.

What's New: A book chapter has recently been published (Recent Advances in Asymmetric Diels-Alder Reactions; author J.P. Miller) that may be of interest in organic chemistry (and includes routes or important synthetic steps towards molecules of antineoplastic activity) :
free open access.

Idarubicin-D(CGATCG) Complex (Ref. 14)

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