Rational Design of DNA Minor Groove-Binding Anti-Tumor Drugs
Many of the most useful antitumor drugs act by binding directly to double-helical DNA, interfering with both replication and transcription. Some of these drugs intercalate between adjacent base pairs. A second important class consists of those that bind within the minor groove of B-DNA. These latter tend to show a sequence specificity, binding best to regions of several successive A.T base pairs. We have embarked on a planned course of study of the molecular structures of complexes of such groove-binding drugs with synthetic DNA oligomers, with two goals: to understand the basis for sequence specificity, and to design new drug analogues that are capable of binding specifically to any desired base sequence. Such sequencereading molecules should be capable of being directed against key sequences typical of neoplastic rather than normal cells, or invader rather than host cells. If such molecules become a reality, they should have considerable importance in chemotherapy, directing their action against targeted cells and avoiding some of the more unpleasant side effects associated with chemotherapy.
KeywordsMinor Groove Piperazine Ring Unpleasant Side Effect Bifurcate Hydrogen Bond Adjacent Base Pair
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- 1.M. L. Kopka, P. Pjura, C. Yoon, D. Goodsell and R. E. Dickerson, The binding of netropsin to double-helical B-DNA, in “Structure and Motion: Membranes, Nucleic Acids and Proteins” E. Clementi, G. Corongiu, M. H. Sarma and R. H. Sarma, Eds., Adenine Press, New York (1985), p. 461.Google Scholar
- 6.D. J. Patcl, Antibiotic-DNA interactions: Intermolecular nuclear Overhauser effects in the netropsin-d(C-G-C-G-A-A-T-T-C-G-C-G) complex in solution. Proc. Natl. Acad. Sci. USA 17:6424 (1982).Google Scholar
- 7.M. H. Sarma, G. Gupta and R. H. Sarma, Netropsin specifically recognizes one of the two conformationally equivalent strands of poly(dA) •poly(dT). One dimensional nmr study at 500 MHz involving NOE transfer between netropsin and DNA protons. J. Biomol. Str. and Dyn. 2:1085 (1985).CrossRefGoogle Scholar
- 8.R. E. Dickerson and M. L. Kopka, Nuclear Overhauser data and stereochemical considerations suggest that netropsin binds symmetrically within the minor groove of poly(dA)•poly(dT), forming hydrogen bonds with both strands of the double helix. J. Biomol. Str. and Dyn. 2:submitted (1985).Google Scholar
- 12.A. V. Fratini, M. L. Kopka, H. R. Drew and R. E. Dickerson. Reversible bending and helix geometry in a B-DNA dodecamer: CCGAATTBrCGCG. J.Biol.Chem.257:14686.Google Scholar
- 14.D. Goodsell and R. E. Dickerson, Isohelical analysis of DNA groove- binding drugs. J. Med. Chem., submitted (1985).Google Scholar