Actinomycin D


1. Actinomycin D (AMD) is an anti-cancer drug, which binds to DNA and inhibits RNA synthesis. 




2. We have crystallized AMD with a short DNA and proved the AMD binding mode (i.e., intercalation).




3. Structure of DNA-AMD complex determined by X-ray diffraction method.




Anti-cancer drug actinomycin D binds to DNA



4. On the basis of the structures, we designed modification and synthesized two potential AMD analogues, N8-AMD and F8-AMD.  F8-AMD shows a strong selective anti-leukemia activity.




5. Structure of synthetic drug N8-AMD bound to DNA






6. Structure of synthetic drug F8-AMD bound to DNA






     S. Kamitori and F. Takusagawa* "Crystal Structure of 2:1 Complex Between d(GAAGCTTC) and Anticancer Drug Actinomycin"  J. Mol. Biol. 225, 445 (1992).

  S. Kamitori and F. Takusagawa* "DNA-Drug Interaction in the Complex between DNA and Actinomycin D" J. Crystallographic Society of Japan 35, 318-326 (1993).

  W. Chu, S. Kamitori, Miho Shinomiya, R. G. Carlson and F. Takusagwa* "Toward the Design of an RNA:DNA Hybrid Binding Agent"  J. Am. Chem. Soc. 116, 2243-2253 (1994).

  S. Kamitori and F. Takusagawa* "Multiple Binding Modes of Anti-Cancer Drug Actinomycin: X-ray, Molecular Modeling and Spectroscopic Studies of d(GAAGCTTC)2-Actinomycin D Complexes and Its Host DNA" J. Am. Chem. Soc.  116, 4154-4165 (1994).

  W. Chu, M. Shinomiya, K. Y. Kamitori, S. Kamitori, R. G. Carlson, R. F. Weaver and F. Takusagawa* "Role of D-Valine Residues in The Antitumor Drug Actinomycin D: Replacement of D-Valines with Other D-Amino Acids Changes The DNA Binding Characteristics and Transcription Inhibitory Activities" J. Am. Chem. Soc. 116, 7971-7982 (1994).

  M. Shinomiya, W. Chu, R.G. Carlson, R. F. Weaver and F. Takusagawa* "Structural, Physical and Biological Characteristics of RNA:DNA Hybrid Binding Agent N8-Actinomycin D" Biochemistry 34, 8481-8491 (1995).

  F. Takusagawa*, L. Wen, Q. Li, W. Chu, K.T. Takusagawa, R.G. Carlson and R.F. Weaver "Physical and Biological Characteristics of the Antitumor Drug Actinomyci D Analogues Derivatized at N-Methyl-L-Valine Residues"   Biochemistry, 35, 13240-13249 (1996).

  F. Takusagawa*, K.T. Takusagawa, R.G. Carlson and R.F. Weaver "Selectivity of F8-Actinomycin D for RNA:DNA Hybrids and Its Anti-Leukemia Activity" Bioorg. Med. Chem. 5, 1197-1207 (1997).

     H. L. Takusagawa and F. Takusagawa* "Crystallization and Preliminary X-ray Diffraction Studies of d(ACGTAGCTACGT)2:[Actinomycin D, Echinomycin2] and d(ACGTAGCTACGT)2:[Actinomycin D, Triostin A2] Complex"  Acta Crystallogr. D56, 344-347 (2000).

    H.-K. Kim, J.-Y. Nam, M. Y. Han, K.-H. Son, J.-D. Choi, B.-M. Kwon*, H. L. Takusagawa, Y. Huang and F. Takusagawa* "Natural and Synthetic Analogues of Actinomycin D as Grb2-Sh2 Domain Blockers"  Bioorg. Med. Chem. Lett. 10, 1455-1457 (2000).

     F. Takusagawa*, R. G. Carlson and R. F. Weaver "Anti-Leukemia Selectivity in Actinomycin Analogues"  Bioorg. Med. Chem. 9, 719-725 (2001).