Communications
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(Eds.: P. J. Stang, F. Diederich), VCH, Weinheim, 1995, p.203;
b) M.E.Maier, Synlett 1995, 13; c) DNA and RNA Cleavers and
Chemotherapy ofCancer and Viral Diseases (Ed.: B. Meunier),
Kluwer, Dordrecht, 1996, p.1; d) Z. Xi, I.H. Goldberg in
Comprehensive Natural Product Chemistry, Vol. 7 (Eds.:
D.H.R. Barton, K. Nakanishi), Pergamon, Oxford,
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p.553; e) W.-M.Dai, K.C.Nicolaou, Angew. Chem. 1991, 103,
Figure 1. DNA cleavage studies. Lane 1: DNA in TAE buffer (pH 8,
1453; Angew. Chem. Int. Ed. Engl. 1991, 30, 1387; f) H.
Lhermite, D.Grierson, Contemp. Org. Synth. 1996, 3, 93;
g) J.W.Grisom, G.U.Gunawardena, D.Klingberg, D.Huang,
Tetrahedron 1996, 52, 6453.
0.4 mm/bp) (5 mL) + acetonitrile (15 mL) at 378C; lane 2: DNA in TAE
buffer (pH 8, 0.4 mm/bp) (5 mL) + aminol (22) (40 mm, 48 h) in aceto-
nitrile (15 mL) at 378C; lane 3: DNA in TAE buffer (pH 8, 0.4 mm/bp)
(5 mL) + aminol (22) (40 mm, 24 h) in acetonitrile (15 mL) at 378C;
lane 4: DNA in TAE buffer (pH 8, 0.4 mm/bp) (5 mL) + sulfonamide
(2) (40 mm, 48 h) in acetonitrile (15 mL) at 378C.
[2] a) K.C.Nicolaou, E.J.Sorensen, R.Discordia, C-.K.Hwang,
R.E. Minto, K.N. Bharucha, R.G. Bergman,
Angew. Chem.
1992, 104, 1094; Angew. Chem. Int. Ed. Engl. 1992, 31, 1044;
b) L.Banfi, G.Guanti, Angew. Chem. 1995, 107, 2613; Angew.
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J. Org. Chem. 1998, 1543; d) A.Basak, U.K.Khamrai, U.K.
Mallick, Chem. Commun. 1996, 749; e) K.C.Nicolaou, W-.M.
Dai, S.-C. Tsay, V. A. Estevez, W. Wrasidlo, Science 1992, 256,
1172.
unsaturated carbonyl system.The stability of the 12-mem-
bered amino ketone 20 is ascribed to its inability to undergo
the transannular reaction, as it involves the formation of a
nine-membered enediyne, which is a kinetically disfavored
reaction.[22]
In conclusion, we have synthesized two novel N-based
macrocyclic enediynes and have been able to activate one of
these by a transannular reaction.The use of a 4-nitro-
phenylsulfonyl group as a deactivating device that renders the
nitrogen non-nucleophilic has been demonstrated.Thiol-
mediated deprotection can act as a triggering mechanism that
activates the enediyne through an intramolecular cyclization
reaction.When the protected amino ketone 2 was incubated
with supercoiled DNA in the presence of glutathione, a
biological thiol, at a pH of 8.0, it was able to cleave
supercoiled DNA (Figure 2).This observation has proven
[3] a) P.Magnus, R.A.Fairhurst,
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J. Am.
Chem. Soc. 1992, 114, 9279; c) M.E. Maier, T. Brandstetter,
Tetrahedron Lett. 1991, 32, 3679; d) A.D.Myers, P.S.Dragovich,
J. Am. Chem. Soc. 1992, 114, 20.
[5] a) W.-M.Dai, K.W.Lai, A.Wu, W.Hamaguchi, M.Y.H.Lee, L.
Zhou, A.Ishii, S.Nishimoto, J. Med. Chem. 2002, 45, 758; b) W.-
M.Dai, Curr. Med. Chem. 2003, 10, 2265.
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Chem. 1996, 108, 821; Angew. Chem. Int. Ed. Engl. 1996, 35, 779;
b) M.Wakayama, H.Nemoto, M.Shibuya,
Tetrahedron Lett.
1996, 37, 5397; c) I.Suzuki, M.Wakayama, A.Shigenaga, H.
Nemotoo, M.Shibuya, Tetrahedron Lett. 2000, 41, 10019; d) I.
Suzuki, A.Shigenaga, H.Nemoto, M.Shibuya,
Heterocycles
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Tetrahedron Lett. 1994, 35, 1879.
[7] a) A.Basak, S.Mandal, S.S.Bag,
Chem. Rev. 2003, 103, 4077;
b) B.Konig, Eur. J. Org. Chem. 2000, 381.
[8] K.C.Nicolaou, G.Zuccarello, Y.Oogawa, E.J.Schweiger, T.
Kumazawa, J. Am. Chem. Soc. 1988, 110, 4866.
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R.G.Bergman, J. Am. Chem. Soc. 1981, 103, 4091.
Figure 2. DNA cleavage studies. Lane 1: DNA in TAE buffer (pH 8,
0.4 mm/bp) (5 mL) + acetonitrile (15 mL) at 378C; lane 2: DNA in TAE
buffer (pH 8, 0.4 mm/bp) (7 mL) + glutathione (25 mm) in TAE buffer
(pH 8, 20 mL) + sulfonamido ketone (2) (20 mm, 48 h) in acetonitrile
(40 mL) at 378C.
[10] The closest conceptually similar example is the activation of a
maduropeptin artifact by aziridine formation involving attack by
a nucleophilic nitrogen atom (D.Schroeder, K.L.Colson, S.E.
Klohr, N.Zein, D.R.Langley, M.S.Lee, J.A.Matson, T.W.
Doyle, J. Am. Chem. Soc. 1994, 116, 935; N.Zein, W.Solomon,
K.L.Colson, D.R.Schroeder, Biochemistry 1995, 34, 11591; C.
Roger, D.S.Grierson, Tetrahedron Lett. 1998, 39, 27).However,
this may be considered to be activation by an allylic rearrange-
ment for which the ring size of the parent system remains the
same.
our design; namely, the activation by way of a biological thiol-
mediated triggering of enediyne towards Bergman cycliza-
tion.Considering the repertoire of amine-protecting groups
and different methods for their deprotection, our design
offers a wide array of triggering mechanisms for the develop-
ment of antitumor agents that work through generation of
diradicals.
[11] S.B.Rollins, R.M.Williams, Tetrahedron Lett. 1997, 38, 4033.
[12] a) K.Sonogashira, Y.Tohoda, N.Hagihara,
Tetrahedron Lett.
1975, 16, 4467; b) S.Takahashi, Y.Kuroyama, K.Sonogashira, N.
Hagihara, Synthesis 1980, 627.
[13] A.Basak, U.K.Khamrai, J.C.Shain, Tetrahedron Lett. 1997, 38,
6067.
Received: May 30, 2004
Revised: July 29, 2004
[14] a) W.Lwowski in 1,3-Dipolar Cycloaddition Chemistry, Vol. 1
(Ed.: A. Padwa), Wiley Interscience, New York, 1984, p.559;
Keywords: cyclization · DNA damage · enediynes · macrocycles
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