806
A. Kamal et al. / Bioorg. Med. Chem. Lett. 17 (2007) 803–806
12. Duschinsky, R.; Pleven, E.; Heidelberger, C. J. Am. Chem.
Soc. 1957, 79, 4559.
13. Lawrence, N. J.; Hepworth, L. A.; Rennison, D.;
McGown, A. T.; Hadfield, J. A. J. Fluoro. Chem 2003,
123, 101.
C2R-fluorinated dimer 6a shows lower DNA melting
temperatures compared to DC-81 dimer (4), while as
the linker length increases from three to five the helix
melting temperature of CT-DNA increases to 16.9 °C
after incubation of 18 h for compound 6c as shown in
Table 1. Further, like many other hybrids of PBD the
linker length plays an important role in these com-
pounds as well. However, some of these newly synthe-
sized fluorinated PBD helix-melting temperatures are
higher than the DC-81 and its dimer (DSB-120).
14. Ming Pu, Y.; Torok, D. S.; Ziffer, H. J. Med. Chem. 1995,
38, 4120.
15. Wu, Y.-J.; Davis, C. D.; Dworetzky, S.; Fitzpatrick, W.
C.; Harden, D.; He, H.; Knox, R. J.; Newton, A. E.;
Philip, T.; Polson, C.; Sivarao, D. V.; Sun, L.-Q.;
Tertyshnikova, S.; Weaver, D.; Yeola, S.; Zoeckler, M.;
Sinz, M. W. J. Med. Chem. 2003, 46, 3778.
16. Smart, B. E. In Chemistry of Organic Fluorine Compounds
II: A Critical Review; Hudlicky, M., Pavlath, A. E., Eds.;
ACS Monograph 187; American Chemical Society: Wash-
ington, DC, 1995; p 979; Smart, B. E. in: Organofluorine
Chemistry: Principles and Commercial Applications;
Banks, R. E.; Smart, B. E.; Tatlow, J. C.; Eds.; New
York, 1994, 57.
The newly synthesized C2R-fluorinated DC-81 and its
dimers have shown significant DNA-binding ability.
Amongst these 6c showed high helix melting tempera-
ture 16.9 °C after 18 h incubation. C2R-fluorinated
DC-81 (3) has exhibited slightly higher DNA melting
temperatures compared to the C2-S isomer (2). These
results suggest that C2R-fluoro isomer offers the better
orientation of the fluorine group in the C2-position for
an efficient binding of the PBD ring system to the DNA.
17. Edwards, P. N. In Organofluorine Chemistry: Principles
and Commercial Applications; Banks, R. E., Smart, B. E.,
Tatlow, J. C., Eds.; Plenum Publishing Corporation: New
York, 1994; p 501; Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T.,
Eds.ACS Symposium Series; American Chemical Society:
Washington, 1996; Vol. 2, Welch, J. T.; Eswarakrishnan,
S. Fluorine in Bioorganic Chemistry; John Wiley: New
York, 1991; Filler, R. In Asymmetric Fluoroorganic
Chemistry: Synthesis; Ramachandran, P. V., Ed.; Appli-
cations and Future Directions. ACS Symposium Series;
American Chemical Society: Washington, DC, 2000; Vol.
746, p 1; For a review focusing on marketed pharmaceu-
ticals, see: Elliott, A. J. In Chemistry of Organic Fluorine
Compounds II: A Critical Review; Hudlicky, M., Pavlath,
A. E., Eds.; ACS Monograph; American Chemical Soci-
ety: Washington, DC, 1995; 187, p 1119; O’Hagan, D.;
Rzepa, H. S. J. Chem. Soc., Chem. Commun. 1997, 645.
18. O’Neil, I. A.; Thompson, S.; Kalindjian, S. B.; Jenkins, T.
C. Tetrahedron Lett. 2003, 44, 7809; Lim, M. H.; Kim, H.
O.; Moon, H. R.; Chun, M. H.; Jeong, L. S. Org. Lett.
2002, 4, 529; Ming Pu, Y.; Torok, D. S.; Ziffer, H. J. Med.
Chem. 1995, 38, 4120; Mayers, A. G.; Barbay, J. K.;
Zhong, B. J. Am. Chem. Soc. 2001, 123, 7207.
Acknowledgments
The authors D.R.S.R. and P.S.M.M.R. are grateful to
CSIR, New Delhi, for the award of Research
Fellowships.
References and notes
1. Dervan, P. B. Science 1986, 232, 464; Hurley, L. H.; Boyd,
F. L. TIPS 1988, 9, 402; Hurley, L. H. J. Med. Chem 1989,
32, 2027.
2. Hurley, L. H.; Thurston, D. E. Pharm. Res. 1984, 52;
Hurley, L. H. J. Antibiot. 1977, 30, 349; Aoki, H.; Miyairi,
N.; Ajisaka, M.; Sakai, H. J. Antibiot. 1969, 22, 201.
3. Reddy, B. S. P.; Sondhi, S. M.; Lown, J. W. Pharmacol.
Therapeut. 1999, 84, 1.
4. Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433;
Kopka, M. L.; Goodless, D. S.; Baiklov, I.; Grzeskowaik,
K.; Cascio, D.; Dickerson, R. E. Biochemistry 1994, 33,
13593.
5. Bose, D. S.; Thompson, A. S.; Ching, J.; Hartely, J. A.;
Berardini, M. D.; Jenkins, T. C.; Neidle, S.; Hurley, L. H.;
Thurston, D. E. J. Am. Chem. Soc. 1992, 114, 4939.
6. Jenkins, T. C.; Hurley, L. H.; Neidle, S.; Thurston, D. E.
J. Med. Chem. 1994, 37, 4529.
19. (a) Kamal, A.; Reddy, P. S. M. M.; Reddy, D. R. Bioorg.
Med. Chem. Lett. 2004, 14, 2669; (b) Kamal, A.; Reddy, P.
S. M. M.; Reddy, D. R.; Laxman, E.; Murthy, Y. L. N.
Bioorg. Med. Chem. Lett. 2004, 14, 5699.
20. Demange, L.; Menez, A.; Dugave, C. Tetrahedron Lett.
1998, 39, 1169.
21. Thurston, D. E.; Murty, V. S.; Langley, D. R.; Jones, G.
B. Synthesis 1990, 81.
22. Spectral data for compound 6c: 1H NMR (CDCl3,
200 MHz): d 2.00–2.22 (m, 4H), 2.30–2.80 (m, 6H), 3.58–
3.85 (m, 6H), 3.92 (s, 6H), 4.00–4.25 (m, 4H), 5.35 (dt, 2H,
J = 53.2, 5.4 Hz), 6.80 (s, 2H), 7.50 (s, 2H), 7.70 (d, 2H,
J = 4.3 Hz); FAB MS: 597 (M++1); Anal. Calcd for
C31H34F2N4O6: C, 62.57; H, 5.75; N, 9.41; Found: C,
62.49; H, 5.66; N, 9.34.
23. (a) Jones, G. B.; Davey, C. L.; Jenkins, T. C.; Kamal,
A.; Kneale, G. G.; Neidle, S.; Webster, G. D.; Thur-
ston, D. E. Anti-Cancer Drug Des. 1990, 5, 249; (b)
McConnaughie, A. W.; Jenkins, T. C. J. Med. Chem.
1995, 38, 3488.
7. Farmer, J. D.; Rudnicki, S. M., Jr.; Suggs, J. W.
Tetrahedron Lett. 1988, 29, 5105.
8. Gregson, S. J.; Howard, P. W.; Hartley, J. A.; Brooks, N.
A.; Adams, L. J.; Jenkins, T. C.; Kelland, L. R.; Thurston,
D. E. J. Med. Chem. 2001, 44, 737; Kamal, A.; Ramesh,
G.; Laxman, N.; Ramulu, P.; Srinivas, O.; Neelima, K.;
Kondapi, A. K.; Sreenu, V. B.; Nagarajaram, H. A. J.
Med. Chem. 2002, 45, 4679.
9. Marais, J. S. C. Onderstepoort J. Vet. Sci. Anim. Ind. 1943,
18, 203.
10. Fried, J.; Sabo, E. F. J. Am. Chem. Soc. 1954, 76, 1455.
11. Peters, R. Endeavour 1954, 13, 147.