Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
권호 표지
DOI QR코드

DOI QR Code

A Theoretical Study on the N-Alkylation of a Pyrimidine with a Cyclopropa[c]inden-5-one; A Model Pharmacophore of Duocarmycins and CC-1065

  • Published : 2004.01.20
Download PDF
⟨ Previous Next ⟩

Abstract

The N-alkylation of 4-aminopyrimidine with a tetrahydro-3-aza-cyclopropa[c]inden-5-one, which is a model reaction of the pharmacophore of duocarmycins, was studied with a quantum chemical method. We consider two factors for the acceleration of the N-alkylation; distortion and protonation of the model pharmacophores. The distortion of the spirocyclopropyl moiety in the model spirocyclopropylcyclohexadienone could induce an intrinsic energy of 3-4 kcal/mol, but the protonation on the carbonyl oxygen of the model cyclohexadienone lowers the transition energy of the N-alkylation of 4-aminopyrimidine dramatically (~46 kcal/mol) and is considered to play a major role in the enzyme reaction. The distorted and protonated spirocyclohexadienone is exothermally relieved to a phenol with the heat of reaction of -37 kcal/mol. The protonation process is proposed to be the mode of action of duocarmycins in the DNA alkylation.

Keywords

References

  1. Hanka, L. J.; Dietx, S. A.; Gerpheide, S. A.; Kuentzel, S. L.; Martin, D. G. J. Antibiot. 1978, 31, 1211. https://doi.org/10.7164/antibiotics.31.1211
  2. Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto, M.; Asano, K.; Kawamoto, I.; Tomita, F.; Nakano, H. J. Antibiot. 1988, 41, 1915. https://doi.org/10.7164/antibiotics.41.1915
  3. Martin, D. G.; Chidester, C. G.; Duchamp, D. J.; Mizsak, S. A. J. Antibiot. 1980, 33, 902. https://doi.org/10.7164/antibiotics.33.902
  4. Bhuyan, B. K.; Newell, K. A.; Crampton, S. L.; Von Hoff, D. D. Cancer Res. 1982, 42, 3532.
  5. Reynolds, V. L.; McGovren, J. P.; Hurley, L. H. J. Antibiot. 1986, 39, 319. https://doi.org/10.7164/antibiotics.39.319
  6. Reynolds, V. L.; Molineaux, I. J.; Kaplan, D. J.; Swensen, D. H.; Hurley, L. H. Biochemistry 1985, 24, 6228. https://doi.org/10.1021/bi00343a029
  7. Hurley, L. H.; Needham-Van Devantear, D. R. Acc. Chem. Res. 1986, 19, 230. https://doi.org/10.1021/ar00128a001
  8. Yasuzawa, T.; Muroi, K.; Ichimura, M.; Takahashi, I.; Takahashi, K.; Sano, H.; Saitoh, Y. Chem. Pharm. Bull. 1995, 43, 378. https://doi.org/10.1248/cpb.43.378
  9. Schnell, J. R.; Ketchem, R. R.; Boger, D. L.; Chazin, W. L. J. Am.Chem. Soc. 1999, 121, 5645. https://doi.org/10.1021/ja983556j
  10. Boger, D. L., Garbaccio, R. M. Acc. Chem. Res. 1999, 32, 1043. https://doi.org/10.1021/ar9800946
  11. Jeon, Y. W.; Jung, J. W.; Kang, M.; Chung, I. K.; Lee, W. Bull.Kor. Chem. Soc. 2002, 23, 391. https://doi.org/10.5012/bkcs.2002.23.3.391
  12. Hurley, L. H.; Lee, C.-S.; McGovern, J. P.; Warpehaski, M. A.;Mitchell, M. A.; Kelly, R. C.; Aristoff, P. A. Biochemistry 1988,27, 3886. https://doi.org/10.1021/bi00410a054
  13. Kim, K. S. Bull. Korean Chem. Soc. 2003, 24, 757. https://doi.org/10.1007/s11814-007-0038-2
  14. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery,J. A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J.M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.;Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.;Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G.A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck,A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J.V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe,M.; Gill, P. M. W.; Johnson, B. G.; Chen, W.; Wong, M. W.;Andres, J. L.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A.Gaussian 98W (Revision A.3); Gaussian, Inc.: Pittsburgh, PA,1998.
  15. Nahm, K.; Kim, Y. J. Korean J. Med. Chem. 1997, 7, 7.