Theoretical studies of the ground state and of the spectroscopic properties of ethyl 5-amino-2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate analogs

authors

  • Sarrazin M
  • Barbier Pascale
  • Briand C
  • Peyrot V

keywords

  • CI980
  • Microtubules
  • Tubulin
  • Semi-empirical calculations
  • Resonance

abstract

The interaction of antimitotic compounds with tubulin has been studied in detail in our laboratory; among them, the two chiral isomers of ethyl 5-amino-2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate, NSC 613863 (R)-(1) and NSC 613862 (S)-(2) (CI980) and the three achiral analogs NSC 330770 (ethyl 5-amino-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate), NSC 337238 (ethyl 5-amino-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate) and C179 (ethyl 5-amino-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate). In this study, by AM1 calculations, we have investigated the ground state (S 0), the near-UV absorption, the fluorescence emission properties of these compounds in the order to better understand the behavior of each drug and to enlighten their binding mechanism to tubulin. A modification of the ring B such as a methyl substituent or a second insaturation center drastically modified the affinity for tubulin. AM1 results indicated that ring A and B were mainly involved in the first step of binding to tubulin, the second step consisted in the interaction of the phenyl ring C. The spectra of the compounds have shown that an excited state rearrangement took place and that the molecules in the S1 state are rendered more planar. The rotation of the phenyl appeared to be an unfavorable pathway but an imino form, stabilized by an intramolecular hydrogen bond between the COO moiety of the side chain and an hydrogen at atom N6 could play a role either in the S0 and/or in the S1 state.

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