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

The interaction of antimitotic compounds with tubulin has been studied in d etail in our laboratory; among them, the two chiral isomers of ethyl 5-amin o-2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate, NSC 613 863 (R)-(+) and NSC 613862 (S)(-) (CI980) and the three achiral analogs NSC 330770 (ethyl 5-amino-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbam ate), 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 carb amate). In this study, by AMI calcutations, we have investigated the ground state (So), the near-UV absorption, the fluorescence emission properties o f these compounds in the order to better understand the behavior of each dr ug and to enlighten their binding mechanism to tubulin. A modification of t he ring B such as a methyl substituent or a second insaturation center dras tically modified the affinity for tubulin. AMI, 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 S-1 state are rendered more planar. The rotat ion 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 S-0 and/or in the S-1 state. (C) 2001 Elsevier Science B.V. All rights reserved .