title: Modeling substituent and conformational effects on the reactivity of antitumor agents containing a cyclopropylcyclohexadienone subunit.
abstract: The uncatalyzed alkylation reactions of ammonia by the parent spirocyclopropylcyclohexadienone (6), its 3-amino analogue (7), the cyclic derivative (8), its N-formyl derivative (9), and a closer model (10) of the CPI (1-4) drugs have been investigated in gas phase and in water solvent bulk, using density functional theory at the B3LYP level with several basis sets and the C-PCM solvation model. The effect of several structural key features such as the vinylogous amide conjugation, the acylation of the 2-amino substituent, the ring constraint of the heterocyclic nitrogen atom at C(2) carbon in a ring, and the presence of a condensed pyrrole ring on the reaction activation energy have been investigated. Substrate 7, which is a flexible conformational model of the cyclopropylpyrroloindole moiety (CPI) contained in the duocarmycins, has been used to model the shape-dependent reactivity of these drugs, in gas phase and water solutions. The calculations indicate that shape dependence of reactivity is strongly operative both in gas phase and in polar solvents, since conformational effects are capable of reducing the reaction activation energy by -8.4 and -4.3 kcal mol(-1) in gas phase and in water solution, respectively, that is required to promote "conformational catalysis".
authors.affiliation: Dipartimento di Chimica Organica, Università di Pavia, V.le Taramelli 10, 27100 Pavia, Italy. freccero@unipv.it
authors.forename: Mauro
authors.initials: M
authors.lastname: Freccero
authors.forename: Remo
authors.initials: R
authors.lastname: Gandolfi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D003512:Cyclohexanones / Q000737:chemistry*; D015394:Molecular Structure
chemical_list: D000970:Antineoplastic Agents; D003512:Cyclohexanones