A detailed quantum mechanical analysis of electronic disposition of five aminopyrimidoisoquinolinequinones (APIQs) was performed after extraction of this subset of compounds from a larger data set of APIQs via a reported clustering methodology (Elfaki, et al. 2020). Both semi empirical PM3 method and DFT quantum mechanical methods were used to calculate global and local quantum mechanical descriptors (QMDs) to define the electronic environment of these molecules in attempt to rationalize their observed anti-cancer response variability. The biological response is the anticancer activity against human gastric adenocarcenoma (AGS) cell line. The correlation matrix between the calculated global electronic descriptors and biological activity demonstrated that the global dipole moment gives the highest correlation. The local electronic environment was analysed by The Mullikan charges (MC) and Fukui functions for N-5, C-6, C-8 in addition to the N atom of phenylamino side group at C-8. MCs furnished no useful information as each of these atoms had almost identical MC values for all the five compounds with exception of C-6 which gave varied values. Regressing MCs of C-6 against the response traces 60% of the latter variability. As C-6 is an extra annular methyl carbon adjacent to N-5 in isoquinoline residue of APIQ, we reasoned that the chemical reactivities of 4 out of the 5 APIQs might be due to a Chichibabin-type tautomerism implying a possible alkylation aspect in their mechanism of action. The corresponding Fukui functions (f-, f+ and f0) showed a considerable consistency with the patterns of chemical reactivity exhibited by this small set of APIQs.
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