Theoretical study on the mechanism of N- and α-carbon oxidation of lapatinib catalyzed by cytochrome P450 monooxygenase

Intriguing generative metabolism discovery of reactive metabolite nitroso of lapatinib and relevant structural modification

“…II‐I‐M 2 easily metabolizes to nitrone (II‐I‐M 3 ), which is detected in the experiment, with an energy barrier of 6.30 kcal/mol for HS pathway (Figure , Figure S1). While the transition state (TS) of the LS pathway is not found despite our many attempts, we can speculate the feasibility of the LS pathway based on similarity with nitrone forming a double bond at C 6 ‐N 7, which is easier to achieve in the LS pathway than the HS pathway with a much lower energy barrier. Subsequently, the hydrolysis reaction of C═N of II‐I‐M 3 gives rise to an o‐dihydroxylamine compound II‐I‐M 4 through five‐membered ring transition state and II‐I‐TS 5 (Figure S2) with an energy barrier of 36.67 kcal/mol (Figure ).…”

“…In path A, II‐M 1 can be oxidized to II‐I‐M 2 , which further produces two kinds of nitrones. One presents a double bond at C 6 ‐N 7 , which has been discussed . Another presents a double bond at C 8 ‐N 7 (II‐I‐M 3 in Scheme ) through HAT by Cpd I, followed by hydrolysis to form the o‐dihydroxylation amine II‐I‐M 4 .…”

“…Based on metabolic characteristic of lapatinib, two metabolic directions of lapatinib, N‐dealkylation, which has been studied before, and N‐hydroxylation, were designed to explore the production of nitroso (Scheme ). Depending on the specific metabolic intermediates, the N‐hydroxylation was further divided into two paths: paths A and B.…”

“…Free energy profiles (kcal/mol) of nitroso formation of lapatinib by P450s (for HS/LS pathways, we just show HS, and the relevant LS energy profiles are shown in supporting information. The data of paths C and BC‐a are obtained from our previous metabolism research of lapatinib)…”

“…The determining step of this process is dehydration with an energy barrier of 35.09 kcal/mol, which is hard to achieve. Our previous study presented details of the primary amine from N‐dealkylation lapatinib, which forms nitroso by dihydroxylation and further dehydration. The rate‐determining step is also difficult to achieve with an energy barrier of 36.71 kcal/mol.…”