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. 2019 Feb 21;9(11):6409-6418.
doi: 10.1039/c8ra10322d. eCollection 2019 Feb 18.

Reactive intermediates in copanlisib metabolism identified by LC-MS/MS: phase I metabolic profiling

Haitham AlRabiah  1 , Adnan A Kadi  1 , Mohamed W Attwa  1   2 , Ali S Abdelhameed  1 , Gamal A E Mostafa  1   3
Affiliations

Reactive intermediates in copanlisib metabolism identified by LC-MS/MS: phase I metabolic profiling

Haitham AlRabiah et al. RSC Adv. .

Abstract

Copanlisib (CNB; Aliqopa™) is a novel, intravenous phosphoinositide 3-kinase inhibitor used to treat various solid and hematological malignancies. CNB was recently approved by the U.S. FDA to treat adults that relapsed after two preceding systemic therapies. Using LC-MS/MS, we screened for the in vitro metabolites of CNB formed in human liver microsomes (HLMs) and probed for the generation of reactive electrophiles using methoxyamine and potassium cyanide as nucleophiles to capture reactive electrophiles by forming stable adducts that are suitable for identification by LC-MS/MS. Seven CNB phase I metabolites generated by oxidation, hydroxylation, oxidative dealkylation, reduction, and N-oxidation were identified. In addition, four reactive electrophiles, 2 aldehydes and 2 iminium ions, were identified, and a prediction of the corresponding bioactivation mechanism is presented. The formation of reactive metabolites may be associated with the side effects reported for CNB. To our knowledge, this is the first report on the detailed structural characterization of reactive intermediates generated in CNB metabolism.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1. Chemical structure of copanlisib.
Fig. 2
Fig. 2. Mass spectrum of copanlisib and its MS/MS fragments.
Fig. 3
Fig. 3. Mass spectra of M497a (A) and M497b (B), and their MS/MS fragments.
Fig. 4
Fig. 4. Mass spectrum of M495 and its MS/MS fragments.
Fig. 5
Fig. 5. Mass spectrum of M455 and its MS/MS fragments.
Fig. 6
Fig. 6. Mass spectra of M483a (A) and M483b (B) and their MS/MS fragments.
Fig. 7
Fig. 7. Mass spectrum of M499 and its MS/MS fragments.
Fig. 8
Fig. 8. Mass spectrum of M506 and its MS/MS fragments.
Fig. 9
Fig. 9. Mass spectrum of M508 and its MS/MS fragments.
Fig. 10
Fig. 10. Mass spectrum of M439 at m/z 439 and its MS/MS fragments.
Fig. 11
Fig. 11. Mass spectrum of M512 at m/z 512 and its MS/MS fragments.
Scheme 1
Scheme 1. Proposed mechanism for the formation of iminium intermediates in CNB metabolism and the potential trapping strategy.
Scheme 2
Scheme 2. Proposed mechanism of aldehyde generation.
Fig. 12
Fig. 12. Chemical structure of copanlisib. Sites of phase I metabolic reactions and pathways of bioactivation are indicated by arrows.
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