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  2. Piperazine ring toxicity in three novel anti-breast cancer drugs: an in silico and in vitro metabolic bioactivation approach using olaparib as a case study

Piperazine ring toxicity in three novel anti-breast cancer drugs: an in silico and in vitro metabolic bioactivation approach using olaparib as a case study

  • Naunyn Schmiedebergs Arch Pharmacol. 2023 Feb 4. doi: 10.1007/s00210-023-02413-9.
Thamer A Alsubi 1 Mohamed W Attwa 2 3 Hany W Darwish 1 4 Hatem A Abuelizz 1 Adnan A Kadi 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.
  • 2 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia. mzeidan@ksu.edu.sa.
  • 3 Students' University Hospital, Mansoura University, Mansoura, 35516, Egypt. mzeidan@ksu.edu.sa.
  • 4 Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt.
Abstract

The metabolic activation of small-molecule drugs into electrophilic reactive metabolites is widely recognized as an indicator of idiosyncratic adverse drug reactions (IADRs). Three novel anti-breast Cancer drugs containing piperazine rings, ribociclib (Kisqali®, RCB), abemaciclib (Verzenio®, ABC), and olaparib (Lynparza®, OLP), were selected to study the effect of different chemical environment on the piperazine ring activation using in silico and in vitro metabolic experiments. ABC and RCB were previously studied and we noticed the piperazine ring in ABC could be strongly bioactivated generating more reactive intermediates than piperazine ring in RCB. OLP was further used as a case study to show the power of in silico software to predict the piperazine ring activation that was approved using in vitro experiments. Initially, predictions of susceptible sites in the metabolism and reactivity pathways were performed using the StarDrop P450 model and XenoSite reactivity tool, respectively. Later, in vitro OLP metabolites were characterized based on rat liver microsomes (RLMs) using KCN (trapping agent) using LC-MS/MS. The main goal of the current study was to answer the question of whether the presence of a piperazine ring in the chemical structure should be always considered a structural alert. Piperazine ring in RBC and ABC was bioactivated through a metabolic sequence that involves the hydroxylation of α-carbon to the tertiary nitrogen atoms of the piperazine ring. In the case of OLP, no cyano adduct was formed due to the presence of two carbonyl groups attached to the two nitrogen atoms of the piperazine ring (neutral amide groups). From the results, piperazine ring in certain cases should not be considered as a structural alert as in the case of OLP due to the presence of two electron withdrawing group that stops the proposed toxicity. Also blocking the bioactive center (α-carbon) using steric hindrances such as methyl group, also the isosteric replacement of α-carbon hydrogen with fluoro atom can aid in reducing the toxic side effects of ABC and RCB. These experiments were done in vitro through incubation with RLMs in the presence of KCN. Also, the results are supported by data generated from in silico software. In the future, drug discovery studies using this concept could be undertaken, allowing for the development of new drugs with reasonable safety profiles. Overall, in vitro RLMs incubations and in silico experiments were able to predict successfully that the piperazine ring should not always be considered a structural alert.

Keywords

DEREK; In silico metabolism; Piperazine reactivity; StarDrop software; Structural alert; XenoSite reactivity model.

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