Laser-Induced Dimeric Photoproducts of Chlorpromazine: LC-MS Identification and Molecular Docking Evidence of Enhanced Anticancer Potential

Abstract

Breast cancer treatments, such as chemotherapy, radiation, and surgery, often face significant limitations, highlighting the need for more effective and targeted therapies. Here, we investigate the potential of 266 nm laser irradiation of chlorpromazine as a novel approach to develop new antitumoral compounds. We identify six chlorpromazine photocompounds with masses in the range of 178-334 u, along with several dimeric compounds with masses between 566 and 600 u, using an HPLC-MS. In silico approaches assess their pharmacokinetic and pharmacodynamic properties while comparing their toxicity with the parent compound. Molecular docking simulations indicate that some photoproducts have a low estimated free energy of binding to cancer-related targets, suggesting enhanced therapeutic potential compared to chlorpromazine. Additionally, ADME-Tox predictions indicate that these photoproducts may have pharmacokinetic and toxicity profiles similar to chlorpromazine. Overall, this study highlights that laser-generated chlorpromazine photoproducts exhibit enhanced biological activity to breast cancer-related targets compared to chlorpromazine while maintaining a similar ADME-Tox profile.

Keywords: ADME-Tox predictions; HPLC-MS; MS2; breast cancer; chlorpromazine; laser irradiation; molecular docking.

Figure 1

Formation of C178, C284 (promazine), C300a (promazine sulfoxide), C300b (2-hydroxypromazine), C316 (2-hydroxypromazine sulfoxide), and C334 (chlorpromazine sulfoxide) photoproducts of CPZ.

Figure 2

(A). Relative abundance and (B). abundance of CPZ irradiation products, where relative abundance = recorded abundance/maximum recorded abundance × 100.

Figure 3

Abundance of high m/z photoproducts of CPZ irradiation over the course of 60 min: (A) C566ab; (B) C582abcde; (C) C598ab; (D) C600abc.

Figure 4

(A). The two-dimensional representation of the neratinib structure and the aa residues from its binding site when interacting with the aromatase receptor. (B). The two-dimensional structure of C600b and the aa residues from its binding site. Both neratinib and C600b compounds exhibit favourable interactions with the aa residues THR310, VAL370, VAL373, MET374, and CYS437.

Figure 5

(A). The two-dimensional representation of the letrozole structure and the aa residues from its binding site when interacting with the FGFR1. (B). The two-dimensional structure of C582e and the aa residues from its binding site. Both letrozole and C582e compounds present favourable interactions with the aa residues ASP641, HIS621, and LEU644.

Figure 6

(A). The two-dimensional representation of the C566a structure and the aa residues from its binding site when interacting with the EGFR. (B). The two-dimensional structure of neratinib and the aa residues from its binding site. Both neratinib and C566a compounds present favourable interactions with the aa residue LYS 45, indicating similar predicted binding sites.

Figure 7

(A). The two-dimensional representation of the C566a structure and the aa residues from its binding site when interacting with HER2. (B). The two-dimensional structure of neratinib and the aa residues from its binding site. Both neratinib and C566a compounds present favourable interactions with the aa residue VAL 734, indicating similar predicted binding sites.