Structural Characterization of Dual-Threat Pt-HDACi Anticancer Agents by Collision Induced Dissociation Tandem Mass Spectrometry
Poster Number
3B
Research or Creativity Area
Natural Sciences
Abstract
Platinum (Pt)-based complexes have been widely applied in cancer treatment, but their clinical utilization is limited by systemic toxicities and chemoresistance. Their use in combination with histone deacetylase inhibitors (HDACis) could potentially overcome those barriers and enhance specificity and efficacy toward cancer cells. Novel Pt-HDACi conjugates are designed and synthesized by combining a platinum intermediate and HDACi, which are derivatized from clinically approved drugs by tuning the linker and the cap domain. The zinc-binding domain contains an unmodified hydroxylamine attached to the linker. The cap contains one or two nitrogen coordination sites, functioning as mono- or bi-dentate ligands to the platinum center, respectively. Mass spectrometry analysis was used to characterize the structure of the Pt-HDACi conjugates. Major peaks observed in the full-scan spectrum provided information about the molecular weight of the complexes. To obtain more detailed structural information of the complexes, collision-induced dissociation tandem mass spectrometry (CID-MS/MS) of all major peaks were conducted using electron spray ionization mass spectrometry with a linear quadrupole ion trap analyzer. The MSn spectra of the precursor ions revealed prominent fragment ions under various collision energy (5-60 a.u.), demonstrating the loss of the ligands in stepwise fashions and fragmentation pathways of the HDAC inhibitors. The observed fragmentation patterns revealed that bidentate ligands form stronger interactions with the Pt center than monodentate ligands. Additionally, it provided valuable information about the connectivity of the ligands to the Pt center and structural features of the Pt-HDACi conjugates.
Purpose
The integration of histone deacetylase inhibitor (HDACi) derivatives to a platinum (Pt) center is one of the promising strategies in enhancing efficacy and reducing toxicity toward cancer treatment. The bifunctional complexes (HDACi-Pt) have shown distinct bioactivities toward a variety of cancer cell lines; however, solid-state structural analysis has been quite challenging. The primary objective of the project is to elucidate the structural details and to analyze the relative stability of coordination bonds in HDACi-Pt, which will be achieved using collision-induced dissociation (CID) mass spectrometry at different collision energies. Tuning the strength of the coordination bond between HDACi and Pt may lead to superior drug candidates of ideal stability.
Results
Major peaks in full-scan mass spectrometry provided insights about the molecular weight and isotope pattern of the HDACi-Pt complexes. MSn studies at varying collision energies on the protonated, sodiated, or potassiated ions demonstrated the loss of the ligands in a stepwise fashion. The observed fragmentation patterns revealed that bidentate ligands form stronger interactions with the Pt center than monodentate ligands. Additionally, CID analysis strongly supported that the Pt ions were connected to HDACi through the intended binding sites on the cap, offering a new characterization method to investigate the detailed structure of coordination compounds. Electric properties of the coordination sites on the HDACi derivatives will be finely tuned by varying the groups linked to the N atoms on the cap. These investigations may help understand the impact of subtle structural variations in the cap domain on the stability of HDACi-Pt dative bond.
Significance
This research significantly advances the development of novel HDAC-Pt complexes, hypothesized to enhance efficacy, and reduce toxicity in cancer treatment. By employing mass spectrometry to study structural connectivity and stability, and future biostudies for comparison, it aims to offer guidance on designing optimal drug-ligand conjugates with precise and desired bindings.
Location
Don and Karen DeRosa University Center (DUC) Poster Hall
Start Date
27-4-2024 10:30 AM
End Date
27-4-2024 12:30 PM
Structural Characterization of Dual-Threat Pt-HDACi Anticancer Agents by Collision Induced Dissociation Tandem Mass Spectrometry
Don and Karen DeRosa University Center (DUC) Poster Hall
Platinum (Pt)-based complexes have been widely applied in cancer treatment, but their clinical utilization is limited by systemic toxicities and chemoresistance. Their use in combination with histone deacetylase inhibitors (HDACis) could potentially overcome those barriers and enhance specificity and efficacy toward cancer cells. Novel Pt-HDACi conjugates are designed and synthesized by combining a platinum intermediate and HDACi, which are derivatized from clinically approved drugs by tuning the linker and the cap domain. The zinc-binding domain contains an unmodified hydroxylamine attached to the linker. The cap contains one or two nitrogen coordination sites, functioning as mono- or bi-dentate ligands to the platinum center, respectively. Mass spectrometry analysis was used to characterize the structure of the Pt-HDACi conjugates. Major peaks observed in the full-scan spectrum provided information about the molecular weight of the complexes. To obtain more detailed structural information of the complexes, collision-induced dissociation tandem mass spectrometry (CID-MS/MS) of all major peaks were conducted using electron spray ionization mass spectrometry with a linear quadrupole ion trap analyzer. The MSn spectra of the precursor ions revealed prominent fragment ions under various collision energy (5-60 a.u.), demonstrating the loss of the ligands in stepwise fashions and fragmentation pathways of the HDAC inhibitors. The observed fragmentation patterns revealed that bidentate ligands form stronger interactions with the Pt center than monodentate ligands. Additionally, it provided valuable information about the connectivity of the ligands to the Pt center and structural features of the Pt-HDACi conjugates.
