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Design, Synthesis and Binding Affinity Evaluation of Cytochrome P450 1B1 Targeted Chelators

Dongmei Chen1, Qiqi Fan1, Ting Xu2

  • 1School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.

Anti-Cancer Agents in Medicinal Chemistry
|April 6, 2021
PubMed
Abstract

Insights

Researchers developed novel chelators targeting Cytochrome P450 1B1 (CYP1B1) for enhanced tumor imaging. Chelator 6a demonstrated the strongest binding affinity, paving the way for improved positron emission tomography (PET) applications in cancer detection.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Radiochemistry

Background:

  • Cytochrome P450 1B1 (CYP1B1) is overexpressed in various tumors, presenting a potential target for cancer imaging.
  • Developing specific molecular probes is crucial for effective tumor detection and characterization.

Purpose of the Study:

  • To design and synthesize novel chelators that selectively target CYP1B1 for positron emission tomography (PET) imaging.
  • To evaluate the inhibitory activity and binding affinity of these chelators to CYP1B1.

Main Methods:

  • Synthesis of 1,4,7-triazacyclononane-1,4-diiacetic acid (NODA) based chelators with varying polyethylene glycol (PEG) linker lengths.
  • In vitro evaluation of CYP1B1 inhibitory activity using the 7-ethoxyresorufin o-deethylation (EROD) assay.
  • In silico molecular docking and cellular competition assays to determine binding affinity.

Main Results:

  • Chelator 6a, featuring the shortest linker, exhibited the highest inhibitory activity against CYP1B1.
  • Molecular simulations indicated that chelator 6a forms a stable complex with CYP1B1, consistent with enzymatic assay results.
  • Cell-based assays confirmed the binding affinity of the synthesized chelators to the CYP1B1 enzyme.

Conclusions:

  • A series of novel CYP1B1-targeting chelators were successfully designed and synthesized.
  • This study represents the first effort to create CYP1B1-targeted chelators for radiolabeling applications.
  • These findings hold promise for advancing CYP1B1-based imaging in tumor detection and diagnosis.
Keywords:
ChelatorPETcytochrome P450 1B1imaging agentsradiopharmaceuticalα-naphthoflavone derivative

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