Prodrug-Cephalosporin Mustard

With advanced technology platforms, Creative Biolabs provides cephalosporin mustards as a prodrug for customized antibody-directed enzyme prodrug therapy (ADEPT) development services to help your projects. Our professional scientists have extensive experience in antibody production, synthetic chemistry, and bio-conjugation. We are committed to providing high-quality products and services to promote the development of innovative cancer treatments.

Cephalosporin Mustards

Cephalosporin mustard (CM) is a compound synthesized from cephalosporin and mustard. It has been developed as an anticancer prodrug that could be activated in a specific tumor site by monoclonal antibody-β-lactamase conjugates targeted to antigens present on tumor cell surfaces. Purified β-lactamases from Bacillus cereus (BCPL) and Escherichia coli (ECBL) can catalyze the cleavage of the β-lactam ring of CM releases the Nitrogen mustards or phenylenediamine mustard through a fragmentation reaction which happens after hydrolyzation. The drug phenylenediamine mustard (PDM) showed about 50-fold more cytotoxic than CM to H2981 cells in previous research. Treatment with prodrug CM resulted in an apparent cytotoxic activity that was comparable to the parent drug PDM. Thus, the CM can be designed as an effective anticancer medicine with immunological specificity via a monoclonal antibody-β-lactamase conjugate.

MOA of Cephalosporin Mustards

The cephalosporin mustards can be catalyzed by the β-lactamases and thus yields high cytotoxic drug nitrogen mustards (NMs). Nitrogen mustards is a chemotherapy medication used to treat cancer. It forms cyclic aminium ions (aziridinium rings) by intramolecular displacement of the chloride by the amine nitrogen. This aziridinium group then alkylates DNA once it is attacked by the N-7 nucleophilic center on the guanine base. A second attack forms after the second alkylation step and results in the formation of interstrand cross-links (ICLs).

Fig.1 Mechanism of action of DNA intercalators. (Singh, 2018)

Cephalosporin Mustards-based ADEPT

Cephalosporin mustard (CM) is designed as an anticancer prodrug in ADEPT. It could be activated in a site-specific manner by monoclonal antibody-β-lactamase conjugates targeted to antigens present on tumor cell surfaces. Purified β-lactamases from Bacillus cereus (BC beta L) and Escherichia coli (EC beta L) catalyzed the release of nitrogen mustards (NMs) from CM. BC beta L. The conjugates retained the enzymatic activity and bound nearly as well as the unmodified F(ab')2 monoclonal antibodies to antigens expressed on the H2981 human lung adenocarcinoma cell line (L6 positive, 1F5 negative). NMs showed approximately 50-fold more cytotoxic than CM to H2981 cells. Treatment of the cells with L6-BC beta L followed by CM achieved a level of cytotoxic activity that was comparable to that of NMs. The pretreatment of H2981 cells with BC beta L or 1F5-BC beta L enhanced the activity of CM to a lesser degree. All the results demonstrated that CM is a prodrug which can be used in ADEPT therapy.

Fig.2 Targeted cancer therapy using ADEPT. (Zhang, 2017)

Equipped with a state-of-the-art technology platform, Creative Biolabs is dedicated to helping our clients design and prepare the most suitable cephalosporin mustards as a prodrug for antibody-β-lactamase conjugate-based ADEPT development. We believe our high-quality services and products will contribute greatly to the success of your projects. Please feel free to contact us for more information and a detailed quote.

References

1. Singh, R. K.; et al. Therapeutic journey of nitrogen mustard as alkylating anticancer agents historic to future perspectives. European Journal of Medicinal Chemistry. 2018, 151, 401.
2. Zhang, X.; et al. Prodrug strategy for cancer cell-specific targeting: a recent overview. European Journal of Medicinal Chemistry. 2017, 139, 542.

For Research Use Only. NOT FOR CLINICAL USE.