Prodrug-Phenol Mustard Glucuronide

As one of the most professional providers, Creative Biolabs has decades of experience and abundant knowledge of drug discovery and development. Now, we offer perfect phenol mustard glucuronide as a prodrug for antibody-directed enzyme prodrug therapy (ADEPT) development such as the antibody-β-glucuronidase conjugate.

Phenol Mustard Glucuronide

Phenol mustard glucuronide is a type of prodrug synthesized from phenol mustard and glucuronide. During the past, a glucuronide prodrug [(ρ-di-2-chloroethylaminophenol-β-D-glucopyranosid) uronic acid, HAMG] of ρ-hydroxyaniline mustard [N, N-di-(2-chloroethyl)-4-hydroxyaniline, HAM] has been used to cure mice bearing well-established PC5 plasma tumors which contain high levels of β-glucuronidase. The relatively nontoxic prodrug HAMG can be apparently formed in the liver of mice when treated with aniline mustard [N, N-di-(2-chloroethyl) aniline], and subsequently, convert to highly cytotoxic ρ-hydroxyaniline mustard by glucuronidase at the tumor site.

MOA of Phenol Mustard Glucuronide

The prodrug phenol mustard glucuronide can be activated by β-glucuronidase hydrolysis, yielding the parent drug phenol mustard. Phenol mustard glucuronide is a latent form of phenol mustard that can be converted to phenol mustard by β-glucuronidase at neutral pH. Phenol mustard is a kind of inhibitor that can bind to the glutamic acid residue, and inhibit the synthesis of protein. Tumor cells expressing tumor-associated antigen on their surface can be selectively killed by targeting β-glucuronidase. Antibody-directed enzymatic activation of glucuronide prodrugs could lead to more specific chemotherapy treatments.

Prodrugs activated by hydrolysis of an aromatic or aliphatic glycosyl bond. Fig.1 Prodrugs activated by hydrolysis of an aromatic or aliphatic glycosyl bond. (Niculescu-Duvaz, 2004)

Phenol Mustard Glucuronide-based ADEPT

ADEPT relies on an antibody directed at a tumor-associated antigen is used to deliver a specific enzyme to the tumor site. The tumor-located enzyme converts a subsequently administered prodrug (phenol mustard glucuronide) into an active cytotoxic agent (phenol mustard). A type of phenol mustard glucuronide prodrug (BHAMG) was activated at hepatoma ascites in Sprague-Dawley rats. Injection of RH1-βG, a conjugate formed between recombinant βG (β-glucuronidase) and monoclonal antibody RH1 with specificity for an antigen expressed on AS-30D rat hepatoma cells, into rats bearing AS-30D ascites resulted in a significant accumulation of conjugate in tumor cells after 2 hr. Treatment of rats bearing established hepatoma ascites with RH1-bG resulted in the cure of most animals. Treatment with antibody-βG conjugate and BHAMG produced significantly greater hematological toxicity when compared to treatment with RH1-bG and BHAMG alone. All cured rats were completely protected from rechallenge with AS-30D cells which show that successful treatment of animals induced protective immunity, and antibody-directed enzymatic activation of glucuronide prodrugs could lead to more specific chemotherapy treatments.

Mechanism of ADEPT action. Fig 2. Mechanism of ADEPT action. (Thanki, 2015)

Creative Biolabs is dedicated to preparing high-quality phenol mustard glucuronide and helping customers develop ADEPT. Our prodrug is suitable for antibody-β-glucuronidase conjugate development through customized linkers or direct fusion protein manner in a cost-effective and timely method. We provide our clients with a wide range of prodrugs for your ADEPT development. Please contact us for more information and a detailed quote.

References

  1. Niculescu-Duvaz, D.; et al. Design of prodrugs for suicide gene therapy. In Suicide Gene Therapy. 2004, (pp. 161-202). Humana Press.
  2. Thanki, K.; et al. Recent advances in tumor targeting approaches. Targeted drug delivery: concepts and design. 2015, (pp. 41-112). Springer, Cham.

Other Antibody-β-glucuronidase Conjugate:

Related Sections

Antibody-directed Enzyme Prodrug Therapy (ADEPT): Antibody-enzyme Conjugates for Cancer Therapy: Services:
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