Self-Immolative Nitrogen Mustards Prodrugs Cleavable by Carboxypeptidase G2 (CPG2) Showing Large Cytotoxicity Differentials in GDEPT

2003 ◽  
Vol 46 (9) ◽  
pp. 1690-1705 ◽  
Author(s):  
Dan Niculescu-Duvaz ◽  
Ion Niculescu-Duvaz ◽  
Frank Friedlos ◽  
Jan Martin ◽  
Panos Lehouritis ◽  
...  
Keyword(s):  
Nitrogen Mustards ◽  
Carboxypeptidase G2

Nitrogen Mustards as Alkylating Agents: A Review on Chemistry, Mechanism of Action and Current USFDA Status of Drugs

2019 ◽  
Vol 19 (9) ◽  
pp. 1080-1102 ◽  
Author(s):  
Ghansham S. More ◽  
Asha B. Thomas ◽  
Sohan S. Chitlange ◽  
Rabindra K. Nanda ◽  
Rahul L. Gajbhiye
Keyword(s):  
Side Effects ◽  
Mechanism Of Action ◽  
Anticancer Agents ◽  
Nitrogen Mustard ◽  
Alkylating Agents ◽  
Cross Linking ◽  
Nitrogen Mustards ◽  
Information Leaflets ◽  
Anti Cancer ◽  
Approved Drugs

Background & Objective: :Nitrogen mustard derivatives form one of the major classes of anti-cancer agents in USFDA approved drugs list. These are polyfunctional alkylating agents which are distinguished by a unique mechanism of adduct formation with DNA involving cross-linking between guanine N-7 of one strand of DNA with the other. The generated cross-linking is irreversible and leads to cell apoptosis. Hence it is of great interest to explore this class of anticancer alkylating agents.Methods::An exhaustive list of reviews, research articles, patents, books, patient information leaflets, and orange book is presented and the contents related to nitrogen mustard anti-cancer agents have been reviewed. Attempts are made to present synthesis schemes in a simplified manner. The mechanism of action of the drugs and their side effects are also systematically elaborated.Results::This review provides a platform for understanding all aspects of such drugs right from synthesis to their mechanism of action and side effects, and lists USFDA approved ANDA players among alkylating anticancer agents in the current market.Conclusion: :Perusing this article, generic scientists will be able to access literature information in this domain easily to gain insight into the nitrogen mustard alkylating agents for further ANDA development. It will help the scientific and research community to continue their pursuit for the design of newer and novel heterocyclic alkylating agents of this class in the coming future.

ChemInform Abstract: PYRIDINIUMS AS POTENTIAL SYNTHETIC SUBSTITUTES FOR NITROGEN MUSTARDS

1983 ◽  
Vol 14 (10) ◽  
Author(s):  
A. R. KATRITZKY ◽  
K. BURGESS ◽  
R. C. PATEL
Keyword(s):  
Nitrogen Mustards

Synthesis and biological activity of stable and potent antitumor agents, aniline nitrogen mustards linked to 9-anilinoacridines via a urea linkage

2008 ◽  
Vol 16 (10) ◽  
pp. 5413-5423 ◽  
Author(s):  
Naval Kapuriya ◽  
Kalpana Kapuriya ◽  
Xiuguo Zhang ◽  
Ting-Chao Chou ◽  
Rajesh Kakadiya ◽  
...  
Keyword(s):  
Biological Activity ◽  
Antitumor Agents ◽  
Nitrogen Mustards

Plasmid pMTL153: a high copy number version of pAT153 and its use to obtain high expression of the Pseudomonas carboxypeptidase G2 gene

1988 ◽  
Vol 29 (6) ◽  
pp. 572-578 ◽  
Author(s):  
Steve P. Chambers ◽  
Sue E. Prior ◽  
Rachell A. Evans ◽  
Roger F. Sherwood ◽  
Nigel P. Minton
Keyword(s):  
Copy Number ◽  
High Expression ◽  
High Copy Number ◽  
Carboxypeptidase G2

scholarly journals Coupling of a Novel TIMP3 Peptide to Carboxypeptidase G2 for Pro-Drug Activation at the Tumour Site

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 625
Author(s):  
Mohammed S. Aldughaim ◽  
Fatimah Alsaffar ◽  
Michael D. Barker
Keyword(s):  
Fold Increase ◽  
Repeated Administration ◽  
Cytotoxic Drugs ◽  
Peptide Sequence ◽  
Tumour Site ◽  
Enzyme Prodrug Therapy ◽  
Nickel Affinity Chromatography ◽  
Glutamic Acid Residue ◽  
Carboxypeptidase G2 ◽  
Effective Delivery

Broad-spectrum cytotoxic drugs have been used in cancer therapy for decades. However, their lack of specificity to cancer cells often results in serious side-effects, limiting efficacy. For this reason, antibodies have been used to attempt to specifically target cytotoxic drugs to tumours. One such approach is antibody-directed enzyme prodrug therapy (ADEPT) which uses a tumour-directed monoclonal antibody, coupled to an enzyme, to convert a systemically administered non-toxic prodrug into a toxic one only at the tumour site. Among the main drawbacks of ADEPT is the immunogenicity of the antibody-enzyme complex, which is exacerbated by slow clearance due to size, hence limiting repeated administration. Additionally, the mono-specificity of the antibody could potentially result in drug resistance with repeated administration. We have identified a novel short peptide sequence, p700, derived from a human tissue inhibitor of metalloproteinases-3 (TIMP-3), which binds to and inhibits a number of tyrosine kinase growth factor receptors (VEGFRs1-3, FGFRs 1-4 and PDGFRα) which are known to be upregulated in many tumours and tumour vasculature. In this report, we fused p700 to His-tagged, codon-optimised, carboxypeptidase G2 (CPG2). CPG2 is a bacterial enzyme used in ADEPT, which activates potent nitrogen-mustard pro-drugs by removal of an inhibitory glutamic acid residue. Recombinant CPG2-p700 was highly expressed in Escherichia coli and successfully purified by nickel affinity chromatography. Biolayer interferometry showed that CPG2-p700 had a 100-fold increase in binding affinity for VEGFR2 compared with CPG2 alone and retained its catalytic activity, as determined by methotrexate cleavage. In the presence of CPG2-p700, the ZD2676P pro-drug showed significant cytotoxicity for 4T1 cells compared with prodrug alone or CPG2 alone. p700 is, therefore, a potentially useful alternative to monoclonal antibodies for enzyme pro-drug therapy and could equally be used for effective delivery of other cytotoxic drugs to tumour tissue.

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