Toxicity mechanism-based prodrugs: glutathione-dependent bioactivation as a strategy for anticancer prodrug design. 2018

Xin-Yu Zhang, and Adnan A Elfarra
a Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Public Health , Shanghai Jiao Tong University School of Medicine , Shanghai , China.

6-Mercaptopurine (6-MP) and 6-thioguanine (6-TG), two anticancer drugs, have high systemic toxicity due to a lack of target specificity. Therefore, increasing target selectivity should improve drug safety. Areas covered: The authors examined the hypothesis that new prodrug designs based upon mechanisms of kidney-selective toxicity of trichloroethylene would reduce systemic toxicity and improve selectivity to kidney and tumor cells. Two approaches specifically were investigated. The first approach was based upon bioactivation of trichloroethylene-cysteine S-conjugate by renal cysteine S-conjugate β-lyases. The prodrugs obtained were kidney-selective but exhibited low turnover rates. The second approach was based on the toxic mechanism of trichloroethylene-cysteine S-conjugate sulfoxide, a Michael acceptor that undergoes rapid addition-elimination reactions with biological thiols. Expert opinion: Glutathione-dependent Michael addition-elimination reactions appear to be an excellent strategy to design highly efficient anticancer drugs. Targeting glutathione could be a promising approach for the development of anticancer prodrugs because cancer cells usually upregulate glutathione biosynthesis and/or glutathione S-transferases expression.

UI MeSH Term Description Entries
D007668 Kidney Body organ that filters blood for the secretion of URINE and that regulates ion concentrations. Kidneys
D009369 Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Neoplasm,Cancer,Malignant Neoplasm,Tumor,Tumors,Benign Neoplasms,Malignancy,Malignant Neoplasms,Neoplasia,Neoplasm,Neoplasms, Benign,Cancers,Malignancies,Neoplasias,Neoplasm, Benign,Neoplasm, Malignant,Neoplasms, Malignant
D011355 Prodrugs A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug. Drug Precursor,Drug Precursors,Pro-Drug,Prodrug,Pro-Drugs,Precursor, Drug,Precursors, Drug,Pro Drug,Pro Drugs
D005978 Glutathione A tripeptide with many roles in cells. It conjugates to drugs to make them more soluble for excretion, is a cofactor for some enzymes, is involved in protein disulfide bond rearrangement and reduces peroxides. Reduced Glutathione,gamma-L-Glu-L-Cys-Gly,gamma-L-Glutamyl-L-Cysteinylglycine,Glutathione, Reduced,gamma L Glu L Cys Gly,gamma L Glutamyl L Cysteinylglycine
D005982 Glutathione Transferase A transferase that catalyzes the addition of aliphatic, aromatic, or heterocyclic FREE RADICALS as well as EPOXIDES and arene oxides to GLUTATHIONE. Addition takes place at the SULFUR. It also catalyzes the reduction of polyol nitrate by glutathione to polyol and nitrite. Glutathione S-Alkyltransferase,Glutathione S-Aryltransferase,Glutathione S-Epoxidetransferase,Ligandins,S-Hydroxyalkyl Glutathione Lyase,Glutathione Organic Nitrate Ester Reductase,Glutathione S-Transferase,Glutathione S-Transferase 3,Glutathione S-Transferase A,Glutathione S-Transferase B,Glutathione S-Transferase C,Glutathione S-Transferase III,Glutathione S-Transferase P,Glutathione Transferase E,Glutathione Transferase mu,Glutathione Transferases,Heme Transfer Protein,Ligandin,Yb-Glutathione-S-Transferase,Glutathione Lyase, S-Hydroxyalkyl,Glutathione S Alkyltransferase,Glutathione S Aryltransferase,Glutathione S Epoxidetransferase,Glutathione S Transferase,Glutathione S Transferase 3,Glutathione S Transferase A,Glutathione S Transferase B,Glutathione S Transferase C,Glutathione S Transferase III,Glutathione S Transferase P,Lyase, S-Hydroxyalkyl Glutathione,P, Glutathione S-Transferase,Protein, Heme Transfer,S Hydroxyalkyl Glutathione Lyase,S-Alkyltransferase, Glutathione,S-Aryltransferase, Glutathione,S-Epoxidetransferase, Glutathione,S-Transferase 3, Glutathione,S-Transferase A, Glutathione,S-Transferase B, Glutathione,S-Transferase C, Glutathione,S-Transferase III, Glutathione,S-Transferase P, Glutathione,S-Transferase, Glutathione,Transfer Protein, Heme,Transferase E, Glutathione,Transferase mu, Glutathione,Transferase, Glutathione,Transferases, Glutathione
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013866 Thioguanine An antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia. 6-Thioguanine,2-Amino-6-Purinethiol,Lanvis,Tabloid,Thioguanin-GSK,Thioguanine Anhydrous,Thioguanine Hemihydrate,Thioguanine Monosodium Salt,Thioguanine Tabloid,Tioguanina Wellcome,Tioguanine,2 Amino 6 Purinethiol,6 Thioguanine,Anhydrous, Thioguanine,Thioguanin GSK,ThioguaninGSK
D015122 Mercaptopurine An antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia. 6-Mercaptopurine,1,7-Dihydro-6H-purine-6-thione,6-Mercaptopurine Monohydrate,6-Thiohypoxanthine,6-Thiopurine,6H-Purine-6-thione, 1,7-dihydro-,BW 57-323H,Leupurin,Mecaptopurine Anhydrous,Mercaptopurina Wellcome,Puri-Nethol,Purimethol,Purinethol,6 Mercaptopurine,6 Mercaptopurine Monohydrate,6 Thiohypoxanthine,6 Thiopurine,BW 57 323H,BW 57323H

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