Antitumor Sulfonylhydrazines: Design, Structure–Activity Relationships, Resistance Mechanisms, and Strategies for Improving Therapeutic Utility
- 9 February 2015
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 58 (9), 3639-3671
- https://doi.org/10.1021/jm501459c
Abstract
1,2-Bis(sulfonyl)-1-alkylhydrazines (BSHs) were conceived as more specific DNA guanine O-6 methylating and chloroethylating agents lacking many of the undesirable toxicophores contained in antitumor nitrosoureas. O(6)-Alkylguanine-DNA alkyltransferase (MGMT) is the sole repair protein for O(6)-alkylguanine lesions in DNA and has been reported to be absent in 5-20% of most tumor types. Many BSHs exhibit highly selective cytotoxicity toward cells deficient in MGMT activity. The development of clinically useful MGMT assays should permit the identification of tumors with this vulnerability and allow for the preselection of patient subpopulations with a high probability of responding. The BSH system is highly versatile, permitting the synthesis of many prodrug types with the ability to incorporate an additional level of tumor-targeting due to preferential activation by tumor cells. Furthermore, it may be possible to expand the spectrum of activity of these agents to include tumors with MGMT activity by combining them with tumor-targeted MGMT inhibitors.Keywords
Funding Information
- National Foundation for Cancer Research
This publication has 99 references indexed in Scilit:
- Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not AnticipateCancer Cell, 2012
- Balancing repair and tolerance of DNA damage caused by alkylating agentsNature Reviews Cancer, 2012
- 4-Nitrobenzyloxycarbonyl Derivatives of O6-Benzylguanine as Hypoxia-Activated Prodrug Inhibitors of O6-Alkylguanine-DNA Alkyltransferase (AGT), Which Produces Resistance to Agents Targeting the O-6 Position of DNA GuanineJournal of Medicinal Chemistry, 2011
- KS900: A hypoxia-directed, reductively activated methylating antitumor prodrug that selectively ablates O6-alkylguanine-DNA alkyltransferase in neoplastic cellsBiochemical Pharmacology, 2011
- Concise Review: Emerging Concepts in Clinical Targeting of Cancer Stem CellsThe International Journal of Cell Cloning, 2011
- Quantitative relationship between guanine O6-alkyl lesions produced by Onrigin™ and tumor resistance by O6-alkylguanine-DNA alkyltransferaseBiochemical Pharmacology, 2010
- Reductive activation of the prodrug 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119) selectively occurs in oxygen-deficient cells and overcomes O6-alkylguanine-DNA alkyltransferase mediated KS119 tumor cell resistanceBiochemical Pharmacology, 2010
- Development of an O6-alkylguanine–DNA alkyltransferase assay based on covalent transfer of the benzyl moiety from [benzene-3H]O6-benzylguanine to the proteinAnalytical Biochemistry, 2008
- Lethality to leukemia cell lines of DNA interstrand cross-links generated by Cloretazine derived alkylating speciesLeukemia Research, 2008
- Initial testing of VNP40101M (Cloretazine®) by the pediatric preclinical testing programPediatric Blood & Cancer, 2008