Influence of Phosphate and Phosphoesters on the Decomposition Pathway of 1,2-Bis(methylsulfonyl)-1-(2-chloroethyhydrazine (90CE), the Active Anticancer Moiety Generated by Laromustine, KS119, and KS119W

3区 · 医学

Article

作者: Zhu, Rui ; Ishiguro, Kimiko ; Shyam, Krishnamurthy ; Penketh, Philip G. ; Baumann, Raymond P. ; Sartorelli, Alan C.

Prodrugs of the short-lived chloroethylating agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) and its methylating analogue 1,2-bis(methylsulfonyl)-1-(methyl)hydrazine (KS90) are potentially useful anticancer agents. This class of agents frequently yields higher ratios of therapeutically active oxophilic electrophiles responsible for DNA O(6)-guanine alkylations to other electrophiles with lower therapeutic relevance than the nitrosoureas. This results in improved selectivity toward tumors with diminished levels of O(6)-alkylguanine-DNA alkyltransferase (MGMT), the resistance protein responsible for O(6)-alkylguanine repair. The formation of O(6)-(2-chloroethyl)guanine, which leads to the formation of a DNA-DNA interstrand cross-link, accounts for the bulk of the anticancer activity of 90CE prodrugs. Herein, we describe a new decomposition pathway that is available to 90CE but not to its methylating counterpart. This pathway appears to be subject to general/acid base catalysis with phosphate (Pi), phosphomonoesters, and phosphodiesters, being particularly effective. This pathway does not yield a chloroethylating species and results in a major change in nucleophile preference since thiophilic rather than oxophilic electrophiles are produced. Thus, a Pi concentration dependent decrease in DNA-DNA interstand cross-link formation was observed. Changes in 90CE decomposition products but not alkylation kinetics occurred in the presence of Pi since the prebranch point elimination of the N-1 methanesulfinate moiety remained the rate-limiting step. The Pi catalyzed route is expected to dominate at Pi and phosphoester concentrations totaling >25-35 mM. In view of the abundance of Pi and phosphoesters in cells, this pathway may have important effects on agent toxicity, tumor selectivity, and resistance to prodrugs of 90CE. Furthermore, it may be possible to design analogues that diminish this thiophile-generating pathway, which is likely superfluous at best and potentially detrimental to the targeting of hypoxic regions where Pi concentrations can be significantly elevated.

2012-09-01·Radiation Research3区 · 医学

Preliminary Studies with a New Hypoxia-Selective Cytotoxin, KS119W,In VitroandIn Vivo

3区 · 医学

Article

作者: Alan C. Sartorelli ; Eugene Y. Kim ; Krishnamurthy Shyam ; Oluwatoyin M. Akintujoye ; Tina A. Grove ; Sara Rockwell ; Yanfeng Liu

Agents with selective toxicity to hypoxic cells have shown promise as adjuncts to radiotherapy. Our previous studies showed that the bioreductive alkylating agent KS119 had an extremely large differential toxicity to severely hypoxic and aerobic cells in cell culture, and was effective in killing the hypoxic cells of EMT6 mouse mammary tumors in vivo. However, the limited solubility of that compound precluded its development as an anticancer drug. Here we report our initial studies with KS119W, a water-soluble analog of KS119. The cytotoxicity of KS119W to EMT6 cells in vitro was similar to that of KS119, with both agents producing only minimal cytotoxicity to aerobic cells even after intensive treatments, while producing pronounced cytotoxicity to oxygen-deficient cells. This resulted in large differentials in the toxicities to hypoxic and aerobic cells (>1,000-fold at 10 μM). Low pH had only minimal effects on the cytotoxicity of KS119W. Under hypoxic conditions, EMT6 cells transfected to express high levels of either human or mouse versions of the repair protein O(6)-alkylguanine-DNA alkyltransferase, which is also known as O(6)-methylguanine DNA-methyltransferase, were much more resistant to KS119W than parental EMT6 cells lacking O(6)-alkylguanine-DNA alkyltransferase, confirming the importance of DNA O-6-alkylation to the cytotoxicity of this agent. Studies with EMT6 tumors in BALB/c Rw mice using both tumor cell survival and tumor growth delay assays showed that KS119W was effective as an adjunct to irradiation for the treatment of solid tumors in vivo, producing additive or supra-additive effects in most combination regimens for which the interactions could be evaluated. Our findings encourage additional preclinical studies to examine further the antineoplastic effects of KS119W alone and in combination with radiation, and to examine the pharmacology and toxicology of this new bioreductive alkylating agent so that its potential for clinical use as an adjuvant to radiotherapy can be evaluated.

2011-10-01·Chemical Biology & Drug Design4区 · 医学

1,2‐Bis(methylsulfonyl)‐1‐(2‐chloroethyl)‐2‐[[1‐(4‐nitrophenyl)ethoxy]carbonyl]hydrazine (KS119): a Cytotoxic Prodrug with Two Stable Conformations Differing in Biological and Physical Properties

4区 · 医学

Article

作者: Rui Zhu ; Emma S. E. Eriksson ; Krishnamurthy Shyam ; Hugh S. Williamson ; Leif A. Eriksson ; Alan C. Sartorelli ; Philip G. Penketh ; Kimiko Ishiguro ; Raymond P. Baumann

The anticancer prodrug 1,2‐bis(methylsulfonyl)‐1‐(2‐chloroethyl)‐2‐[[1‐(4‐nitrophenyl)ethoxy]carbonyl]hydrazine (KS119) selectively releases a short‐lived cytotoxin following enzymatic reduction in hypoxic environments found in solid tumors. KS119, in addition to two enantiomers, has two stable atropisomers (conformers differing in structure owing to hindered bond rotation) that interconvert at 37 °C in aqueous solution by first‐order kinetics with t1/2 values of ∼50 and ∼64 h. The atropisomers differ in physical properties such as partition coefficients that allow their chromatographic separation on non‐chiral columns. A striking difference in the rate of metabolism of the two atropisomers occurs in intact EMT6 murine mammary carcinoma cells under oxygen‐deficient conditions. A structurally related molecule, 1,2‐bis(methylsulfonyl)‐1‐(2‐chloroethyl)‐2‐[[1‐(3‐hydroxy‐4‐nitrophenyl)ethoxy]carbonyl]hydrazine (KS119WOH), was also found to exist in similar stable atropisomers. The ratio of the atropisomers of KS119 and structurally related agents has the potential to impact the bioavailability, activation, and therapeutic activity. Thus, thermally stable atropisomers/conformers in small molecules can result in chemically and enantiomerically pure compounds having differences in biological activities.

100 项与 KS-119 相关的药物交易

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