title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology and Yale Cancer Center, Yale University School of Medicine , 333 Cedar Street, New Haven, Connecticut 06520-8066, United States.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Penketh
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Shyam
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Baumann
authors.forename: Kimiko
authors.initials: K
authors.lastname: Ishiguro
authors.forename: Alan C
authors.initials: AC
authors.lastname: Sartorelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D006834:Hydrazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C530954:1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine; C118156:1,2-bis(methylsulfonyl)-1--(2-chloroethyl)-2-((1-(4-nitrophenyl)ethoxy)carbonyl)hydrazine; D000970:Antineoplastic Agents; D006834:Hydrazines; D007364:Intercalating Agents; D010710:Phosphates; D011355:Prodrugs; D013449:Sulfonamides; C483604:laromustine; D004247:DNA