title: Chloroethylating and methylating dual function antineoplastic agents display superior cytotoxicity against repair proficient tumor cells.
abstract: Two new agents based upon the structure of the clinically active prodrug laromustine were synthesized. These agents, 2-(2-chloroethyl)-N-methyl-1,2-bis(methylsulfonyl)-N-nitrosohydrazinecarboxamide (1) and N-(2-chloroethyl)-2-methyl-1,2-bis(methylsulfonyl)-N-nitrosohydrazinecarboxamide (2), were designed to retain the potent chloroethylating and DNA cross-linking functions of laromustine, and gain the ability to methylate DNA at the O-6 position of guanine, while lacking the carbamoylating activity of laromustine. The methylating arm was introduced with the intent of depleting the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT). Compound 1 is markedly more cytotoxic than laromustine in both AGT minus EMT6 mouse mammary carcinoma cells and high AGT expressing DU145 human prostate carcinoma cells. DNA cross-linking studies indicated that its cross-linking efficiency is nearly identical to its predicted active decomposition product, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE), which is also produced by laromustine. AGT ablation studies in DU145 cells demonstrated that 1 can efficiently deplete AGT. Studies assaying methanol and 2-chloroethanol production as a consequence of the methylation and chloroethylation of water by 1 and 2 confirmed their ability to function as methylating and chloroethylating agents and provided insights into the superior activity of 1.
authors: Department of Pharmacology, Yale Comprehensive Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, United States.
authors: Rui
authors: R
authors: Zhu
authors: Raymond P
authors: RP
authors: Baumann
authors: Eric
authors: E
authors: Patridge
authors: Philip G
authors: PG
authors: Penketh
authors: Krishnamurthy
authors: K
authors: Shyam
authors: Kimiko
authors: K
authors: Ishiguro
authors: Alan C
authors: AC
authors: Sartorelli
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry; D019175:DNA Methylation; D006207:Half-Life; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D008770:Methylnitrosourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D051379:Mice; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: C583202:2-(2-chloroethyl)-N-methyl-1,2-bis(methylsulfonyl)-N-nitrosohydrazinecarboxamide; D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D006834:Hydrazines; C583201:N-(2-chloroethyl)-2-methyl-1,2-bis(methylsulfonyl)-N-nitrosohydrazinecarboxamide; D013449:Sulfonamides; C483604:laromustine; D008770:Methylnitrosourea; D004247:DNA; D019853:O(6)-Methylguanine-DNA Methyltransferase
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