1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylaminocarbonyl) hydrazine (101M) is an alkylating agent that is cytotoxic to cancer cells. Various alkylating agents are approved for the treatment of cancer including cyclophosphamide, busulfan, melphalan, nitrogen mustard, chlorambucil, and the nitrosoureas. The clinical activity and toxicity of these agents are well characterized. I01M is distinguished from currently approved agents by its relative specificity for alkylation of the O/6 position of guanine, a low frequency of induced single-strand breaks in DNA, and the formation of methyl isocyanate that diminishes the cellular enzyme, O/6 alkylguanine DNA alkyltransferase. Despite the in vivo activity displayed by 101M, the therapeutic potential of this compound may be limited by its poor water-solubility. Therefore to improve its water solubility and therapeutic index, the synthesis and biological evaluation of four phosphate- and two glutamic acid-bearing prodrugs will be attempted. Phase I research will focus on (1) the synthesis of four phosphate and two glutamic acid bearing water-soluble analogs; (2) the determination of the stability and water-solubility as well as in vivo bioavailability of the newly synthesized analogs; and (3) the in vitro activation of the novel drugs via incubation with enzymes, such as alkaline phosphatase and carboxypeptidase G2 (CPG2). Phase II effort will focus on (1) the in vivo evaluation of these prodrugs, and (2) the development of these prodrugs for clinical trials. PROPOSED COMMERCIAL APPLICATION: Successful completion of Phase I and Phase II studies will provide water-soluble prodrugs of 101M, which may possess desirable pharmaceutical properties and may be employed as antitumor agents against a variety of cancers.
