Alkylating agents are among the most useful and extensively used anticancer agents. Thus, they occupy a central position in cancer chemotherapy. Our laboratory has been involved in the design and synthesis of a new class of tumor inhibitory compounds, the 1, 2 bis(sulfonyl)hydrazines, which generate through activation reactive electrophilic structures with the capacity to cross-link DNA. Preliminary studies have demonstrated that 1, 2-bis (methylsulfonyl)- 1 -(2-chloroethyl)-2- about (methylamino) ca (designated 10 1M throughout this application) is therapeutically superior to other 1, 2-bis (sulfonyl) hydrazines and to 1, 3-bis(2-chloroethyl)- 1-nitrosourea (BCNU), which, like 1O1M, are biological chloroethylating agents, against transplanted murine and human tumors. Compound 1O1M also is capable of readily crossing the blood brain barrier, is active when administered both orally and parenterally, is not cross-resistant with cyclophosphamide, BCNU and melphalan, and a by-product of its activation, methyl isocyanate, is capable of inhibiting 06-alkylguanine-DNA alkyltransferase activity (AGT), a major mechanism of resistance to compounds which alkylate the 06 position of guanine in DNA. Thus, 1O1M has properties that are sufficiently promising to warrant clinical evaluation and 1O1M is currently in a phase I trial. The limited aqueous solubility of 1O1M, however, has created difficulties in formulating this agent for clinical usage and the formulation being used in the phase I trial increase the toxicity of this agent. Therefore, the specific aims of this application include not only studies on the mechanism of action of 1O1M but also (a) the design and synthesis of prodrugs of 1O1M with aqueous solubility, and the synthesis of analogs thereof with various electron donating and withdrawing abilities, thereby varying the rates (t1/2) of prodrug activation in an effort to further increase therapeutic efficacy; (b) the synthesis of a prodrug of 1O1M to target BCNU resistant tumor cells rich in GST mu prodrugs of this agent targeting hypoxic tumor cells and 1O1M analogs with decreased toxicity to bone marrow and intestinal mucosa; and (c) a comparison of the mechanism of action of newly synthesized prodrugs with that of 1O1M to ensure the superiority of newly generated second generation agents. These studies will include measurements of antitumor efficacy, toxicity, capacity for activation and cross-linking of DNA and capacity to inhibit AGT.
NIH ExPorter
NIH ExPorter