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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090671-02
Application #
6621549
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Lees, Robert G
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$327,409
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Penketh, Philip G; Finch, Richard A; Sauro, Rachel et al. (2018) pH-dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine prodrugs. Chem Biol Drug Des 91:62-74
Penketh, Philip G; Shyam, Krishnamurthy; Zhu, Rui et al. (2014) 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. Chem Res Toxicol 27:818-33
Penketh, Philip G; Patridge, Eric; Shyam, Krishnamurthy et al. (2014) Influence of glutathione and glutathione S-transferases on DNA interstrand cross-link formation by 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine, the active anticancer moiety generated by laromustine. Chem Res Toxicol 27:1440-9
Zhu, Rui; Baumann, Raymond P; Penketh, Philip G et al. (2013) Hypoxia-selective O6-alkylguanine-DNA alkyltransferase inhibitors: design, synthesis, and evaluation of 6-(benzyloxy)-2-(aryldiazenyl)-9H-purines as prodrugs of O6-benzylguanine. J Med Chem 56:1355-9
Zhu, Rui; Seow, Helen A; Baumann, Raymond P et al. (2012) Design of a hypoxia-activated prodrug inhibitor of O6-alkylguanine-DNA alkyltransferase. Bioorg Med Chem Lett 22:6242-7
Patridge, Eric V; Eriksson, Emma S E; Penketh, Philip G et al. (2012) 7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide. Arch Toxicol 86:1613-25
Penketh, Philip G; Shyam, Krishnamurthy; Baumann, Raymond P et al. (2012) A strategy for selective O(6)-alkylguanine-DNA alkyltransferase depletion under hypoxic conditions. Chem Biol Drug Des 80:279-90
Penketh, Philip G; Baumann, Raymond P; Shyam, Krishnamurthy et al. (2011) 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. Chem Biol Drug Des 78:513-26
Zhu, Rui; Liu, Mao-Chin; Luo, Mei-Zhen et al. (2011) 4-nitrobenzyloxycarbonyl derivatives of O(6)-benzylguanine as hypoxia-activated prodrug inhibitors of O(6)-alkylguanine-DNA alkyltransferase (AGT), which produces resistance to agents targeting the O-6 position of DNA guanine. J Med Chem 54:7720-8
Baumann, Raymond P; Ishiguro, Kimiko; Penketh, Philip G et al. (2011) KS900: A hypoxia-directed, reductively activated methylating antitumor prodrug that selectively ablates O(6)-alkylguanine-DNA alkyltransferase in neoplastic cells. Biochem Pharmacol 81:1201-10

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