Development of Anticancer 1,2-Bis(sulfonyl)hydrazines

Summary

Principal Investigator: ALAN CLAYTON SARTORELLI
Affiliation: Yale University
Country: USA
Abstract: Alkylating agents are among the most useful and extensively used anticancer agents; they occupy a central position in cancer chemotherapy. Our laboratory has designed and synthesized a new class of tumor inhibitory prodrugs, the 1,2-bis(sulfonyl) hydrazines, which generate through activation reactive electrophilic structures that cross-link DNA. Preclinical studies have shown that 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)- 2-[(methylamino)carbonyl]hydrazine, designated Cloretazine, is therapeutically superior to other 1,2- bis(sulfonyl) hydrazines and to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), which like Cloretazine are biological chloroethylating agents, against a variety of transplanted murine and human tumors. Cloretazine also readily crosses the blood brain barrier, is active both orally and parenterally, is not cross-resistant with cyclophosphamide, BCNU, or melphalan, and a by-product of its activation, methyl isocyanate, has synergistic cytotoxic activity with the generated chloroethylating species. Methyl isocyanate functions in part by inhibiting O6-alkylguanine-DNA alkyltransferase activity (AGT), a major mechanism of resistance to agents such as Cloretazine, which alkylate the O-6 position of guanine in DNA. Methyl isocyanate also enhances the cytotoxicity of the chloroethylating species generated from Cloretazine in cell lines devoid of AGT indicating that methyl isocyanate produces other metabolic lesions. Cloretazine has shown significant antileukemic activity against adult AML in Phase I and II clinical trials; it is presently in a Phase III trial in combination with AraC in adult AML and in Phase II trials in adult and pediatric glioblastoma. A second 1,2-bis(sulfonyl)hydrazine, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1- (4-nitrophenyl) ethoxy] carbonyl]hydrazine, designated KS119, with selective activation by and kill of hypoxic cells of solid tumors, is in preclinical development. The Specific Aims of this application include continued studies on the mechanism(s) of action of Cloretazine and KS119 and also (a) the synthesis of analogs of Cloretazine designed to circumvent the resistance afforded by AGT, and analogs designed to release increased quantities of the methyl isocyanate to enhance the chloroethylating properties of Cloretazine; (b) the synthesis of analogs of KS119 and water-soluble derivatives thereof that not only release an alkylating species but also of methyl isocyanate upon activation; and (c) a comparison of the mechanism(s) of action of newly synthesized 1,2-bis(sulfonyl)hydrazines to ensure preclinical superiority of newly developed second generation agents. These studies will include measurements of antitumor efficacy against a broad spectrum of transplanted tumors, of toxicity, pharmacological disposition, cross-linking and repair of DNA, and the capacity to inhibit AGT. These investigations should lead to optimization of the anticancer potential of the 1,2-bis(sulfonyl)hydrazine prodrugs.
Funding Period: 2006-08-01 - 2010-07-31
more information: NIH RePORT

Top Publications

  1. ncbi 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine: an anticancer agent targeting hypoxic cells
    Helen A Seow
    Department of Pharmacology and Therapeutic Radiology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA
    Proc Natl Acad Sci U S A 102:9282-7. 2005
  2. ncbi Role of O6-alkylguanine-DNA alkyltransferase in the cytotoxic activity of cloretazine
    Kimiko Ishiguro
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA
    Mol Cancer Ther 4:1755-63. 2005
  3. ncbi The antineoplastic efficacy of the prodrug Cloretazine is produced by the synergistic interaction of carbamoylating and alkylating products of its activation
    Raymond P Baumann
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA
    Oncol Res 15:313-25. 2005
  4. ncbi Mode of action of the chloroethylating and carbamoylating moieties of the prodrug cloretazine
    Kimiko Ishiguro
    Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
    Mol Cancer Ther 5:969-76. 2006
  5. ncbi Lethality to leukemia cell lines of DNA interstrand cross-links generated by Cloretazine derived alkylating species
    Philip G Penketh
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA
    Leuk Res 32:1546-53. 2008
  6. ncbi Development of an O(6)-alkylguanine-DNA alkyltransferase assay based on covalent transfer of the benzyl moiety from [benzene-3H]O(6)-benzylguanine to the protein
    Kimiko Ishiguro
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA
    Anal Biochem 383:44-51. 2008
  7. ncbi Generation of oxygen deficiency in cell culture using a two-enzyme system to evaluate agents targeting hypoxic tumor cells
    Raymond P Baumann
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Radiat Res 170:651-60. 2008

Detail Information

Publications7

  1. ncbi 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine: an anticancer agent targeting hypoxic cells
    Helen A Seow
    Department of Pharmacology and Therapeutic Radiology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA
    Proc Natl Acad Sci U S A 102:9282-7. 2005
    ..KS119 has significant potential as a hypoxia-selective tumor-cell cytotoxin and is unlikely to cause major toxicity to well oxygenated normal tissues...
  2. ncbi Role of O6-alkylguanine-DNA alkyltransferase in the cytotoxic activity of cloretazine
    Kimiko Ishiguro
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA
    Mol Cancer Ther 4:1755-63. 2005
    ..Preferential toxicity of cloretazine against AGT- tumor cells coupled with decreased toxicity to AGT+ cells in host tissues constitute the therapeutic basis for cloretazine...
  3. ncbi The antineoplastic efficacy of the prodrug Cloretazine is produced by the synergistic interaction of carbamoylating and alkylating products of its activation
    Raymond P Baumann
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA
    Oncol Res 15:313-25. 2005
    ..These findings provide further evidence that the methyl isocyanate produced by the activation of Cloretazine can be a major contributor to the cytotoxicity produced by this antineoplastic agent...
  4. ncbi Mode of action of the chloroethylating and carbamoylating moieties of the prodrug cloretazine
    Kimiko Ishiguro
    Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
    Mol Cancer Ther 5:969-76. 2006
    ....
  5. ncbi Lethality to leukemia cell lines of DNA interstrand cross-links generated by Cloretazine derived alkylating species
    Philip G Penketh
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA
    Leuk Res 32:1546-53. 2008
    ..Only 1 in approximately 20,000 90CE molecules produces a cross-link in the AGT (O6-alkylguanine-DNA alkyltransferase) negative L1210 and U937 cell lines and 1 in 400,000 in the AGT positive HL-60 cell line...
  6. ncbi Development of an O(6)-alkylguanine-DNA alkyltransferase assay based on covalent transfer of the benzyl moiety from [benzene-3H]O(6)-benzylguanine to the protein
    Kimiko Ishiguro
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA
    Anal Biochem 383:44-51. 2008
    ..Rodent cell lines frequently lacked AGT expression, and AGT levels in rodent cells were much lower than in human cells...
  7. ncbi Generation of oxygen deficiency in cell culture using a two-enzyme system to evaluate agents targeting hypoxic tumor cells
    Raymond P Baumann
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Radiat Res 170:651-60. 2008
    ....