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. pmc 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
    Philip G Penketh
    Department of Pharmacology and Yale Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520 8066, United States
    Chem Res Toxicol 27:818-33. 2014
  2. pmc Hypoxia-selective O6-alkylguanine-DNA alkyltransferase inhibitors: design, synthesis, and evaluation of 6-(benzyloxy)-2-(aryldiazenyl)-9H-purines as prodrugs of O6-benzylguanine
    Rui Zhu
    Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA
    J Med Chem 56:1355-9. 2013
  3. pmc Design of a hypoxia-activated prodrug inhibitor of O6-alkylguanine-DNA alkyltransferase
    Rui Zhu
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520 8066, United States
    Bioorg Med Chem Lett 22:6242-7. 2012
  4. pmc 7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide
    Eric V Patridge
    Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
    Arch Toxicol 86:1613-25. 2012
  5. pmc A strategy for selective O(6)-alkylguanine-DNA alkyltransferase depletion under hypoxic conditions
    Philip G Penketh
    Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
    Chem Biol Drug Des 80:279-90. 2012
  6. pmc 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
    Rui Zhu
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, CT 06520 8066, USA
    J Med Chem 54:7720-8. 2011
  7. pmc 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
    Philip G Penketh
    Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
    Chem Biol Drug Des 78:513-26. 2011
  8. pmc KS900: A hypoxia-directed, reductively activated methylating antitumor prodrug that selectively ablates O(6)-alkylguanine-DNA alkyltransferase in neoplastic cells
    Raymond P Baumann
    Department of Pharmacology and Cancer Center, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA
    Biochem Pharmacol 81:1201-10. 2011
  9. pmc Quantitative relationship between guanine O(6)-alkyl lesions produced by Onrigin™ and tumor resistance by O(6)-alkylguanine-DNA alkyltransferase
    Kimiko Ishiguro
    Department of Pharmacology, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States
    Biochem Pharmacol 80:1317-25. 2010
  10. pmc Reductive activation of the prodrug 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119) selectively occurs in oxygen-deficient cells and overcomes O(6)-alkylguanine-DNA alkyltransferase mediated KS119 tumor cel
    Raymond P Baumann
    Department of Pharmacology and Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States
    Biochem Pharmacol 79:1553-61. 2010

Scientific Experts

  • Raymond P Baumann
  • Philip G Penketh
  • Alan C Sartorelli
  • Krishnamurthy Shyam
  • Kimiko Ishiguro
  • Rui Zhu
  • Helen A Seow
  • Eric V Patridge
  • Leif A Eriksson
  • Emma S E Eriksson
  • Mei Zhen Luo
  • Mao Chin Liu
  • Yong Lian Zhu
  • Sara Rockwell

Detail Information

Publications17

  1. pmc 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
    Philip G Penketh
    Department of Pharmacology and Yale Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520 8066, United States
    Chem Res Toxicol 27:818-33. 2014
    ....
  2. pmc Hypoxia-selective O6-alkylguanine-DNA alkyltransferase inhibitors: design, synthesis, and evaluation of 6-(benzyloxy)-2-(aryldiazenyl)-9H-purines as prodrugs of O6-benzylguanine
    Rui Zhu
    Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA
    J Med Chem 56:1355-9. 2013
    ..We report the synthesis of a new AGT inhibitor (5c) which selectively depletes AGT in hypoxic tumor cells...
  3. pmc Design of a hypoxia-activated prodrug inhibitor of O6-alkylguanine-DNA alkyltransferase
    Rui Zhu
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520 8066, United States
    Bioorg Med Chem Lett 22:6242-7. 2012
    ..Consistent with this design, 7 demonstrates both hypoxia selective conversion by EMT6 cells of 7 to 3 and hypoxic sensitization of AGT containing DU145 cells to the cytotoxic actions of laromustine, while exhibiting improved solubility...
  4. pmc 7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide
    Eric V Patridge
    Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
    Arch Toxicol 86:1613-25. 2012
    ..Electrochemical and computational analyses suggest that partial reduction of NBF-SPh enhances electrophilicity, which appears to encourage scavenging activity and contribute to electrophilic toxicity...
  5. pmc A strategy for selective O(6)-alkylguanine-DNA alkyltransferase depletion under hypoxic conditions
    Philip G Penketh
    Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
    Chem Biol Drug Des 80:279-90. 2012
    ....
  6. pmc 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
    Rui Zhu
    Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, CT 06520 8066, USA
    J Med Chem 54:7720-8. 2011
    ..While 3 had little or no effect on laromustine cytotoxicity under aerobic conditions, significant enhancement occurred under oxygen deficiency, providing evidence for the preferential release of the AGT inhibitor O(6)-BG under hypoxia...
  7. pmc 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
    Philip G Penketh
    Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
    Chem Biol Drug Des 78:513-26. 2011
    ..Thus, thermally stable atropisomers/conformers in small molecules can result in chemically and enantiomerically pure compounds having differences in biological activities...
  8. pmc KS900: A hypoxia-directed, reductively activated methylating antitumor prodrug that selectively ablates O(6)-alkylguanine-DNA alkyltransferase in neoplastic cells
    Raymond P Baumann
    Department of Pharmacology and Cancer Center, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA
    Biochem Pharmacol 81:1201-10. 2011
    ..Furthermore, the hypoxia-directed intracellular activation of KS900 allows it to preferentially ablate AGT pools under the oxygen-deficient conditions that are present in malignant tissue...
  9. pmc Quantitative relationship between guanine O(6)-alkyl lesions produced by Onrigin™ and tumor resistance by O(6)-alkylguanine-DNA alkyltransferase
    Kimiko Ishiguro
    Department of Pharmacology, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States
    Biochem Pharmacol 80:1317-25. 2010
    ..These studies imply that the antitumor activity of Onrigin™ stems from guanine O(6)-chloroethylation and define the threshold concentration of AGT that negates its antineoplastic activity...
  10. pmc Reductive activation of the prodrug 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119) selectively occurs in oxygen-deficient cells and overcomes O(6)-alkylguanine-DNA alkyltransferase mediated KS119 tumor cel
    Raymond P Baumann
    Department of Pharmacology and Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States
    Biochem Pharmacol 79:1553-61. 2010
    ....
  11. pmc 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
    ....
  12. pmc 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...
  13. pmc 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...
  14. pmc 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
    ....
  15. 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...
  16. 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...
  17. pmc 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...