Efficacious Cyclic N-acyl O-amino Phenol Duocarmycin Prodrugs

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2013 May 1

PMID 23627265

Citations 10

Authors

Amanda L Wolfe

Katharine K Duncan

Nikhil K Parelkar

Douglas Brown

George A Vielhauer

Dale L Boger

Affiliations

Soon will be listed here.

Abstract

Two novel cyclic N-acyl O-amino phenol prodrugs are reported as new members of a unique class of reductively cleaved prodrugs of the duocarmycin family of natural products. These prodrugs were explored with the expectation that they may be cleaved selectively within hypoxic tumor environments that have intrinsically higher concentrations of reducing nucleophiles and were designed to liberate the free drug without the release of an extraneous group. In vivo evaluation of the prodrug 6 showed that it exhibits extraordinary efficacy (T/C > 1500, L1210; 6/10 one year survivors), substantially exceeding that of the free drug, that its therapeutic window of activity is much larger, permitting a dosing ≥ 40-fold higher than the free drug, and yet that it displays a potency in vivo that approaches the free drug (within 3-fold). Clearly, the prodrug 6 benefits from either its controlled slow release of the free drug or its preferential intracellular reductive cleavage.

Citing Articles

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References

Lajiness J, Robertson W, Dunwiddie I, Broward M, Vielhauer G, Weir S . Design, synthesis, and evaluation of duocarmycin O-amino phenol prodrugs subject to tunable reductive activation. J Med Chem. 2010; 53(21):7731-8. PMC: 2974002. DOI: 10.1021/jm1010397. View

Tietze L, Schuster H, Schmuck K, Schuberth I, Alves F . Duocarmycin-based prodrugs for cancer prodrug monotherapy. Bioorg Med Chem. 2008; 16(12):6312-8. DOI: 10.1016/j.bmc.2008.05.009. View

Tietze L, Lieb M, Herzig T, Haunert F, Schuberth I . A strategy for tumor-selective chemotherapy by enzymatic liberation of seco-duocarmycin SA-derivatives from nontoxic prodrugs. Bioorg Med Chem. 2001; 9(7):1929-39. DOI: 10.1016/s0968-0896(01)00098-0. View

Aristoff P, Johnson P, Sun D, Hurley L . Synthesis and biochemical evaluation of the CBI-PDE-I-dimer, a benzannelated analog of (+)-CC-1065 that also produces delayed toxicity in mice. J Med Chem. 1993; 36(14):1956-63. DOI: 10.1021/jm00066a004. View

Boger D, Johnson D . CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents. Proc Natl Acad Sci U S A. 1995; 92(9):3642-9. PMC: 42018. DOI: 10.1073/pnas.92.9.3642. View

Tse W, Boger D . Sequence-selective DNA recognition: natural products and nature's lessons. Chem Biol. 2004; 11(12):1607-17. DOI: 10.1016/j.chembiol.2003.08.012. View

Li L, DeKoning T, Kelly R, KRUEGER W, McGovren J, Padbury G . Cytotoxicity and antitumor activity of carzelesin, a prodrug cyclopropylpyrroloindole analogue. Cancer Res. 1992; 52(18):4904-13. View

Wolkenberg S, Boger D . Mechanisms of in situ activation for DNA-targeting antitumor agents. Chem Rev. 2002; 102(7):2477-95. DOI: 10.1021/cr010046q. View

Boger D, Zarrinmayeh H, Munk S, Kitos P, Suntornwat O . Demonstration of a pronounced effect of noncovalent binding selectivity on the (+)-CC-1065 DNA alkylation and identification of the pharmacophore of the alkylation subunit. Proc Natl Acad Sci U S A. 1991; 88(4):1431-5. PMC: 51032. DOI: 10.1073/pnas.88.4.1431. View

10.

Parrish J, Kastrinsky D, Wolkenberg S, Igarashi Y, Boger D . DNA alkylation properties of yatakemycin. J Am Chem Soc. 2003; 125(36):10971-6. DOI: 10.1021/ja035984h. View

11.

Searcey M . Duocarmycins--natures prodrugs?. Curr Pharm Des. 2002; 8(15):1375-89. DOI: 10.2174/1381612023394539. View

12.

Wolfe A, Duncan K, Parelkar N, Weir S, Vielhauer G, Boger D . A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct. J Med Chem. 2012; 55(12):5878-86. PMC: 3386426. DOI: 10.1021/jm300330b. View

13.

Boger D, Yun W, Cai H, Han N . CBI-CDPBO1 and CBI-CDPBI1: CC-1065 analogs containing deep-seated modifications in the DNA binding subunit. Bioorg Med Chem. 1995; 3(6):761-7. DOI: 10.1016/0968-0896(95)00066-p. View

14.

Williams R, Rajski S, Rollins S . FR900482, a close cousin of mitomycin C that exploits mitosene-based DNA cross-linking. Chem Biol. 1997; 4(2):127-37. DOI: 10.1016/s1074-5521(97)90256-8. View

15.

Balendiran G, Dabur R, Fraser D . The role of glutathione in cancer. Cell Biochem Funct. 2004; 22(6):343-52. DOI: 10.1002/cbf.1149. View

16.

Kastrinsky D, Boger D . Effective asymmetric synthesis of 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI). J Org Chem. 2004; 69(7):2284-9. DOI: 10.1021/jo035465x. View

17.

Parrish J, Kastrinsky D, Stauffer F, Hedrick M, Hwang I, Boger D . Establishment of substituent effects in the DNA binding subunit of CBI analogues of the duocarmycins and CC-1065. Bioorg Med Chem. 2003; 11(17):3815-38. DOI: 10.1016/s0968-0896(03)00194-9. View

18.

Zhao R, Erickson H, Leece B, Reid E, Goldmacher V, Lambert J . Synthesis and biological evaluation of antibody conjugates of phosphate prodrugs of cytotoxic DNA alkylators for the targeted treatment of cancer. J Med Chem. 2011; 55(2):766-82. DOI: 10.1021/jm201284m. View

19.

Tichenor M, Trzupek J, Kastrinsky D, Shiga F, Hwang I, Boger D . Asymmetric total synthesis of (+)- and ent-(-)-yatakemycin and duocarmycin SA: evaluation of yatakemycin key partial structures and its unnatural enantiomer. J Am Chem Soc. 2006; 128(49):15683-96. PMC: 2515590. DOI: 10.1021/ja064228j. View

20.

Tichenor M, MacMillan K, Trzupek J, Rayl T, Hwang I, Boger D . Systematic exploration of the structural features of yatakemycin impacting DNA alkylation and biological activity. J Am Chem Soc. 2007; 129(35):10858-69. PMC: 2519902. DOI: 10.1021/ja072777z. View