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. 2012 Jun 28;55(12):5878-86.
doi: 10.1021/jm300330b. Epub 2012 Jun 12.

A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct

Amanda L Wolfe  1 , Katharine K Duncan, Nikhil K Parelkar, Scott J Weir, George A Vielhauer, Dale L Boger
Affiliations

A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct

Amanda L Wolfe et al. J Med Chem. .

Abstract

A unique heterocyclic carbamate prodrug of seco-CBI-indole(2) that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug. An in vivo evaluation of the prodrug found that its efficacy exceeded that of the parent drug, that its therapeutic window of efficacy versus toxicity is much larger than the parent drug, and that its slow free drug release permitted the safe and efficacious use of doses 150-fold higher than the parent compound.

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Figures

Figure 1
Figure 1
Natural Products.
Figure 2
Figure 2
Carbamate prodrug design.
Figure 3
Figure 3
Cyclic carbamate prodrug 6.
Figure 4
Figure 4
N-Boc prodrug 16 stability under basic conditions.
Figure 5
Figure 5
In vitro cytotoxic activity.
Figure 6
Figure 6
In vivo antitumor activity (L1210, ip).
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Scheme 3
Scheme 3
See this image and copyright information in PMC

References

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    1. For duocarmycin SA, see: Boger DL, Johnson DS, Yun W. (+)- and ent-(−)-Duocarmycin SA and (+)- and ent-(−)-N-BOC-DSA DNA Alkylation Properties. Alkylation Site Models That Accommodate the Offset AT-Rich Adenine N3 Alkylation Selectivity of the Enantiomeric Agents. J. Am. Chem. Soc. 1994;116:1635–1656.. For yatakemycin, see: Parrish JP, Kastrinsky DB, Wolkenberg SE, Igarashi Y, Boger DL. DNA Alkylation Properties of Yatakemycin. J. Am. Chem. Soc. 2003;125:10971–10976.. Trzupek JD, Gottesfeld JM, Boger DL. Alkylation of Duplex DNA in Nucleosome Core Particles by Duocarmycin SA and Yatakemycin. Nat. Chem. Biol. 2006;2:79–82.. Tichenor MS, MacMillan KS, Trzupek JD, Rayl TJ, Hwang I, Boger DL. Systematic Exploration of the Structural Features of Yatakemycin Impacting DNA Alkylation and Biological Activity. J. Am. Chem. Soc. 2007;129:10858–10869.. For CC-1065, see: Hurley LH, Lee C-S, McGovren JP, Warpehoski MA, Mitchell MA, Kelly RC, Aristoff PA. Molecular Basis for Sequence-Specific DNA Alkylation by CC-1065. Biochemistry. 1988;27:3886–3892.. Boger DL, Johnson DS, Yun W, Tarby CM. Molecular Basis for Sequence Selective DNA Alkylation by (+)- and ent-(−)-CC-1065 and Related Agents: Alkylation Site Models that Accommodate the Offset AT-Rich Adenine N3 Alkylation Selectivity. Bioorg. Med. Chem. 1994;2:115–135.. Boger DL, Munk SA, Zarrinmayeh H. (+)-CC-1065-DNA Alkylation: Key Studies Demonstrating a Noncovalent Binding Selectivity Contribution to the Alkylation Selectivity. J. Am. Chem. Soc. 1991;113:3980–3983.. Boger DL, Zarrinmayeh H, Munk SA, Kitos PA, 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. Nat. Acad. Sci. U.S.A. 1991;88:1431–1435.. Boger DL, Coleman RS, Invergo BJ, Sakya SM, Ishizaki T, Munk SA, Zarrinmayeh H, Kitos PA, Thompson SC. Synthesis and Evaluation of Aborted and Extended CC-1065 Functional Analogs: (+)- and (−)-CPI-PDE-I1, (+)- and (−)-CPI-CDPI1, and (+)- and (−)-CPI-CDPI3. Preparation of Key Partial Structures and Definition of an Additional Functional Role of the CC-1065 Central and Right-Hand Subunits. J. Am. Chem. Soc. 1990;112:4623–4632.. Boger DL, Munk SA, Ishizaki T. (+)-CC-1065 DNA Alkylation: Observation of An Expected Relationship Between Cyclopropane Electrophile Reactivity and the Efficiency of DNA Alkylation. J. Am Chem. Soc. 1991;113:2779–2780.. Boger DL, Coleman RS, Invergo BJ, Zarrinmayeh H, Kitos PA, Thompson SC, Leong T, McLaughlin LW. A Demonstration of the Intrinsic Importance of Stabilizing Hydrophobic Binding and Noncovalent van der Waals Contacts Dominant in the Noncovalent CC-1065:DNA Binding. Chem.-Biol. Interactions. 1990;73:29–52.. For duocarmycin A, see: Boger DL, Ishizaki T, Zarrinmayeh H, Munk SA, Kitos PA, Suntornwat O. Duocarmycin-Pyrindamycin DNA Alkylation Properties and Identification, Synthesis, and Evaluation of Agents Incorporating the Pharmacophore of the Duocarmycin-Pyrindamycin Alkylation Subunit. Identification of the CC-1065 Duocarmycin Common Pharmacophore. J. Am. Chem. Soc. 1990;112:8961–8971.. Boger DL, Ishizaki T, Zarrinmayeh H. Isolation and Characterization of the Duocarmycin-Adenine DNA Adduct. J. Am. Chem. Soc. 1991;113:6645–6649.. Boger DL, Yun W, Terashima S, Fukuda Y, Nakatani K, Kitos PA, Jin Q. DNA Alkylation Properties of the Duocarmycins: (+)-Duocarmycin A, epi-(+)-Duocarmycin A, ent-(−)-Duocarmycin A and epi,ent-(−)-Duocarmycin A. Bioorg. Med. Chem. Lett. 1992;2:759–765.. Boger DL, Yun W. Reversibility of the Duocarmycin A and SA DNA Alkylation Reaction. J. Am. Chem. Soc. 1993;115:9872–9873.

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