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. 2009 Jan 28;131(3):1187-94.
doi: 10.1021/ja808108q.

Total synthesis and evaluation of iso-duocarmycin SA and iso-yatakemycin

Karen S MacMillan  1 , Trinh Nguyen, Inkyu Hwang, Dale L Boger
Affiliations

Total synthesis and evaluation of iso-duocarmycin SA and iso-yatakemycin

Karen S MacMillan et al. J Am Chem Soc. .

Erratum in

  • J Am Chem Soc. 2014 Dec 3;136(48):16947. Nguyen, Trihn [corrected to Nguyen, Trinh]

Abstract

The total synthesis and evaluation of iso-duocarmycin SA (5) and iso-yatakemycin (6), representing key analogues of the corresponding natural products incorporating an isomeric alkylation subunit, are detailed. This pyrrole isomer of the natural alkylation subunit displayed an enhanced reaction regioselectivity and a 2-fold diminished stability. Although still exceptionally potent, the iso-duocarmycin SA derivatives and natural product analogues exhibited a corresponding approximate 3-5-fold reduction in cytotoxic activity [L1210 IC(50) for (+)-iso-duocarmycin SA = 50 pM and for (+)-iso-yatakemycin = 15 pM] consistent with their placement on a parabolic relationship correlating activity with reactivity. The DNA alkylation selectivity of the resulting key natural product analogues was unaltered by the structure modification in spite of the minor-groove presentation of a potential H-bond donor. Additionally, a unique ortho-spirocyclization with such derivatives was explored via the preparation, characterization, and evaluation of 34 that is incapable of the more conventional para-spirocyclization. Although 34 proved sufficiently stable for isolation and characterization, it displayed little stability in protic solvents (t(1/2) = 0.19 h at pH 3, t(1/2) = 0.20 h at pH 7), a pH-independent (H(+) independent) solvolysis rate profile at pH 3/4-7, and a much reduced cytotoxic potency, but a DNA alkylation selectivity and efficiency comparable to those of duocarmycin SA and iso-duocarmycin SA. The implications of these observations on the source of the DNA alkylation selectivity and catalysis for this class of natural products are discussed.

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Figures

Figure 1
Figure 1
Natural products.
Figure 2
Figure 2
iso-Duocarmycin SA (5) and iso-yatakemycin (6).
Figure 3
Figure 3
Alternate reactive forms of iso-duocarmycin SA.
Figure 4
Figure 4
Rates of solvolysis (k), half-life (t1/2), and pH rate profile for solvolysis of 34 at pH 2–7. Importantly, the intrinsic reactivity of 34 indicates that while o-spirocyclization of iso-DSA represents an alternative mode of activation,, it is less productive than the more conventional p-spirocyclization.
Figure 5
Figure 5
Parabolic relationship between rate of solvolysis and cytotoxic activity of the alkylation subunits.
Figure 6
Figure 6
Thermally-induced strand cleavage of w794 DNA (144 bp, nucleotide no. 5238–138) after DNA–agent incubation with duocarmycin SA and iso-duocarmycin SA (48 h, 23 °C), removal of unbound agent by EtOH precipitation and 30 min thermolysis (100 °C), followed by denaturing 8% PAGE and autoradiography. Lane 1, control DNA; lanes 2–5, Sanger G, C, A, and T sequencing standards; lanes 6 and 7, (+)-duocarmycin SA and ent-(−)-duocarmycin SA (1, 1 × 10−5 M); lanes 8 and 9, (+)-iso-duocarmycin SA and ent-(−)-iso-duocarmycin SA (5, 1 × 10−5 M).
Figure 7
Figure 7
Thermally-induced strand cleavage of w836 DNA (146 bp, nucleotide no. 5189–91) after DNA–agent incubation with yatakemycin and iso-yatakemycin (48 h, 23 °C), removal of unbound agent by EtOH precipitation and 30 min thermolysis (100 °C), followed by denaturing 8% PAGE and autoradiography. Lane 1, control DNA; lanes 2–5, Sanger G, C, A, and T sequencing standards; lane 6, (+)-yatakemycin (3, 1 × 10−6 M); lane 7, (+)-iso-yatakemycin (6, 1 × 10−6 M).
Figure 8
Figure 8
Thermally-induced strand cleavage of w794 DNA (144 bp, nucleotide no. 5238–138) after DNA–agent incubation with duocarmycin SA and 34 (22 h, 23 °C), removal of unbound agent by EtOH precipitation and 30 min thermolysis (100 °C), followed by denaturing 8% PAGE and autoradiography. Lane 1, control DNA; lanes 2–5, Sanger G, C, A, and T sequencing standards; lane 6, (+)-duocarmycin SA (1, 1 × 10−5 M); lane 7, (−)-34 (natural enantiomer, 1 × 10−5 M).
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Scheme 3
Scheme 3
Scheme 4
Scheme 4
Scheme 5
Scheme 5
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