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. Author manuscript; available in PMC: 2011 Mar 15.
Published in final edited form as: Bioorg Med Chem Lett. 2010 Feb 2;20(6):1854–1857. doi: 10.1016/j.bmcl.2010.01.145

Synthesis and evaluation of duocarmycin SA analogs incorporating the methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) alkylation subunit

Kristopher E Boyle 1, Karen S MacMillan 1, David A Ellis 1, James P Lajiness 1, William M Robertson 1, Dale L Boger 1,*
PMCID: PMC2965170  NIHMSID: NIHMS246086  PMID: 20171886

Abstract

The design, synthesis and evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) derivatives are detailed representing analogs of duocarmycin SA containing an oxazole replacement for the fused pyrrole found in the alkylation subunit.

Duocarmycin SA (1)1 and duocarmycin A (2)2 represent the parent members of a small class of naturally occurring antitumor antibiotics that additionally includes yatakemycin (3)3 and CC-1065 (4)4 and that derive their properties through a sequence-selective alkylation of duplex DNA (Figure 1).5–9 Substantial efforts have been devoted to determining the origin of their DNA alkylation properties,9 including the preparation of derivatives possessing fundamental structural changes used to define relationships between structure, functional reactivity, and biological properties.10 Most notable of these are the structural features that contribute to the AT-rich noncovalent binding selectivity dominating the minor groove adenine N3 alkylation selectivity,11 those that are responsible for the source of catalysis for the DNA alkylation reaction,12,13 and those that subtly impact the unusual and intrinsic stability of the alkylation subunits.10,13–17

Figure 1.

Figure 1

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Natural products.

Herein, we report the synthesis of an analog of duocarmycin SA in which the left-hand subunit pyrrole ring is replaced by an oxazole, providing the methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) alkylation subunit (6 and 7, Figure 2). This structural modification changes the hydrogen bond donating pyrrole nitrogen of 1 into a Lewis basic oxazole nitrogen, potentially provides an alkylation subunit heterocyclic system capable of tunable metal cation activation,18 and changes the electronic nature of the cyclopropylcyclohexadienone alkylation subunit by attaching two inductively withdrawing heteroatoms. The oxazole oxygen potentially represents a cross-conjugated vinylogous ester with the cyclohexadienone carbonyl and is positioned to be deeply imbedded in the minor groove at a site that is sensitive to steric interactions contributing to the differences between the natural and unnatural enantiomers of the natural products.19 Consequently, the examination of COI and its derivatives was anticipated to additionally probe the effect of replacing this center (CH for 1 and C=O for 2) with the less sterically demanding lone pair electrons on oxygen that would be directed into the DNA minor groove.20

Figure 2.

Figure 2

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Duocarmycin SA analog.

The synthesis21 of the duocarmycin SA analog 6 commenced with protection of 2-nitroresorcinol as the ditosylate (2.05 equiv TsCl, 3 equiv Et3N, THF, 23 °C, 5 h, 93%) followed by reduction of the nitro group (10 equiv Zn, 15 equiv NH4Cl, acetone, H2O, quantitative) to provide aniline 8 (Scheme 1). Acetylation (1.5 equiv AcCl, 0.2 equiv DMAP, 3.0 equiv pyridine, DMF, 80%) followed by nitration (15 equiv Ac2O, 1.7 equiv HNO3, 0.5 equiv H2SO4, 99%) of aniline 8 produced 9, which provided aniline 10 (77%) when exposed to concentrated sulfuric acid resulting from p-nitration and O-tosylate deprotection.22 Acid-catalyzed condensation of 10 with trimethoxymethyl acetate (1.8 equiv, 0.05 equiv TsOH, toluene, DME, 80 °C, 87%) produced benzoxazole 11. Benzylation of the remaining free phenol (1.5 equiv BnBr, 1.8 equiv K2CO3, DMF, quantitative), nitro reduction (10 equiv Zn, 15 equiv NH4Cl, acetone, H2O) and Boc protection of the resultant aniline (4.0 equiv Boc2O, 2.2 equiv Et3N, dioxane, 60 °C, 51%, 2 steps) gave benzoxazole 12. Regioselective iodination of 12 using N-iodosuccinimide (1.4 equiv, 0.1 equiv TsOH, THF, MeOH, 87%) yielded aryl iodide 13. Alkylation of aniline 13 using P4-t-Bu phosphazene base and 1,3-dichloropropene (1.4 equiv P4-base, 1.8 equiv 1,3-dichloropropene, benzene, 86%) produced vinyl chloride 14 as a mixture of alkene isomers.15m,n Once installed, the benzoxazole methyl ester proved especially sensitive to hydrolysis and this influenced our choice of reaction conditions, including the use of P4-base/benzene for the N-alkylation of 13. Free radical 5-exo-trig ring closure of 14 using freshly prepared Bu3SnH (0.3 equiv AIBN, 1.2 equiv Bu3SnH, benzene, 80%) produced 15.23 Debenzylation (10% Pd/C, 1 atm H2 gas, THF, MeOH, 50%) of 15 resulted in formation of phenol 16.

Scheme 1.

Scheme 1

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Exposure of phenol 16 to the basic conditions commonly employed to effect spirocyclization in duocarmycin-like systems (NaH, THF; NaHCO3, DMF, H2O; DBU, CH3CN) did not provide 6 and instead resulted in rapid hydrolysis of the methyl ester. Replacement of the methyl ester with a tert-butyl ester, as in 17, stabilized the molecule to competitive ester hydrolysis. However, even exposure of 17 to basic spirocyclization conditions did not result in ring closure, and the phenol starting material was recovered. Deprotonation of the phenol precursors to the spirocyclopropane alkylation units typically results in the formation of a yellow reaction mixture, which changes to colorless upon formation of the spirocyclopropane. Exposure of 17 to NaHCO3 in DMF and H2O resulted in a bright yellow solution, but dissipation of the yellow color and spirocyclization were not observed. This suggests that the phenolate ion forms, but does not react to displace chloride and form the cyclopropane.

Attempts to promote the spirocyclization of phenol 17 using silver salts or Bu4NI as additives were also unsuccessful. In order to probe the impact of the ester on the problematic spirocyclization, reduction of the methyl ester 15 (5.0 equiv NaBH4, MeOH) and methylation of the resultant alcohol (2.0 equiv NaH, 10 equiv MeI, THF, quantitative) produced methyl ether 18 (Scheme 2). After debenzylation, exposure of phenol 19 to DBU in CH3CN slowly produced spirocycle 20 in poor yield (~20%) and with decomposition occurring during isolation and purification. Due to this reactivity and despite our expertise in handling even the most reactive alkylation subunits,24 it was not possible to isolate a pure sample of 20.

Scheme 2.

Scheme 2

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The reactivity of 20 and the inability of 16 to spirocyclize to provide N-Boc-COI (6) suggest that there is an intrinsic reactivity of this modified alkylation subunit that substantially exceeds that of duocarmycin SA. To date, the spirocyclization precursors to the alkylation subunits containing the cyclopropane have displayed biological properties indistinguishable from the final products. Consequently, we elected to examine the cytotoxic activity of 16, the seco precursor to N-Boc-COI (6), as well as 21 (Scheme 3), the seco precursor to COI–TMI (Table 1, TMI = 5,6,7-trimethoxyindole). Consistent with the indirect observations on their intrinsic reactivity and the observation of a direct relationship between chemical stability and cytotoxic potency,16 16 and 21 proved to be 100 and 550 times less potent than (+)-N-Boc-DSA (5) or (+)-duocarmycin SA (1), respectively. While this represents a substantial reduction in the activity relative to duocarmycin SA, it is still of a magnitude that is quite active (21, IC50 = 5.4 nM) and perhaps surpasses the anticipated potency given its inferred reactivity. The origin of the reactivity of the modified COI alkylation subunit and the resulting loss in cytotoxic activity is not well understood, especially when compared to the analogous CPyI,18 CBI,24,25 and CTI17 alkylation subunit analogs.

Scheme 3.

Scheme 3

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Table 1.

In Vitro Cytotoxic Activity, L1210 cell line

Compound IC50 (pM)
(+)-5, (+)-N-Boc-DSA 6000
16, seco-N-Boc-COI 550000
(+)-1, (+)-duocarmycin SA 10
21, seco-COI–TMI 5400
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To further characterize the modified alkylation subunit, the DNA alkylation selectivity and efficiency of compound 21 were examined using an assay previously described and singly 32P end-labeled double-stranded w794 DNA.26 Figure 3 illustrates the DNA alkylation selectivity of racemic seco-COI–TMI alongside (+)- and ent-(–)-duocarmycin SA. Within w794 DNA, seco-COI–TMI was found to alkylate the same site as (+)-duocarmycin SA, and with an efficiency nearly identical to (+)-duocarmycin SA. In this comparison, it is notable that the natural enantiomer of seco-COI–TMI (in the racemic mixture) alkylates DNA much more effectively than the unnatural enantiomer (not detected), and that its natural enantiomer DNA alkylation properties (efficiency and selectivity) are not readily distinguishable from those of (+)-duocarmycin SA (natural enantiomer).

Figure 3.

Figure 3

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Thermally-induced strand cleavage of w794 DNA (144 bp. nucleotide no. 5238–138) after DNA-agent incubation with (+)- or ent-(–)-duocarmycin SA and COI–TMI (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, (+)-duocarmycin SA (1 × 10–5 M, natural enantiomer); lane 7, (–)-duocarmycin SA (1 × 10–4 M, unnatural enantiomer); lane 8, seco-COI–TMI (21, 1 × 10–5 M, racemic mixture).

What is remarkable is that the DNA alkylation selectivity and efficiency of 21 nearly match those of (+)-duocarmycin SA when conducted with cell free DNA, yet it fails to cyclize to the spirocyclopropane with the ease or facility of duocarmycin SA. Moreover, the cytotoxic potency of 21 does not reflect its DNA alkylation efficiency. Not only is it difficult to rationalize the origin of these observations, but to our knowledge it represents the first instance of such a dramatic lack of correlation between DNA alkylation efficiency and biological activity.

Supplementary Material

Supplementary Data

Acknowledgments

We gratefully acknowledge the financial support of the National Institutes of Health (CA041986) and the Skaggs Institute for Chemical Biology. KSM, JPL, and WMR were Skaggs Fellows.

Footnotes

Supplementary Data. Full details of the synthesis of 16 and 21 and their experimental examination are provided. The supplementary data associated with this article can be found in the online version at doi:

References and notes

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