Shape-Dependent Catalysis:  Insights into the Source of Catalysis for the CC-1065 and Duocarmycin DNA Alkylation Reaction

and, Dale L. Boger; Garbaccio, R. M.

doi:10.1021/ar9800946

Cited by 140 publications

(156 citation statements)

References 39 publications

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“…Although detailed kinetic studies are needed to fully establish this point, this result suggests that 1 may become activated toward nucleophilic addition and DNA cleavage on binding to DNA. Such "shape-dependent catalysis" is reminiscent of the DNA-mediated activation of CC-1065 and duocarmycin elegantly elucidated by Boger and coworkers (45)(46)(47).…”

Section: Discussionmentioning

confidence: 96%

Structural basis for DNA cleavage by the potent antiproliferative agent (–)-lomaiviticin A

Woo

Paulson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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(-)-Lomaiviticin A (1) is a complex antiproliferative metabolite that inhibits the growth of many cultured cancer cell lines at low nanomolar-picomolar concentrations. (-)-Lomaiviticin A (1) possesses a C 2 -symmetric structure that contains two unusual diazotetrahydrobenzo [b]fluorene (diazofluorene) functional groups. Nucleophilic activation of each diazofluorene within 1 produces vinyl radical intermediates that affect hydrogen atom abstraction from DNA, leading to the formation of DNA double-strand breaks (DSBs). Certain DNA DSB repair-deficient cell lines are sensitized toward 1, and 1 is under evaluation in preclinical models of these tumor types. However, the mode of binding of 1 to DNA had not been determined. Here we elucidate the structure of a 1:1 complex between 1 and the duplex d(GCTATAGC) 2 by NMR spectroscopy and computational modeling. Unexpectedly, we show that both diazofluorene residues of 1 penetrate the duplex. This binding disrupts base pairing leading to ejection of the central AT bases, while placing the proreactive centers of 1 in close proximity to each strand. DNA binding may also enhance the reactivity of 1 toward nucleophilic activation through steric compression and conformational restriction (an example of shape-dependent catalysis). This study provides a structural basis for the DNA cleavage activity of 1, will guide the design of synthetic DNA-activated DNA cleavage agents, and underscores the utility of natural products to reveal novel modes of small molecule-DNA association. (-)-Lomaiviticin A (1) possesses half-maximal inhibitory potencies (IC 50 s) in the low nanomolar-picomolar range against several cultured cancer cell lines (1, 2). (-)-Lomaiviticin C (3) and (-)-kinamycin C (4) are several orders of magnitude less potent, whereas (-)-lomaiviticin B (2) is ∼10-100-fold less potent. The cytotoxicity of 1 derives from the induction of double-strand breaks (DSBs) in DNA (18,19). K562 cells exposed to 5 nM of 1 for 30 min accumulated DSB levels that were comparable to 40 Gy of ionizing radiation. This DNA cleavage activity is not recapitulated by 3 or 4, suggesting both diazofluorenes of 1 are essential for cleavage activity. DNA DSBs are exceedingly cytotoxic (20), and these data provide an explanation for the remarkable potency of 1.The molecular mechanism of DNA DSB induction by (-)-lomaiviticin A (1) has been studied (18). Cell-free deuteriumlabeling experiments are consistent with a pathway comprising reductive activation of one diazofluorene (Fig. 1B) to generate the vinyl radical intermediate 1•, followed by hydrogen atom abstraction from the deoxyribose chain, a process known to lead to singlestrand breaks (SSBs) (21). Reductive activation of the remaining diazofluorene, followed by hydrogen atom abstraction, is believed to cleave the complementary DNA (cDNA) strand, leading to the observed DSB.However, the mode of interaction of (-)-lomaiviticin A (1) with DNA has not been elucidated. As C(sp 2 ) radicals are high-energy species, the mechanistic model outlined above pr...

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Section: Discussionmentioning

confidence: 96%

Structural basis for DNA cleavage by the potent antiproliferative agent (–)-lomaiviticin A

Woo

Paulson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…These geometric parameters are well correlated with the parameters from the experimental crystallography works (X-ray crystallography). 5 The model aminopyrimidine ring in the QuinTS approaches vertically to the cyclohexadienenone ring. The cyclopropyl ring angle θ in QuinTS, the index of the ring opening, is 92.1 degree and the length of the bond e in QuinTS is 2.1421 Å (those of Quin2 and QuinPD are 1.5184 Å and 2.4508 Å, respectively), which indicates almost 70% ring opening.…”

Section: Resultsmentioning

confidence: 99%

“…3b The sequence selective DNA alkylation is thought to be originated from the noncovalent binding selectivity of the agents (shape-selective recognition). 5,6 There is also a report that a water molecule is fixed toward the oxygen of the dienone during the DNA alkylation of the pharmacophore, 7 which suggest the presence of catalytic proton during the alkylation. However the detail of the mode of action of the agents is yet to be studied.…”

Section: 4mentioning

confidence: 99%

A Theoretical Study on the N-Alkylation of a Pyrimidine with a Cyclopropa[c]inden-5-one; A Model Pharmacophore of Duocarmycins and CC-1065

Nahm¹

2004

Bulletin of the Korean Chemical Society

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The N-alkylation of 4-aminopyrimidine with a tetrahydro-3-aza-cyclopropa[c]inden-5-one, which is a model reaction of the pharmacophore of duocarmycins, was studied with a quantum chemical method. We consider two factors for the acceleration of the N-alkylation; distortion and protonation of the model pharmacophores. The distortion of the spirocyclopropyl moiety in the model spirocyclopropylcyclohexadienone could induce an intrinsic energy of 3-4 kcal/mol, but the protonation on the carbonyl oxygen of the model cyclohexadienone lowers the transition energy of the N-alkylation of 4-aminopyrimidine dramatically (~46 kcal/mol) and is considered to play a major role in the enzyme reaction. The distorted and protonated spirocyclohexadienone is exothermally relieved to a phenol with the heat of reaction of -37 kcal/mol. The protonation process is proposed to be the mode of action of duocarmycins in the DNA alkylation.

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“…57 Binding in the minor groove requires some rotation about the amide bond, disrupting conjugation of the vinylogous amide and increasing the electrophilicity of the dienone cyclopropane. 58,59 Its position next the N3 of adenine causes a proximity-induced alkylation of this heteroatom. 57 There are a number of examples of natural products that bear an enone adjacent to a cyclopropyl group.…”

Section: Natural Products That Covalently Modify Nucleobasesmentioning

confidence: 99%

Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics

2016

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Developments in epigenomics, toxicology, and therapeutic nucleic acids all rely on a precise understanding of nucleic acid properties and chemical reactivity. In this review we discuss the properties and chemical reactivity of each nucleobase and attempt to provide some general principles for nucleic acid targeting or engineering. For adenine-thymine and guaninecytosine base pairs, we review recent quantum chemical estimates of their Watson-Crick interaction energy, - stacking energies, as well as the nuclear quantum effects on tautomerism. Reactions that target nucleobases have been crucial in the development of new sequencing technologies and we believe further developments in nucleic acid chemistry will be required to deconstruct the enormously complex transcriptome.

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Shape-Dependent Catalysis: Insights into the Source of Catalysis for the CC-1065 and Duocarmycin DNA Alkylation Reaction

Cited by 140 publications

References 39 publications

Structural basis for DNA cleavage by the potent antiproliferative agent (–)-lomaiviticin A

Structural basis for DNA cleavage by the potent antiproliferative agent (–)-lomaiviticin A

A Theoretical Study on the N-Alkylation of a Pyrimidine with a Cyclopropa[c]inden-5-one; A Model Pharmacophore of Duocarmycins and CC-1065

Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics

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