Efficient and Accurate Characterization of the Bergman Cyclization for an Expanded Substructure of Esperamicin A1

Incorporation of enediynes into anticancer drugs remains an intriguing yet elusive strategy for the design of therapeutically active agents. Density functional theory was used to locate reactants, products, and transition states along the Bergman cyclization pathways connecting enediynes to reactive para-biradicals. Sum method correction to low-level calculations confirmed B3LYP/6-31G(d,p) as the method of choice in investigating enediynes. Herein described as MI:Sum, calculated reaction enthalpies differed from experiment by an average of 2.1 kcal·mol−1 (mean unsigned error). A combination of strain energy released across the reaction coordinate and the critical intramolecular distance between reacting diynes explains reactivity differences. Where experimental and calculated barrier heights are in disagreement, higher level multireference treatment of the enediynes confirms lower level estimates. Previous work concerning the chemically reactive fragment of esperamcin, MTC, is expanded to our model system MTC2.

An ONIOM Study of the Bergman Reaction: A Computationally Efficient and Accurate Method for Modeling the Enediyne Anticancer Antibiotics

The Bergman cyclization of large polycyclic enediyne systems that mimic the cores of the enediyne anticancer antibiotics was studied using the ONIOM hybrid method. Tests on small enediynes show that ONIOM can accurately match experimental data. The effect of the triggering reaction in the natural products is investigated, and we support the argument that it is strain effects that lower the cyclization barrier. The barrier for the triggered molecule is very low, leading to a reasonable half-life at biological temperatures. No evidence is found that would suggest a concerted cyclization/H-atom abstraction mechanism is necessary for DNA cleavage.

Semiempirical Study of the Bergman Reaction: Towards a Computationally Efficient and Accurate Method for Modeling Enediyne Anticancer Antibiotics

Over the past 7 years, the enediyne anticancer antibiotics have been widely studied due to their DNA cleaving ability. The focus of these antibiotics, represented by kedarcidin chromophore, neocarzinostatin chromophore, calicheamicin, esperamicin A, and dynemicin A, is on the enediyne moiety contained within each of these antibiotics. In its inactive form, the moiety is benign to its environment. Upon suitable activation, the system undergoes a Bergman cycloaromatization proceeding through a 1,4-dehydrobenzene diradical intermediate. It is this diradical intermediate that is thought to cleave double-stranded dna through hydrogen atom abstraction. Semiempirical, semiempiricalci, Hartree–Fock ab initio, and mp2 electron correlation methods have been used to investigate the inactive hex-3-ene-1,5-diyne reactant, the 1,4-dehydrobenzene diradical, and a transition state structure of the Bergman reaction. Geometries calculated with different basis sets and by semiempirical methods have been used for single-point calculations using electron correlation methods. These results are compared with the best experimental and theoretical results reported in the literature. Implications of these results for computational studies of the enediyne anticancer antibiotics are discussed.

Antiestrogenic and anticancer activities of peptides derived from the active site of alpha-fetoprotein

Cyclo[EKTOVNOGN] (AFPep), a cyclic 9-amino acid peptide derived from the active site of alpha-fetoprotein, has been shown to prevent carcinogen-induced mammary cancer in rats and inhibit the growth of ER+ human breast cancer xenografts in mice. Recently, studies using replica exchange molecular dynamics predicted that the TOVN region of AFPep might form a dynamically stable putative Type I beta-turn, and thus be biologically active without additional amino acids. The studies presented in this paper were performed to determine whether TOVN and other small analogs of AFPep would inhibit estrogen-stimulated cancer growth and exhibit a broad effective-dose range. These peptides contained nine or fewer amino acids, and were designed to bracket or include the putative pharmacophoric region (TOVN) of AFPep. Biological activities of these peptides were evaluated using an immature mouse uterine growth inhibition assay, a T47D breast cancer cell proliferation assay, and an MCF-7 breast cancer xenograft assay. TOVN had very weak antiestrogenic activity in comparison to AFPep's activity, whereas TOVNO had antiestrogenic and anticancer activities similar to AFPep. OVNO, which does not form a putative Type I beta-turn, had virtually no antiestrogenic and anticancer activities. A putative proteolytic cleavage product of AFPep, TOVNOGNEK, significantly inhibited E2-stimulated growth in vivo and in vitro over a wider dose range than AFPep or TOVNO. We conclude that TOVNO has anticancer potential, that TOVNOGNEK is as effective as AFPep in suppressing growth of human breast cancer cells, and that it does so over a broader effective-dose range.