The persistence of genetic damage produced by alkylating agents 1 as well as the antagonism of essential biochemical processes such as transcription can have lethal consequences for malignant cells. 2 Both mechanisms have been identified in studies to uncover the reasons for the efficacy of cisplatin in the treatment of several cancers. 2a, 3 We describe a synthetic strategy to create bifunctional molecules that produce DNA adducts capable of binding the estrogen receptor (ER), which is aberrantly expressed in many breast cancer cells. 4 It is speculated that DNA adducts that form complexes with the ER will be poorly repaired in these cells because they are camouflaged from detection by DNA repair enzymes. Consequently, the DNA lesions persist. Furthermore, the DNA adducts would be expected to act as "molecular decoys" capable of displacing the ER from its natural targets and antagonizing its role in malignant growth. In healthy cells, where the abundance of the ER is minimal, no such ER-DNA adduct complexes will be present, and the cell should survive. 5 In this report we describe the design and synthesis of compound 1, a bifunctional agent that can form covalent DNA adducts capable of binding the ER with high affinity and specificity. We show that 1 has selective toxicity toward ER+ breast cancer cells compared to ER-cells in vitro.Compound 1 consists of a bis-chloroethyl aniline mustard as the DNA alkylating unit tethered to estradiol, the natural ligand for the ER. The site of substitution of estradiol in 1 was based on reports that relatively large alkyl groups can be attached at the 7α position with retention of high affinity for the ER 6 . The synthetic strategy for 1 is shown in Scheme 1. Compound 7, a key compound in the synthesis, was prepared by a modification of a published strategy. 7 Briefly, 3 was functionalized with a 6-carbon chain at the 7-position in α-stereochemistry to provide the alkenyl steroid 4. Efficient reduction of the 6-oxo group in 4 was achieved with Et 3 SiH/BF 3 .Et 2 O; however, this treatment also caused the loss of 3,17-tetrahydropyranoxy (THP) groups producing diol 5. The 3,17-OHs of 5 were reprotected with THP groups to afford 6, followed by oxidation of the alkene at the terminus of the linker to provide alcohol 7. Steroid alcohol 7 was converted to bromide 8, which was subsequently allowed to react with a protected ethanolamine to give 9. Compound 9 was desilylated with tetrabutylammonium fluoride (TBAF) and converted to a carbonate Next, the ability of 1 to modify DNA covalently was investigated. Plasmid DNA was incubated with 100 μM [ 14 C]-1 10 at 37 °C for up to 6 h. After unbound 1 was removed by phenol-CHCl 3 extraction and ethanol precipitation, the radioactivity associated with DNA was measured. The amount of radioactivity bound to DNA increased at a constant rate over the 6-h period indicating the formation of covalently bound 1 (see Supporting Information). Based on previous studies on DNA alkylation by nitrogen mustards, 11 it is likely that covalent adducts of...
The butadienediyl-bridged complexes [(η 5 -C 5 R 5 )Fe(dppe)] 2 (µ-CHdCHCHdCH) (R ) H, Me) and their radical cationic and dicationic forms have been prepared and characterized by cyclic voltammetry, electronic spectroscopy (UV-vis and near-IR), EPR, and X-ray crystallography (R ) Me). Comparisons with each other and with the literature complexes [(η 5 -C 5 H 5 )Fe(dppm)] 2 (µ-CHdCHCHdCH), [(η 5 -C 5 Me 5 )Fe(dppe)] 2 (µ-CtCCtC), and [(η 5 -C 5 Me 5 )-Fe(dppe)] 2 (µ-C(OMe)dCHCHdC(OMe)) have allowed for systematic evaluation of several structural variations (C 5 H 5 vs C 5 Me 5 , dppm vs dppe, µ-CHdCHCHdCH vs µ-CtCCtC, and µ-CHdCHCHdCH vs µ-C(OMe)dCHCHdC(OMe)) and their effects on spectra and electronic intermetal coupling. Some of the structural changes have opposite effects on H ab , the effective coupling parameter, and K c , the comproportionation constant. The data for the mixed-valence cations are most consistent with electronic delocalization.Many recent examples of transition metals linked with conjugated bridges have shown that such bridges can promote electronic coupling between metal centers. 1 Studies of mixed-valence (MV) ions in comparison with fully oxidized and fully reduced states have provided much insight concerning delocalization and/or intramolecular electron transfer 2 and have allowed more accurate predictions concerning potential use as molecular wires. 3 Through systematic evaluation of trends related to isolated structural variations, the role of different structural aspects has sometimes been discerned. 4 For complexes linked by conjugated hydrocarbon bridges, such systematic studies are rare. 5 We have previously described the preparation of several butadienediyl-bridged diiron complexes, [CpFeLL′] 2 (µ-CHdCHCHdCH) (1-4, Cp ) η 5 -C 5 H 5 ; Scheme 1), and the oxidation of these neutral species to dicationic and MV radical cationic species. 6 Lapinte and co-workers have reported the closely related butadiynediyl-bridged complex [Cp*Fe(dppe)] 2 (µ-CtCCtC) (7, Cp* ) η 5 -C 5 Me 5 , dppe ) Ph 2 PCH 2 CH 2 PPh 2 ) 7 and the butadienediyl-bridged complex [Cp*Fe(dppe)] 2 -(µ-C(OMe)dCHCHdC(OMe)) ( 8), 8 each also prepared in three oxidation levels. Though the MV cation forms of all of these species were found to be delocalized, class III 9 complexes, several interesting differences were
A series of bifunctional compounds was prepared consisting of 17β estradiol linked to a DNA damaging N,N-bis(2-chloroethyl)-aniline. The objective of our studies was to detem1ine the characteristics of the linker that permitted both reaction with DNA and binding of the resultant covalent adducts to the estrogen receptor. Linker characteristics were pivotal determinants underlying the ability of the compounds to kill selectively breast cancer cells that express the estrogen receptor.
A strategy is described for the re-design of DNA damaging platinum(II) complexes to afford elevated toxicity towards cancer cells expressing the estrogen receptor (ER). Two platinum-based toxicants are described in which a DNA damaging warhead, [Pt(en)Cl2] (en, ethylenediamine), is tethered to either of two functional groups. The first agent, [6-(2-amino-ethylamino)-hexyl]-carbamic acid 2-[6-(7α-estra-1,3,5,(10)-triene)-hexylamino]-ethyl ester platinum(II) dichloride ((Est-en)PtCl2), terminates in a ligand for the ER. The second agent is a control compound lacking the steroid; this compound, N-[6-(2-amino-ethylamino)-hexyl]-benzamide platinum(II) dichloride ((Bz-en)PtCl2)), terminates in a benzamide moiety, which lacks affinity for the ER. Using a competitive binding assay, Est-en had 28% relative binding affinity (RBA) for the ER as compared to 17β-estradiol. After covalent binding to a synthetic DNA duplex 16-mer, the compound retained its affinity for the ER; specificity of the binding event was demonstrated by the ability of free 17β-estradiol as a competitor to disrupt the DNA adduct-ER complex. The (Est-en)PtCl2 compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl2 was also more toxic to the ER positive breast cancer line, MCF7, than to an ER negative line, MDA-MB231.
Synthesis of bacterial cell wall peptidoglycan requires glycosyltransferase enzymes that transfer the disaccharide-peptide from lipid II onto the growing glycan chain. The polymerization of the glycan chain precedes cross-linking by penicillin-binding proteins and is essential for growth for key bacterial pathogens. As such, bacterial cell wall glycosyltransferases are an attractive target for antibiotic drug discovery. However, significant challenges to the development of inhibitors for these targets include the development of suitable assays and chemical matter that is suited to the nature of the binding site. We developed glycosyltransferase enzymatic activity and binding assays using the natural products moenomycin and vancomycin as model inhibitors. In addition, we designed a library of disaccharide compounds based on the minimum moenomycin fragment with peptidoglycan glycosyltransferase inhibitory activity and based on a more drug-like and synthetically versatile disaccharide building block. A subset of these disaccharide compounds bound and inhibited the glycosyltransferase enzymes, and these compounds could serve as chemical entry points for antibiotic development.
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