Furans with basic side chains: synthesis and biological evaluation of a novel series of antagonists with selectivity for the estrogen receptor alpha.

3-alkyl-2,4,5-triarylfurans with basic side-chain substituents were prepared as ligands for the estrogen receptor. Those analogues having the basic side chain on the C(4) phenol were high-affinity, ERalpha-selective antagonists.     

Tetrahydrofluorenones with conformationally restricted side chains as selective estrogen receptor beta ligands

A series of 2-9a bridged tetrahydrofluorenone derivatives were prepared which exhibited significant binding affinity for ERbeta and were highly selective.     

1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains

The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.     

4-(4-alkylpiperazin-1-yl)phenyl group: a novel class of basic side chains for selective estrogen receptor modulators

In the structure–activity relationships of spiro[indene-1,1′-indane] series, the 4-(4-alkylpiperazin-1-yl)phenyl group was found to be functionally equipotent to the 4-(1-piperidinoethoxy)phenyl group, the most widely used basic side chain in selective estrogen receptor modulators.     

Estrogen receptor ligands. Part 5: The SAR of dihydrobenzoxathiins containing modified basic side chains

Dihydrobenzoxathiin analogs (1-11) with modifications on the basic side chain region were prepared and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. The compounds generally maintained a high degree of selectivity for ERalpha over ERbeta, similar to the original lead compound I. Many of the compounds also maintained high potency in the inhibition of human carcinoma MCF-7 cell growth. However, all were less potent in the inhibition of estradiol-triggered uterine growth. This work demonstrates the sensitive nature of modification to the antagonist basic side chain region.     

1,3,4 Trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains

A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC(95)=50 nM). Compound 4a also has improved PK properties relative to 1.     

The binding of estrogen and estrogen antagonists to the estrogen receptor.

The model of the estrogen receptor as a dimer of identical, interacting subunits and data obtained by Sasson and Notides (1988, Mol. Endocrinol. 2, 307-312) were used to find the standard free energy changes that describe the binding of estradiol and 4-hydroxytamoxifen to the estrogen receptor. For the binding of estradiol or 4-hydroxytamoxifen to the estrogen receptor the data do not deviate systematically from the best fit to the model. The standard free energy change for binding of one molecule of estradiol at one site and one molecule of 4-hydroxytamoxifen at the second site of estrogen receptor indicates that 4-hydroxytamoxifen antagonizes the binding of estradiol to the estrogen receptor.     

Identification of novel estrogen receptor alpha antagonists

We have identified novel estrogen receptor alpha (ERalpha) antagonists using both cell-based and computer-based virtual screening strategies. A mammalian two-hybrid screen was used to select compounds that disrupt the interaction between the ERalpha ligand binding domain (LBD) and the coactivator SRC-3. A virtual screen was designed to select compounds that fit onto the LxxLL peptide-binding surface of the receptor, based on the X-ray crystal structure of the ERalpha LBD complexed with a LxxLL peptide. All selected compounds effectively inhibited 17-beta-estradiol induced coactivator recruitment with potency ranging from nano-molar to micromolar. However, in contrast to classical ER antagonists, these novel inhibitors poorly displace estradiol in the ER-ligand competition assay. Nuclear magnetic resonance (NMR) suggested direct binding of these compounds to the receptors pre-complexed with estradiol and further demonstrated that no estradiol displacement occurred. Partial proteolytic enzyme digestion revealed that, when compared with 17-beta-estradiol- and 4 hydroxy-tamoxifen (4-OHT) bound receptors, at least one of these compounds might induce a unique receptor conformation. These small molecules may represent new classes of ER antagonists, and may have the potential to provide an alternative for the current anti-estrogen therapy.     

Substituted phenanthrenes with basic amino side chains: a new series of anti-breast cancer agents

In the course of our search for new anti-breast cancer agents, substituted phenanthrenes with basic amino side chains were synthesized and some of them showed remarkable antiproliferative activity against ER +ve MCF-7 cell line with IC(50) in the range of 3.53-22.25 microM. One of the compounds 15 ca showed anti-breast cancer activity in 7,12-dimethylbenz[a]anthracene (DMBA) induced hormone-dependent mammary tumor in rat and the activity was comparable to that shown by tamoxifen.     

Estrogen receptor ligands. Part 8: Dihydrobenzoxathiin SERAMs with heteroatom-substituted side chains

A series of benzoxathiin SERAMs with heteroatom-substituted amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.     

Estrogen receptor ligands. Part 7: Dihydrobenzoxathiin SERAMs with bicyclic amine side chains

A series of benzoxathiin SERAMs with bicyclic amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.     

Structure-based design of eugenol analogs as potential estrogen receptor antagonists

Eugenol is an essential oil mainly found in the buds and leaves of clove (Syzygium aromaticum (L.) Merrill and Perry), which has been reported to have activity on inhibition of cell proliferation and apoptosis induction in human MCF-7 breast cancer cells. This biological activity is correlated to its activity as an estrogen receptor antagonist. In this article, we present the construction and validation of structure-based virtual screening (SBVS) protocols to identify the potent estrogen receptor α (ER) antagonists. The selected protocol, which gave acceptable enrichment factors as a virtual screening protocol, subsequently used to virtually screen eugenol, its analogs and their dimers. Based on the virtual screening results, dimer eugenol of 4-[4-hydroxy-3-(prop-2-en-1- yl)phenyl]-2-(prop-2-en-1-yl)phenol is recommended to be developed further in order to discover novel and potent ER antagonists.     

Sterols with modified side chains.

Radio immunoassays for aldosterone and deoxycorticosterone (DOC)are described in which a simple separation procedure using ammonium sulfate stabilization of bound steroid and extraction of free steroid into toluene scintillant allows an “in vial” assay without mechanical separation of the two phase system. Extraction and thin layer Chromatographic methods for purification of aldosterone and DOC are free of solvent and plate blank effects. Normal values are given for unconjugated aldosterone and DOC in urine, for aldosterone and DOC in plasma and for aldosterone 18-glucuronide in urine.     

Estrogen receptor ligands. Part 9: Dihydrobenzoxathiin SERAMs with alkyl substituted pyrrolidine side chains and linkers

A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.     

Inhibition of HIV-1 Tat-TAR interaction by diphenylfuran derivatives: effects of the terminal basic side chains.

A series of four biscationic diphenylfuran derivatives was used to investigate drug binding to the transactivation response element (TAR) RNA. The drugs, which are active against the Pneumocystis carinii pathogen (PCP), differ by the nature of the terminal basic side chains. Furimidazoline (DB60) is more potent at inhibiting binding of the Tat protein to TAR than furamidine (DB75) and the amidine-substituted analogues DB244 and DB226. In vivo studies using the fusion-induced gene stimulation (FIGS) assay entirely agree with the in vitro gel mobility shift data. The capacity of the drugs to antagonize Tat binding correlates with their RNA binding properties determined by melting temperature and RNase protection experiments. Footprinting studies indicate that the bulge region of TAR provides the identity element for the diphenylfurans. Access of the drugs to the major groove cavity at the pyrimidine bulge depends on the bulk of the alkylamine substituents. Experiments using TAR mutants show that the bulge of TAR is critical for drug binding but also reveal that the fit of the drugs into the major groove cavity of TAR does not involve specific contacts with the highly conserved residue U23 or the C x G26-39 base pair. The binding essentially involves shape recognition. The results are also discussed with respect to the known activity of the drug against PCP which is the major cause of mortality in AIDS patients. This study provides guidelines for future development of TAR-targeted anti-HIV-1 drugs.     

Synthesis of sterols with modified side chains.

Synthesis of sterols with side chain containing from four to nine carbons are described.     

Optimum interaction of sterol side chains with phosphatidylcholine

The specificity of the interaction between the cholesterol side chain and egg phosphatidylcholine was precisely defined by examining the effect of three new analogues of cholesterol with modified side chains on the ordering of two steroid spin labels in liposomes. The complete side chain of cholesterol was shown to be required for maximum ordering. Sterols with side chains shorter or longer than cholesterol caused significantly less ordering.     

Acidic-basic properties of three alanine-based peptides containing acidic and basic side chains: comparison between theory and experiment

The purpose of this work was to evaluate the effect of the nature of the ionizable end groups, and the solvent, on their acid-base properties in alanine-based peptides. Hence, the acid-base properties of three alanine-based peptides: Ac-KK-(A)(7)-KK-NH(2) (KAK), Ac-OO-(A)(7)-DD-NH(2) (OAD), Ac-KK-(A)(7)-EE-NH(2) (KAE), where A, D, E, K, and O denote alanine, aspartic acid, glutamic acid, lysine, and ornithine, respectively, were determined in water and in methanol by potentiometry. With the availability of these data, the ability of two theoretical methods to simulate pH-metric titration of those peptides was assessed: (i) the electrostatically driven Monte Carlo method with the ECEPP/3 force field and the Poisson-Boltzmann approach to compute solvation energy (EDMC/PB/pH), and (ii) the molecular dynamics method with the AMBER force field and the Generalized Born model (MD/GB/pH). For OAD and KAE, pK(a1) and pK(a2) correspond to the acidic side chains. For all three compounds in both solvents, the pK(a1) value is remarkably lower than the pK(a) of a compound modeling the respective isolated side chain, which can be explained by the influence of the electrostatic field from positively charged ornithine or lysine side chains. The experimental titration curves are reproduced well by the MD/GB/pH approach, the agreement being better if restraints derived from NMR measurements are incorporated in the conformational search. Poorer agreement is achieved by the EDMC/PB/pH method.     

Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 1: Discovery and SAR study of 4-pyrazolylpiperidine side chains

Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.