Photomodulation of G protein-coupled adenosine receptors by a novel light-switchable ligand.

The adenosinergic system operates through G protein-coupled adenosine receptors, which have become promising therapeutic targets for a wide range of pathological conditions. However, the ubiquity of adenosine receptors and the eventual lack of selectivity of adenosine-based drugs have frequently diminished their therapeutic potential. Accordingly, here we aimed to develop a new generation of light-switchable adenosine receptor ligands that change their intrinsic activity upon irradiation, thus allowing the spatiotemporal control of receptor functioning (i.e., receptor activation/inactivation dependent on location and timing). Therefore, we synthesized an orthosteric, photoisomerizable, and nonselective adenosine receptor agonist, nucleoside derivative MRS5543 containing an aryl diazo linkage on the N(6) substituent, which in the dark (relaxed isomer) behaved as a full adenosine A3 receptor (A3R) and partial adenosine A2A receptor (A2AR) agonist. Conversely, upon photoisomerization with blue light (460 nm), it remained a full A3R agonist but became an A2AR antagonist. Interestingly, molecular modeling suggested that structural differences encountered within the third extracellular loop of each receptor could modulate the intrinsic, receptor subtype-dependent, activity. Overall, the development of adenosine receptor ligands with photoswitchable activity expands the pharmacological toolbox in support of research and possibly opens new pharmacotherapeutic opportunities.

Antiproliferative 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides, a new tubulin inhibitor chemotype.

We discovered a new chemical class of antiproliferative agents, 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides. SAR-guided optimization of the two distinct terminal fragments yielded a compound with 120 nM potency in an antiproliferative assay. Biological activity profile studies (COMPARE analysis) demonstrated that 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides act as tubulin inhibitors, and this conclusion was confirmed via biochemical assays with pure tubulin and demonstration of increased numbers of mitotic cells following treatment of a leukemia cell line.

Trifluoromethylated heterocycles.

This review is a follow-up to the previous chapter, "Monofluorinated Heterocycles" (Topics in Heterocyclic Chemistry, 2012, 33-63), and presents an overview of synthetic chemistry of heterocycles with only one trifluoromethyl group directly attached to the ring (trifluoromethylated heterocycles). Particular attention is given to the modern direct trifluoromethylation methods, including catalytic reactions, organometallic reagents, carbene and hypervalent chemistry, utilization of ionic nucleophilic and electrophilic trifluoromethylating agents, and to other pertinent trends. One of the emphases of the review is compounds with biomedical potential.

Identification of diaryl 5-amino-1,2,4-oxadiazoles as tubulin inhibitors: the special case of 3-(2-fluorophenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole.

The combination of experimental (inhibition of colchicine binding) and computational (COMPARE, docking studies) data unequivocally identified diaryl 5-amino-1,2,4-oxadiazoles as potent tubulin inhibitors. Good correlation was observed between tubulin binding and cytostatic properties for all tested compounds with the notable exception of the lead candidate, 3-(3-methoxyphenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole (DCP 10500078). This compound was found to be substantially more active in our in vitro experiments than the monofluorinated title compound, 3-(2-fluorophenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole (DCP 10500067/NSC 757486), which in turn demonstrated slightly better tubulin binding activity. Comparative SAR analysis of 25 diaryl 5-amino-1,2,4-oxadiazoles with other known tubulin inhibitors, such as combretastatin A-4 (CA-4) and colchicine, provides further insight into the specifics of their binding as well as a plausible mechanism of action.

Optimization of adenosine 5'-carboxamide derivatives as adenosine receptor agonists using structure-based ligand design and fragment screening.

Structures of G protein-coupled receptors (GPCRs) have a proven utility in the discovery of new antagonists and inverse agonists modulating signaling of this important family of clinical targets. Applicability of active-state GPCR structures to virtual screening and rational optimization of agonists, however, remains to be assessed. In this study of adenosine 5' derivatives, we evaluated the performance of an agonist-bound A(2A) adenosine receptor (AR) structure in retrieval of known agonists and then employed the structure to screen for new fragments optimally fitting the corresponding subpocket. Biochemical and functional assays demonstrate high affinity of new derivatives that include polar heterocycles. The binding models also explain modest selectivity gain for some substituents toward the closely related A(1)AR subtype and the modified agonist efficacy of some of these ligands. The study suggests further applicability of in silico fragment screening to rational lead optimization in GPCRs.

Trans-, cis-, and dihydro-resveratrol: a comparative study.

BACKGROUND: Recent studies showed that moderate consumption of red or white wines increased the chances of breast cancer, while similar consumption of red wines, rich in trans-resveratrol (trans-R), decreased the rate of prostate cancer. This prompted us to explore the role of various forms of R in cancer proliferation. RESULTS: Trans-R was found to be the most potent antiproliferative agent. Cis-R demonstrated somewhat less potency compared to trans-R. Unlike cis-R and trans-R, dihydro-R exhibits moderate proliferative effect on androgen-independent prostate cancer cell lines PC-3 and DU-145 at picomolar concentrations. At higher concentrations, dihydro-R caused proliferation inhibition, similar to cis-R and trans-R. The proliferative effect of dihydro-R at low concentrations can be reversed by trans-R which acts as a partial antagonist in the presence of dihydro-R. Mixtures of dihydro-R and trans-R demonstrated complex non-monotonic cross-modulation activity patterns. CONCLUSIONS: Dihydro-R exhibits proliferative effects in androgen-independent prostate cancer cells at picomolar and nanomolar concentrations. While the exact mechanism of these effects requires further evaluation, our preliminary results point to hormone receptor modulation activity. We also observed strong cross modulation between trans-R and dihydro-R at sub-picomolar concentrations. The role of dihydro-R in cancer proliferation related to moderate consumption of red wine remains an open question because dihydro-R has a very complex activity pattern in the presence of trans-R.

Modular Chemical Descriptor Language (MCDL): Stereochemical modules.

BACKGROUND: In our previous papers we introduced the Modular Chemical Descriptor Language (MCDL) for providing a linear representation of chemical information. A subsequent development was the MCDL Java Chemical Structure Editor which is capable of drawing chemical structures from linear representations and generating MCDL descriptors from structures. RESULTS: In this paper we present MCDL modules and accompanying software that incorporate unique representation of molecular stereochemistry based on Cahn-Ingold-Prelog and Fischer ideas in constructing stereoisomer descriptors. The paper also contains additional discussions regarding canonical representation of stereochemical isomers, and brief algorithm descriptions of the open source LINDES, Java applet, and Open Babel MCDL processing module software packages. CONCLUSIONS: Testing of the upgraded MCDL Java Chemical Structure Editor on compounds taken from several large and diverse chemical databases demonstrated satisfactory performance for storage and processing of stereochemical information in MCDL format.

Dihydro-resveratrol--a potent dietary polyphenol.

Dihydro-resveratrol (dihydro-R), a prominent polyphenol component of red wine, has a profound proliferative effect on hormone-sensitive tumor cell lines such as breast cancer cell line MCF7. We found a significant increase in MCF7 tumor cells growth rates in the presence of picomolar concentrations of this compound. The proliferative effect of dihydro-R was not observed in cell lines that do not express hormone receptors (MDA-MB-231, BT-474, and К-562).

Discovery and SAR exploration of N-aryl-N-(3-aryl-1,2,4-oxadiazol-5-yl)amines as potential therapeutic agents for prostate cancer.

A new chemical series of antiproliferative compounds was identified via high-throughput screening on DU-145 human prostate carcinoma cell line (hit compound potency - 5.7 microM). Exploration of the two peripheral diversity vectors of the hit molecule in a hit-targeted library and testing of the resulting compounds led to SAR generalizations and identification of the 'best' pharmacophoric moieties. The latter were merged in a single compound that exhibited a 200-fold better potency than the original hit compound. Specific cancer cell cytotoxicity was confirmed for the most potent compounds.

Synthesis of 1-(4-trifluoromethoxyphenyl)-2,5-dimethyl-3-(2-R-thiazol-4-yl)-1H-pyrroles via chain heterocyclization.

The title compounds, (4-trifluoromethoxyphenyl)-2,5-dimethyl-3-(2-R-thiazol-4-yl)-1H-pyrroles, were prepared in four steps starting from commercially available 4-trifluoromethoxyaniline. The pyrrole (second ring) was added in one step using the Paal-Knorr method. The thiazole (third ring) was added in three steps using chloroacylation with chloroacetonitrile followed by heterocyclization with thioamides/thioureas.

Discovery and potency optimization of 2-amino-5-arylmethyl-1,3-thiazole derivatives as potential therapeutic agents for prostate cancer.

A new chemical series was identified via high-throughput screening as having antiproliferative activity on DU-145 human prostate carcinoma cell line (hit compound potency - 2.9 microM). Medicinal chemistry optimization of two peripheral diversity vectors of the hit molecule, independently, led to SAR generalizations and identification of the 'best' moieties. The latter were merged in a single compound that exhibited an over 100-fold better potency than the hit compound. For the most potent compounds it was confirmed that the observed antiproliferative potency was not associated with the compounds' non-specific cytotoxicity.

A Java chemical structure editor supporting the Modular Chemical Descriptor Language (MCDL).

A compact Modular Chemical Descriptor Language (MCDL) chemical structure editor (Java applet) is described. The small size (approximately 200 KB) of the applet allows its use to display and edit chemical structures in various Internet applications. The editor supports the MCDL format, in which structures are presented in compact canonical form and is capable of restoring bond orders as well as of managing atom and bond drawing overlap. A small database of cage and large cyclic fragment is used for optimal representation of difficult-to-draw molecules. The improved algorithm of the structure diagram generation can be used for other chemical notations that lack atomic coordinates (SMILES, InChI).

Thermodynamic rearrangement synthesis and NMR structures of C1, C3, and T isomers of C60H36.

The structures of three C60H36 isomers, produced by high-temperature transfer hydrogenation of C(60) in a 9,10-dihydroanthracene melt, was accomplished by 2D (1)H-detected NMR experiments, recorded at 800 MHz. The unsymmetrical C(1) isomer is found to be the most abundant one (60-70%), followed by the C(3) isomer (25-30%) and the least abundant T isomer (2-5%). All three isomers are closely related in structure and have three vicinal hydrogens located on each of the 12 pentagons. Facile hydrogen migration on the fullerene surface during annealing at elevated temperatures is believed to be responsible for the preferential formation of these thermodynamically most stable C60H36 isomers. This hypothesis was further supported by thermal conversion of C60H36 isomers to a single C(3v) isomer of C60H18.