Synthesis and anticancer activity of some 5-fluoro-2'-deoxyuridine phosphoramidates.

Two series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3'-O-(t-butoxycarbonyl)-5-fluoro-2'-deoxyuridine (3'-BOC-FdU) (9a-9j) and 5-fluoro-2'-deoxyuridine (FdU) (10a-10j) were synthesized by means of phosphorylation of 3'-BOC-FdU (4) with 4-chlorophenyl phosphoroditriazolide (7), followed by a reaction with the appropriate amine. Phosphoramidates 9a-9j were converted to the corresponding 10a-10j by removal of the 3'-t-butoxycarbonyl protecting group (BOC) under acidic conditions. The synthesized phosphoramidates 9a-9j and 10a-10j were evaluated for their cytotoxic activity in five human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), liver (HepG2), osteosarcoma (143B) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Two phosphoramidates 9b and 9j with the N-ethyl and N-(methoxy-(S)-alaninyl) substituents, respectively, displayed remarkable activity in all the investigated cancer cells, and the activity was considerably higher than that of the parent nucleoside 4 and FdU. Among phosphoramidates 10a-10j compound 10c with the N-(2,2,2-trifluoroethyl) substituent showed the highest activity. Phosphoramidate 10c was more active than the FdU in all the cancer cell lines tested.

The minimal pharmacophore for silent agonism of the α7 nicotinic acetylcholine receptor.

The minimum pharmacophore for activation of the human α7 nicotinic acetylcholine receptor (nAChR) is the tetramethylammonium cation. Previous work demonstrated that larger quaternary ammonium compounds, such as diethyldimethylammonium or 1-methyl quinuclidine, were α7-selective partial agonists, but additional increase in the size of the ammonium cation or the quinuclidine N-alkyl group by a single carbon to an N-ethyl group led to a loss of efficacy for ion channel activation. We report that although such compounds are ineffective at inducing the normal channel open state, they nonetheless regulate the induction of specific conformational states normally considered downstream of channel activation. We synthesized several panels of quaternary ammonium nAChR ligands that systematically varied the size of the substituents bonded to the central positively charged nitrogen atom. In these molecular series, we found a correlation between the molecular volume of the ligand and/or charge density, and the receptor's preferred distribution among conformational states including the closed state, the active state, a nonconducting state that could be converted to an activated state by a positive allosteric modulator (PAM), and a PAM-insensitive nonconducting state. We hypothesize that the changes of molecular volume of an agonist's cationic core subtly impact interactions at the subunit interface constituting the orthosteric binding site in such a way as to regulate the probability of conversions among the conformational states. We define a new minimal pharmacophore for the class of compounds we have termed "silent agonists," which are able to induce allosteric modulator-dependent activation but not the normal activated state.

Synthesis and evaluation of a conditionally-silent agonist for the α7 nicotinic acetylcholine receptor.

We introduce the term 'silent agonists' to describe ligands that can place the α7 nicotinic acetylcholine receptor (nAChR) into a desensitized state with little or no apparent activation of the ion channel, forming a complex that can subsequently generate currents when treated with an allosteric modulator. KC-1 (5'-phenylanabaseine) was synthesized and identified as a new silent agonist for the α7 nAChR; it binds to the receptor but does not activate α7 nAChR channel opening when applied alone, and its agonism is revealed by co-application with the type II positive allosteric modulator PNU-120596 in the Xenopus oocyte system. The concise synthesis was accomplished in three steps with the C-C bonds formed via Pd-catalyzed mono-arylation and organolithium coupling with N-Boc piperidinone. Comparative structural analyses indicate that a positive charge, an H-bond acceptor, and an aryl ring in a proper arrangement are needed to constitute one class of silent agonist for the α7 nAChR. Because silent agonists may act on signaling pathways not involving ion channel opening, this class of α7 nAChR ligands may constitute a new alternative for the development of α7 nAChR therapeutics.

Synthetic studies on the solanacol ABC ring system by cation-initiated cascade cyclization: implications for strigolactone biosynthesis.

We report a new method for constructing the ABC ring system of strigolactones, in a single step from a simple linear precursor by acid-catalyzed double cyclization. The reaction proceeds with a high degree of stereochemical control, which can be qualitatively rationalized using DFT calculations. Our concise synthetic approach offers a new model for thinking about the (as yet) unknown chemistry that is employed in the biosynthetic pathways leading to this class of plant hormones.