Divergent Cytotoxic and Metabolically Stimulative Functions of Sigma-2 Receptors: Structure-Activity Relationships of 6-Acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79) Derivatives.

Sigma-2 receptors, recently identified as TMEM97, have been implicated in cancer and neurodegenerative disease. Structurally distinct sigma-2 receptor ligands induce cell death in tumor cells, linking sigma-2 receptors to apoptotic pathways. Recently, we reported that sigma-2 receptors can also stimulate glycolytic hallmarks, effects consistent with a prosurvival function and upregulation in cancer cells. Both apoptotic and metabolically stimulative effects were observed with compounds related to the canonical sigma-2 antagonist SN79. Here we investigate a series of 6-substituted SN79 analogs to assess the structural determinants governing these divergent effects. Substitutions on the benzoxazolone ring of the core SN79 structure resulted in high-affinity sigma-2 receptor ligands (K i = 0.56-17.9 nM), with replacement of the heterocyclic oxygen by N-methyl (producing N-methylbenzimidazolones) generally decreasing sigma-1 affinity and a sulfur substitution (producing benzothiazolones) imparting high affinity at both subtypes, lowering subtype selectivity. Substitution at the 6-position with COCH3, NO2, NH2, or F resulted in ligands that were not cytotoxic. Five of these ligands induced an increase in metabolic activity, as measured by increased reduction of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) in human SK-N-SH neuroblastoma cells, further supporting a role for sigma-2 receptors in metabolism. Substitution with 6-isothiocyanate resulted in ligands that were sigma-2 selective and that irreversibly bound to the sigma-2 receptor, but not to the sigma-1 receptor. These ligands induced cell death upon both acute and continuous treatment (EC50 = 7.6-32.8 µM), suggesting that irreversible receptor binding plays a role in cytotoxicity. These ligands will be useful for further study of these divergent roles of sigma-2 receptors.

A focused library of protein tyrosine phosphatase inhibitors.

Protein tyrosine phosphatases such as PTP1B and YopH are potential targets for the development of therapeutic agents against a variety of pathological conditions including diabetes, obesity, and infection by the bacterium Yersinia pestis. A focused library of bidentate α-ketoacid-based inhibitors has been screened against several tyrosine phosphatases. Compound 2a has IC(50) values of 43 and 220 nM against YopH and PTP1B, respectively, and shows a 30-fold selectivity for PTP1B over the closely related phosphatase TCPTP.

The binding site of zinc and indium metal to amino acid derivatized squarate complexes - Implications in inhibitor and mediator designs.

Three novel metal squaric acid-peptide complexes, SQI-SQIII were prepared by addition of indium triflate or zinc chloride to the previously reported compounds [1], 3-(hydroxymethylamino)-4-(l-isoleucine methyl ester)-3-cyclobutene-1,2-dione (squarate 1), and 3-(hydroxymethylamino)-2-(l-isoleucine methyl ester)-4-thioxo-2-cyclobuten-1-one (squarate 2). The structures of SQI-SQIII were elucidated using NMR analysis. The electrochemical applications of two of these metal-squaric acid systems (SQI and SQII) were also investigated. Incorporation of SQII as a mediator, in the previously optimized Pt/p(HEMA)/p(pyrrole)/GOx electrode using the ionic liquid [bmim][BF(4)] as the solvent medium, produced a biosensor with enhanced properties, namely a sensitivity of 175.9mA/M d-glucose, working potential of +200mV, large linear range (0-12mM) and a detection limit of 1x10(-6)M.

Squaric acid-based peptidic inhibitors of matrix metalloprotease-1.

[structure: see text] A series of squaric acid-peptide conjugates were synthesized and evaluated as inhibitors of MMP-1. The cyclobut-3-enedione core was substituted at the 3-position with several functional groups, such as -N(alkyl)OH, -NHOH, and -OH, that are designed to bind to the zinc atom in the active site of the metalloprotease. The 4-position of the cyclobut-3-enedione was derivatized with mono- or dipeptides that are designed to bind in the S1' and S2' subsites of the enzyme, and position the metal chelating group appropriately in the active site for binding to zinc. Positional scanning revealed that -N(Me)OH provided the highest level of inhibition among the chelating groups that were tested, and Leu-Tle-NHMe was the preferred amino acid sequence. A combination of these groups yielded an inhibitor with an IC50 value of 95 microM. For one inhibitor, conversion of one of the carbonyl groups on the cyclobut-3-enedione core to a thiocarbonyl group resulted in a 18-fold increase in potency, and yielded a compound with an IC50 value of 15 microM.

Squaric acids: a new motif for designing inhibitors of protein tyrosine phosphatases.

[structure: see text] Protein tyrosine phosphatases (PTPases) are important targets in medicinal chemistry. These enzymes play a role in a number of human diseases, including type II diabetes and infection by Yersinia pestis, the causative agent of bubonic plague. Derivatives of squaric acids such as 2-aryl-1-hydroxycyclobut-1-ene-3,4-diones represent a new class of monoanionic inhibitors for PTPases.

Antibacterial activity of some Peruvian medicinal plants from the Callejon de Huaylas.

Extracts of eight medicinal plants from the Callejon de Huaylas in Peru were screened for antibacterial activity in eighteen bacterial strains by the agar-diffusion method; six of these were active against a variety of bacteria.