Phosphonate derivatives of tetraazamacrocycles as new inhibitors of protein tyrosine phosphatases.

α,α-Difluoro-ß-ketophosphonated derivatives of tetraazamacrocycles were synthesized and found to be potential inhibitors of protein tyrosine phosphatases. N-Substituted conjugates of cyclam and cyclen with bioisosteric phosphonate groups displayed good activities toward T-cell protein tyrosine phosphatase with IC50 values in the micromolar to nanomolar range and showed selectivity over PTP1B, CD45, SHP2, and PTPß. Kinetic studies indicated that the inhibitors can occupy the region of the active site of TC-PTP. This study demonstrates a new approach which employs tetraazamacrocycles as a molecular platform for designing inhibitors of protein tyrosine phosphatases.

Design and synthesis of new potent inhibitors of farnesyl pyrophosphate synthase.

Predictive QSAR models for the inhibition activities of nitrogen-containing bisphosphonates (N-BPs) against farnesyl pyrophosphate synthase (FPPS) from Leishmania major (LeFPPS) were developed using a data set of 97 compounds. The QSAR models were developed through the use of Artificial Neural Networks and Random Forest learning procedures. The predictive ability of the models was tested by means of leave-one-out cross-validation; Q(2)values ranging from 0.45-0.79 were obtained for the regression models. The consensus prediction for the external evaluation set afforded high predictive power (Q(2)=0.76 for 35 compounds). The robustness of the QSAR models was also evaluated using a Y-randomization procedure. A small set of 6 new N-BPs were designed and synthesized applying the Michael reaction of tetrakis (trimethylsilyl) ethenylidene bisphosphonate with amines. The inhibition activities of these compounds against LeFPPS were predicted by the developed QSAR models and were found to correlate with their fungistatic activities against Candida albicans. The antifungal activities of N-BPs bearing n-butyl and cyclopropyl side chains exceeded the activities of Fluconazole, a triazole-containing antifungal drug. In conclusion, the N-BPs developed here present promising candidate drugs for the treatment of fungal diseases.

Methylidynetrisphosphonates: Promising C1 building block for the design of phosphate mimetics.

Methylidynetrisphosphonates are representatives of geminal polyphosphonates bearing three phosphonate (PO3H2) groups at the bridged carbon atom. Like well-known methylenebisphosphonates (BPs), they are characterized by a P-C-P backbone structure and are chemically stable mimetics of the endogenous metabolites, i.e., inorganic pyrophosphates (PPi). Because of its analogy to PPi and an ability to chelate metal ions, the 1,1,1-trisphosphonate structure is of great potential as a C1 building block for the design of phosphate mimetics. The purpose of this review is to present a concise summary of the state of the art in trisphosphonate chemistry with particular emphasis on the synthesis, structure, reactions, and potential medicinal applications of these compounds.

Persistent phosphinyl radicals featuring a bulky amino substituent and the 2,6-bis(trifluoromethyl)phenyl group.

Persistent phosphinyl radicals featuring the 2,6-bis(trifluoromethyl)phenyl group were prepared and characterized. Their electronic structure was theoretically investigated, and their low-temperature dimerization into the corresponding diphosphines was found to be strongly inhibited when the sterically very demanding (tert-butyl)(trimethylsilyl)amino substituent was used.

Mono- and diaminocarbenes from chloroiminium and -amidinium salts: synthesis of metal-free bis(dimethylamino)carbene.

Bis(trimethylsilyl)mercury cleanly reacts at low temperature with chloroamidinium and -iminium chlorides, generating persistent metal-free cyclic and acyclic diaminocarbenes, as well as transient aryl-, chloro-, and hydrogenoaminocarbenes; with the latter, the corresponding olefin dimers were isolated, whereas with the former, no dimerization processes were observed.