Influence of N-arylsulfonamido d-valine N-substituents on the selectivity and potency of matrix metalloproteinase inhibitors.

To develop matrix metalloproteinase inhibitors (MMPIs) for both therapy and medicinal imaging by fluorescence-based techniques or positron-emission tomography (PET), a small library of eighteen N-substituted N-arylsulfonamido d-valines were synthesized and their potency to inhibit two gelatinases (MMP-2, and MMP-9), two collagenases (MMP-8, and MMP-13) and macrophage elastase (MMP-12) was determined in a Structure-Activity-Relation study with ({4-[3-(5-methylthiophen-2-yl)-1,2,4-oxadiazol-5-yl]phenyl}sulfonyl)-d-valine (1) as a lead. All compounds were shown to be more potent MMP-2/-9 inhibitors (nanomolar range) compared to other tested MMPs. This is a remarkable result considering that a carboxylic acid group is the zinc binding moiety. The compound with a terminal fluoropropyltriazole group at the furan ring (P1' substituent) was only four times less potent in inhibiting MMP-2 activity than the lead compound 1, making this compound a promising probe for PET application (after using a prosthetic group approach to introduce fluorine-18). Compounds with a TEG spacer and a terminal azide or even a fluorescein moiety at the sulfonylamide N atom (P2' substituent) were almost as active as the lead structure 1, making the latter derivative a suitable fluorescence imaging tool.

New in Vivo Compatible Matrix Metalloproteinase (MMP)-2 and MMP-9 Inhibitors.

Matrix metalloproteinases (MMPs) are emerging as pivotal fine-tuners of cell function in tissue homeostasis and in various pathologies, in particular inflammation. In vivo monitoring of the activity of specific MMPs, therefore, provides high potential for assessing disease progression and tissue function, and manipulation of MMP activity in tissues and whole organisms may further provide a mode of controlling pathological processes. We describe here the synthesis of novel fluorinated and nonfluorinated analogues of a secondary sulfonamide-based lead structure, compound 2, and test their efficacy as in vivo inhibitors and tracers of the gelatinases, MMP-2 and MMP-9. Using a murine neuroinflammatory model, we show that compound 2 is a highly effective in vivo inhibitor of both MMP-2 and MMP-9 activity with little or no adverse effects even after long-term daily oral administration. A fluorescein-labeled derivative compound 17 shows direct binding to activated gelatinases surrounding inflammatory cuffs in the neuroinflammation model and to pancreatic ß-cells in the islets of Langerhans, colocalizing with MMP-2 and MMP-9 activity as detected using in situ zymography techniques. These results demonstrate that compound 2 derivatives have potential as in vivo imaging tools and for future development for specific MMP-2 versus MMP-9 probes. Our chemical modifications mainly target the residues directed toward the S1' and S2' pockets and, thereby, provide new information on the structure-activity relationships of this inhibitor type.

Synthesis of α-(Pentafluorosulfanyl)- and α-(Trifluoromethyl)-Substituted Carboxylic Acid Derivatives by Ireland-Claisen Rearrangement.

Earlier studies have shown that [3,3]-sigmatropic rearrangements of allyl esters are useful for the construction of fluorine-containing carboxylic acid derivatives. This paper describes the synthesis of 3-aryl-pent-4-enoic acid derivatives bearing either a pentafluorosulfanyl (SF5) or a trifluoromethyl (CF3) substituent in the 2-position by treatment of corresponding SF5- or CF3-acetates of p-substituted cinnamyl alcohols with triethylamine followed by trimethylsilyl triflate (TMSOTf). This Ireland-Claisen rearrangement delivered approximate 1:1 mixtures of syn/anti diastereoisomers due to tiny differences (<0.5 kcal/mol) both in the energy of (Z)/(E)-isomeric ester enolates and in the alternative Zimmerman-Traxler transition states of model compounds as shown by DFT calculations. Acidic reaction conditions have to be avoided since addition of the reagents in opposite sequence (first TMSOTf then Et3N) led to oligomerization of the cinnamyl SF5- and CF3-acetates. Treatment of the corresponding regioisomeric 1-phenyl-prop-2-en-1-yl acetates under the latter conditions resulted in [1,3]-sigmatropic rearrangement and subsequent oligomerization of the intermediately formed cinnamyl esters. When Et3N was added first followed by TMSOTf, no further reaction of the formed ester was detected.

Fluorinated matrix metalloproteinases inhibitors--Phosphonate based potential probes for positron emission tomography.

Fluorine-containing inhibitors of matrix metalloproteinases (MMPs) can serve as lead structures for the development of (18)F-labeled radioligands. These compounds might be useful as non-invasive imaging probes to characterize pathologies associated with increased MMP activity. Results with a series of fluorinated analogs of a known biphenyl sulfonamide inhibitor have shown that fluorine can be incorporated into two different positions of the molecular scaffold without significant loss of potency in the nanomolar range. Additionally, the potential of a hitherto unknown fluorinated tertiary sulfonamide as MMP inhibitor has been demonstrated.

Correction: perfluoropropenyl-containing phosphines from HFC replacements.

Correction for 'Perfluoropropenyl-containing phosphines from HFC replacements' by Alan K. Brisdon et al., Dalton Trans., 2015, DOI: 10.1039/c5dt02043c.

Perfluoropropenyl-containing phosphines from HFC replacements.

A series of new perfluoropropenyl-containing phosphines of the type R3-nP(E-CF[double bond, length as m-dash]CFCF3)n (R = Ph, iPr, n = 1, 2; R = tBu, n = 2) have been prepared from the reaction of the hydrofluoroolefin Z-CF3CF[double bond, length as m-dash]CFH (HFO-1225ye) with base and the appropriate chlorophosphine, while reaction with Cl2PCH2CH2PCl2 gave (CF3CF[double bond, length as m-dash]CF)2PCH2CH2P(CF[double bond, length as m-dash]CFCF3)2, the first example of a bidentate perfluoroalkenyl-containing phosphine. An alternative route to these phosphines based on the room- or low-temperature deprotonation of CF3CF2CH2F (HFC-236ea) gives mainly the E-isomer, but also a small amount of the Z-isomer, the ratio of which depends on the reaction temperature. All of the phosphines could be readily oxidised with either H2O2 or urea·H2O2, and the phosphine selenides R3-nP(Se)(E-CF[double bond, length as m-dash]CFCF3)n (R = Ph, n = 1,2; R = iPr, n = 1; R = tBu, n = 2) were also prepared. The steric and electronic properties of these ligands were determined based on their platinum(ii), palladium(ii) and molybdenum carbonyl complexes. The crystal structures of (CF3CF[double bond, length as m-dash]CF)2PCH2CH2P(CF[double bond, length as m-dash]CFCF3)2, (CF3CF[double bond, length as m-dash]CF)2P(O)CH2CH2P(O)(CF[double bond, length as m-dash]CFCF3)2, iPr2P(Se)(CF[double bond, length as m-dash]CFCF3)2, trans-[PtCl2{Ph(3-n)P(E-CF[double bond, length as m-dash]CFCF3)n}2] (n = 1 or 2), trans-[PdCl2{R2P(E-CF[double bond, length as m-dash]CFCF3)}2] (R = Ph, iPr) and [Mo(CO)4{(CF3CF[double bond, length as m-dash]CF)2PCH2CH2P(CF[double bond, length as m-dash]CFCF3)2}] are reported.

Rotational dependence of the proton-transfer reaction HBr+ + CO2 → HOCO+ + Br. II. Comparison of HBr+ (2Π(3/2)) and HBr+ (2Π(1/2)).

The effects of reactant ion rotational excitation on the exothermic proton-transfer reactions of HBr(+)((2)Π(1/2)) and DBr(+)((2)Π(1/2)), respectively, with CO(2) were studied in a guided ion beam apparatus. Cross sections are presented for collision energies in the center of mass system E(c.m.) in the range of 0.23 to 1.90 eV. The HBr(+)/DBr(+) ions were prepared in a state-selective manner by resonance enhanced multiphoton ionization. The mean rotational energy was varied from 3.4 to 46.8 meV for HBr(+)((2)Π(1/2)) and from 1.8 to 40.9 meV for DBr(+)((2)Π(1/2)). Both reactions studied are inhibited by collision energy, as expected for exothermic reactions. For all collision energies considered, the cross section decreases with increasing rotational energy of the ion, but the degree of the rotational dependence differs depending on the collision energy. For E(c.m.) = 0.31 eV, the cross sections of the deuteron transfer are significantly larger than those of the proton transfer. For higher E(c.m.) they differ very little. The current results for the exothermic proton transfer are systematically compared to previously published data for the endothermic proton transfer starting from HBr(+)((2)Π(3/2)) [L. Paetow et al., J. Chem. Phys. 132, 174305 (2010)]. Additional new data regarding the latter reaction are presented to further confirm the conclusions. The dependences on rotational excitation found cannot be explained by the corresponding change in the total energy of the system. For both the endothermic and the exothermic reaction, the cross section is maximized for the smallest rotational energy, at least well above the threshold.