Search

Phosphonamide-based inhibitors were synthesized and evaluated for the inhibitory activities against the shedding of epidermal growth factors, amphiregulin and heparin-binding EGF-like growth factor, that would participate in the development of psoriasis. All compounds exhibited excellent inhibitory activities for these EGF sheddings; however, they also inhibited matrix metalloproteinases (MMPs). To avoid adverse effects reported by the clinical development of MMP inhibitors, the antedrug concept was introduced. Among the phosphonamide inhibitors, the 2,2,2-trifluoroethyl ester 8d and 2,2-difluoroethyl ester 8c showed rapid decomposition in human plasma, which is an essential property for the antedrug. Topical applications of these compounds significantly suppressed TPA-induced epidermal hyperplasia in murin skin, a model of psoriasis. These results suggested that the phosphonamide-based inhibitors have a therapeutic potential for the treatment of psoriasis as an antedrug application.

A series of phosphonamide-based hydroxamate derivatives were synthesized, and the inhibitory activities were evaluated against various metalloproteinases in order to clarify its selectivity profile. Among the four diastereomeric isomers resulting from the chirality at the C-3 and P atoms, the compound with a (R,R)-configuration both at the C-3 position and the phosphorus atom was found to be potently active, while the other diastereomeric isomers were almost inactive. A number of (R,R)-compounds synthesized here exhibited broad spectrum activities with nanomolar Ki values against MMP-1, -3, -9, and TACE and also showed nanomolar IC50 values against HB-EGF shedding in a cell-based inhibition assay. The modeling study using X-ray structure of MMP-3 suggested the possible binding mode of the phosphonamide-based inhibitors.

We measured reticulated platelets (RPs) and plasma glycocalicin (GC) and thrombopoietin (TPO) levels simultaneously in 107 thrombocytopenic patients to clarify the diagnostic value of these tests for discriminating hyperdestructive from hypoplastic thrombocytopenia. The percentage of RPs and GC index (plasma GC level normalized for the individual platelet count) were markedly elevated in patients with idiopathic thrombocytopenic purpura (ITP) but normal or slightly elevated in patients with aplastic anemia (AA) or chemotherapy-induced thrombocytopenia (ChemoT). For RP percentage for diagnosing hyperdestructive thrombocytopenia the sensitivity and specificity were excellent but were lower for the GC index. Absolute RP counts and plasma GC levels were markedly decreased and plasma TPO levels markedly elevated in patients with AA or ChemoT, but absolute RP counts and plasma GC levels were moderately decreased and plasma TPO levels only slightly elevated in patients with ITP. The sensitivity and specificity of plasma TPO levels for diagnosing hypoplastic thrombocytopenia were excellent. Using the RP percentage and plasma TPO levels in combination improved specificities. Simultaneous measurement of RP percentage and plasma TPO level may help discriminate thrombocytopenia of unknown cause in routine hematologic practice.

We describe a mimic of the sugar unit of the E-selectin ligand, sialyl Lewis X (sLe^X). Carbohydrates are entering the realm of rational drug design, aided by the growing understanding of the structure−function relationships. We investigated a new methodology of preparing sLe^X mimetics and developed a potent E-selectin blocker characterized by β-turn dipeptides. Another characteristic point of this E-selectin blocker is that the six-membered fucose ring was replaced with a five-membered fucose ring. Interestingly, it was found that the five-membered fucose ring could also bind to a calcium ion on the E-selectin, which could be an important role of the six-membered fucose ring. Especially, the l-Ser-d-Glu and d-Ser-l-Glu derivatives 3a,b showed 65−90-fold more potent inhibitory activities than the sulfated Le^X analogue 1. In addition, molecular dynamics (MD) studies indicated that the 2- and 3-OH groups of the six-membered fucose ring, which were necessary for the calcium binding, overlapped well with the 2- and 3-OH groups of the five-membered fucose ring. These new findings could be useful for the design of new types of selectin blockers.

We have rationally designed a sLe^x mimetic based on molecular modeling, synthesized type II and type II‘ β-turn dipeptides (3a,b), and evaluated their biological profiles both in vitro and in vivo. Against E-selectin−sLe^x binding, the type II β-turn dipeptide l-Ser-d-Glu 3a (IC50, 13 μM) and the type II‘ β-turn dipeptide d-Ser-l-Glu 3b (IC50, 5.5 μM) were 20−100-fold more potent blockers than sLe^x (1; IC50, 600 μM) and a 3‘-sulfated Le^x analog (2; IC50, 280 μM). On the other hand, other stereoisomers, such as l-Ser-l-Glu 3c and d-Ser-d-Glu 3d, were very weak blockers, with IC50 > 1000 μM for both 3c,d. Against the P- and L-selectins, despite much different stereochemistry of compounds 3a−d, the dipeptides 3a−d were all more potent blockers than either sLe^x or compound 2. Interestingly, compound 3b provided significant in vivo efficacy against an immunoglobulin E-mediated skin reaction in a mouse model. These findings indicate that sLe^x mimetics with type II and type II‘ β-turn dipeptides could be useful in the design of an active selectin blocker in vitro and/or in vivo.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The Pd(0)‐catalyzed reaction of 1,4‐difunctionalized butenes such as (I) with the ethylenediamine derivatives (II) yields the 2‐vinylpiperazines (III).

Cross‐coupling of the naphthyl‐MgBr (III) with the naphthyl bromide (II) in the presence of a Ni catalyst prepared in situ from NiBr2and the chiral ferrocenylphosphine (I) gives a high yield of the (R)‐binaphthyl (IV).

The triethoxyallylsilane (I) reacts with benzaldehyde (II) after activation to form mainly the erythro‐adduct (IIIa), together with minor parts of the threo‐isomer (IIIb).