Hiroshi Kosugi

Inhibition of inflammatory actions of aminobisphosphonates by dichloromethylene bisphosphonate, a non‐aminobisphosphonate

When injected intraperitoneally into mice in doses larger than those used clinically, all the amino derivatives of bisphosphonates (aminoBPs) tested induce a variety of inflammatory reactions such as induction of histidine decarboxylase (HDC, the histamine‐forming enzyme), hypertrophy of the spleen, atrophy of the thymus, hypoglycaemia, ascites and accumulation of exudate in the thorax, and an increase in the number of macrophages and/or granulocytes in the peritoneal cavity of blood. On the other hand, dichloromethylene bisphosphonate (Cl2MBP) a typical non‐aminoBP, has no such inflammatory actions. In the present study, we found that this agent can suppress the inflammatory actions of aminoBPs. Cl2MBP, when injected into mice before or after injection of 4‐amino‐1‐hydroxybutylidene‐1,1‐bisphosphonic acid (AHBuBP; a typical aminoBP), inhibited the induction of HDC activity by AHBuBP in a dose‐ and time‐dependent manner. The increase in HDC activity induced by AHBuBP was largely suppressed by the injection of an equimolar dose of Cl2MBP. Cl2MBP also inhibited other AHBuBP‐induced inflammatory reactions, as well as the inflammatory actions of two other aminoBPs. However, Cl2MBP did not inhibit the increase in HDC activity induced by lipopolysaccharide (LPS). We have previously reported that AHBuBP augments the elevation of HDC activity and the production of interleukin‐1β (IL‐1β) that are induced by LPS. These actions of AHBuBP were also inhibited by Cl2MBP. Based on these results and reported actions of bisphosphonates, the mechanisms underlying the contrasting effects of aminoBPs and Cl2MBP, a non‐aminoBP are discussed. The results suggest that combined administration of Cl2MBP and an aminoBP in patients might be a useful way of suppressing the inflammatory side effects of aminoBPs.

Contrasting effects of an aminobisphosphonate, a potent inhibitor of bone resorption, on lipopolysaccharide‐induced production of interleukin‐1 and tumour necrosis factor α in mice

1 Aminobisphosphonates (aminoBPs), potent inhibitors of bone resorption, have been reported to induce inflammatory reactions such as fever and an increase in acute phase proteins in human patients, and to induce the histamine‐forming enzyme, histidine decarboxylase, in mice. In the present study, we examined the effect of aminoBP, 4‐amino‐1‐hydroxybutylidene‐1,1‐bisphosphonic acid (AHBuBP), on the production of the pro‐inflammatory cytokines, IL‐1 and TNFα, in mice. 2 Intraperitoneal injection of AHBuBP did not itself produce detectable levels of IL‐1 (α and β) and TNFα in the serum. However, the elevation of serum IL‐1 induced by lipopolysaccharide (LPS) was greatly augmented in mice injected with AHBuBP 3 days before the LPS injection, whereas the LPS‐induced elevation of serum TNFα was almost completely abolished. 3 Spleen and bone marrow cells taken from mice injected with AHBuBP produced IL‐1β in vitro spontaneously, and the production was augmented following the addition of LPS. Cells that accumulated in the peritoneal cavity in response to AHBuBP produced a particularly large amount of IL‐1β. However, AHBuBP treatment of mice did not lead to an impairment of the in vitro production of TNFα by these three types of cells. 4 Liposomes encapsulating dichloromethylene bisphosphonate (a non‐amino BP) selectively deplete phagocytic macrophages. When an intraperitoneal injection of these liposomes was given 2 days after an injection of AHBuBP, there was a marked decrease in the LPS‐induced elevation of serum IL‐1 (α and β) (LPS being injected 3 days after the injection of AHBuBP). 5 These results indicate that AHBuBP has contrasting effects on the in vivo LPS‐induced production of IL‐1 and TNFα in mice, enhancing the production of IL‐1 by phagocytic macrophages and suppressing the production of TNFα, although underling mechanisms remain to be clarified.

Highly diastereoselective reduction of chiral β-ketosulphoxides under chelation control: application to the synthesis of (R)-(+)-n-hexadecano-1,5-lactone

The presence of zinc chloride in the reduction of chiral β-ketosulphoxides with di-isobutylaluminium hydride effects high 1,3-asymmetric induction to give β-hydroxysulphoxides; this method can be successfully applied to the synthesis of optically pure 1,4- or 1,5-lactones.

Highly enantiofacial protonation of prochiral lithium enolates with chiral β-hydroxy sulfoxides

Abstract Highly enantioselective protonation of prochiral lithium enolates is disclosed. The present method employed ( S,R s )-CF 3 -hydroxy sulfoxide (3b) as the chiral protonating agent, and the protonation of lithium enolates of cyclohexanone derivatives with 3b proceeded with high enantioselectivities.

A time kinetic study of the effect of aminobisphosphonate on murine haemopoiesis

We previously showed that aminobisphosphonates (aminoBPs), potent inhibitors of bone resorption, increased the number of osteoclasts and granulocytes, and enhanced the cell size of osteoclasts in vivo, indicating that aminoBPs have a profound effect on murine haemopoiesis. The possible effect of an aminoBP (4‐amino‐1‐hydroxybutylidene‐1,1‐bisphosphonate; AHBuBP) on murine haemopoiesis in vivo was examined in more detail. Macroscopically, AHBuBP induced the whitened bone marrow (BM) and splenomegaly. Flow cytometric analysis indicated that in BM, AHBuBP reduced the number of mature monocyte‐macrophage lineage cells and erythroid cells 1 and 2 d after treatment, respectively, whereas it enhanced granulopoiesis on day 4. In the spleen, both erythropoiesis and granulopoiesis were significantly increased. BM haemopoietic progenitors of granulocyte lineage and of monocyte‐macrophage lineage (CFU‐G, CFU‐M and CFU‐GM) were well maintained by the injection of AHBuBP, and even a small increment in these progenitors was observed 2–4 d after treatment. Immunohistochemical examination of BM demonstrated that residential macrophages of erythroblastic islands disappeared. Increased numbers of osteoclasts, as well as enlarged cell size, was confirmed up to 7 d after the treatment, implicating that the inhibition of bone resorption was not due to the reduced generation of osteoclasts by AHBuBP. These results suggest (1) that AHBuBP treatment in vivo rapidly deleted mature residential macrophages from BM, (2) that mature macrophages once deleted did not reappear even when CFU‐M and CFU‐GM increased in number and the number of Mac‐1+/Gr‐1− cells recovered to normal, (3) that BM erythropoiesis was significantly decreased due to the lack of erythroblastic islands, and (4) that compensatory erythropoiesis was evoked in the spleen to induce splenomegaly.

Generation of 3-Carbanion Species from 3-Phenylsulfinyl- and 3-Phenylsulfonyl Propionic Acids

Abstract During the course of studies on butenolide synthesis1 we have investigated the utilities of 3-sulfur-functionalized propionic acid derivatives. We report the results with 3-carbanion species obtained from 3-phenylsulfiny1- and 3-phenylsulfonylpropionic acids (1) and (2). These compounds were easily prepared from 3-phenylthiopropionic acid.

New route to enantiomerically pure 4,4-Disubstituted cyclohex-2-en-1-ones: Asymmetric synthesis of (+)-mesembrine

Abstract Enantiomerically pure β,β-disubstituted vinyl sulfoxides undergo cycloaddition with dichloroketene to give β,β-disubstituted γ-lactones which are transformed into synthetically important 44-disubstituted cyclohex-2-enones in optically pure form. The present method is applied to the synthesis of enantiomerically pure (+)-mesembrine.

Highly enantioselective rearrangement of (S)-E-α-p-tolysulphinyl-α,β-enoates to (R)-E-γ-hydroxy-α,β-enoates

On treatment with pyridine–camphorsulphonic acid, (S)-E-α-p-tolysulphinyl-α-β-enoates (4) undergo enantio-selectively a sequential prototropic shift and allylic sulphoxide–sulphenate rearrangement to produce (R)-E-γ-hydroxy-α,β-enoates (2) in 64–72% optical purity.

Reactions of the α-carbanion species of (phenylthio)acetic acid and its ester with carbonyl compounds

Reactions of the (phenylthio)acetic acid dianion (2) and its ester monoanion (3) with carbonyl compounds are described. Both the carbanions (2) and (3) react well with saturated aldehydes and ketones to give the α-(1-hydroxyalkyl) substituted derivatives in excellent yields. In the reaction with conjugated enones, the dianion (2) undergoes exclusive 1,2-addition, while the monoanion (3) gives 1,4-addition. Reaction of the dianion (2) with saturated esters produces directly phenylthiomethyl ketones through decarboxylation of the intermediates, whereas the reaction with αβ-unsaturated esters was found to be unsatisfactory. On the other hand, unlike the reaction with saturated esters, the reaction of the monoanion (3) with αβ-unsaturated esters proceeds well to yield 1,4-addition products.

Highly stereospecific conversion of C-centrochirality of a 3,4-dihydro-2H-1,1′-binaphthalen-1-ol into axial chirality of a 3,4-dihydro-1,1′-binaphthalene

Abstract C -Centrochirality of 3,4-dihydro-2′-methoxy-2-methyl-2 H -1,1′-binaphthalen-1-ol ( R , R )- 3e , which had been prepared by diastereoselective 1,2-addition of a 2-methoxy-1-naphthylytterbium reagent to 2-methyl-1-tetralone ( R )- 1b , was stereospecifically converted into axial chirality of 3,4-dihydro-2′-methoxy-2-methyl-1,1′-binaphthalene (a R )- 4 with up to 95% ee by dehydration with trifluoroacetic anhydride. DDQ aromatization of (a R )- 4 gave 2′-methoxy-2-methyl-1,1′-binaphthalene (a R )- 5 without appreciable loss of the axial integrity. The net process provides a potential access to nonracemic 1,1′-binaphthalenes.