Chisato Mukai

Investigation of the Role of Breast Cancer Resistance Protein (Bcrp/Abcg2) on Pharmacokinetics and Central Nervous System Penetration of Abacavir and Zidovudine in the Mouse

Many anti-human immunodeficiency virus 1 nucleoside reverse-transcriptase inhibitors have low central nervous system (CNS) distribution due in part to active efflux transport at the blood-brain barrier. We have previously shown that zidovudine (AZT) and abacavir (ABC) are in vitro substrates for the efflux transport protein breast cancer resistance protein (Bcrp) 1. We evaluated the influence of Bcrp1 on plasma pharmacokinetics and brain penetration of zidovudine and abacavir in wild-type and Bcrp1-deficient (Bcrp1-/-) FVB mice. There was no difference in either area under the concentration-time profiles for plasma (AUCplasma) or brain (AUCbrain) for zidovudine between the wild-type and Bcrp1-/- mice. The AUCplasma of abacavir was 20% lower in the Bcrp1-/- mice, whereas the AUCbrain was 20% greater. This difference resulted in a 1.5-fold increase in abacavir brain exposure in the Bcrp1-/- mice. The effect of selective and nonselective transport inhibitors on the ABC brain/plasma ratio at a single time point was evaluated. 3-(6-Isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6, 7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-3-yl)-propionicacid tert-butyl ester (Ko143), N[4[2-(6, 7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide (GF120918), probenecid, and Pluronic P85 increased abacavir plasma concentrations in the wild-type mice. Abacavir plasma concentrations in Bcrp1-/- mice were increased by (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo (a,e)cyclopropa(c)cycloheptan-6-yl)-α-((5-quinoloyloxy)methyl)-1-piperazineethanol trihydrochloride (LY335979), GF120918, and probenecid, but not by Ko143. Brain/plasma concentration ratios in both the wild-type and Bcrp1-/- mice were increased by the P-glycoprotein inhibitors LY335979 and GF120918, but not by BCRP-selective inhibitors. These data indicate that deletion of Bcrp1 has little influence on the pharmacokinetics or brain penetration of AZT. However, for abacavir, deletion of Bcrp1 reduces plasma exposure and enhances brain penetration. These findings suggest that Bcrp1 does not play a significant role in limiting the CNS distribution of zidovudine and abacavir; however, brain penetration of abacavir is dependent on P-glycoprotein-mediated efflux.

Rhodium(I)‐Catalyzed Intramolecular [5+2] Cycloaddition Reactions of Alkynes and Allenylcyclopropanes: Construction of Bicyclo[5.4.0]undecatrienes and Bicyclo[5.5.0]dodecatrienes

Highly strained cyclopropane derivatives have served as useful and powerful C3 building blocks [1] for the construction of various ring systems, and the metal-catalyzed cleavage of the activated carbon-carbon s bond of the cyclopropane ring 3] must be one of the most attractive methods from a synthetic point of view. Of particular interest is the Rhcatalyzed [5+2] cycloaddition of vinylcyclopropanes with carbon–carbon p-components for the efficient formation of seven-membered compounds. In 1995, Wender et al. reported the first example of the Rh-catalyzed [5+2] cycloaddition reaction of vinylcyclopropanes with alkynes to provide bicyclo[5.3.0]decadienes. This method was successfully applied to the [5+2] cycloaddition reactions of allenes as well as alkenes 4a] as an alternative carbon–carbon p-counterpart. In sharp contrast to the extensive investigation of vinylcyclopropanes, 3–5] very few examples of the ringclosing reaction of allenylcyclopropane, which is regarded as an alkylidene homologue of vinylcyclopropane, have been reported. Two representative examples are shown in Scheme 1; one involves the Rh-catalyzed cycloisomeriza-

ATP-Binding Cassette Transporter G2 Mediates the Efflux of Phototoxins on the Luminal Membrane of Retinal Capillary Endothelial Cells

PurposeThe purpose of this study was to clarify the localization and function of the ATP-binding cassette transporter G2 (ABCG2; BCRP/MXR/ABCP) in retinal capillary endothelial cells, which form the inner blood–retinal barrier, as an efflux transport system.MethodsThe expression was determined by reverse transcriptase polymerase chain reaction and Western blotting. The localization was identified by immunostaining. The transport function of ABCG2 was measured by flow cytometry.ResultsWestern blotting indicated that ABCG2 was expressed as a glycosylated disulfide-linked complex in the mouse retina and in peripheral tissues, including liver, kidney, and small intestine. Double immunolabeling of ABCG2 and glucose transporter 1 suggested that ABCG2 was localized on the luminal membrane of mouse retinal capillary endothelial cells. ABCG2 mRNA and protein were found to be expressed in a conditionally immortalized rat retinal capillary endothelial cell line, TR-iBRB, and rat retina. Treatment with Ko143, an ABCG2 inhibitor, restored the accumulation of pheophorbide a and protoporphyrin IX in TR-iBRB cells.ConclusionABCG2 is expressed on the luminal membrane of retinal capillary endothelial cells, where ABCG2 acts as the efflux transporter for photosensitive toxins such as pheophorbide a and protoporphyrin IX. ABCG2 could play an important role at the inner blood–retinal barrier in restricting the distribution of phototoxins and xenobiotics in retinal tissue.

Total syntheses of (-)- and (+)-goniomitine.

The Stille coupling reaction of 3-(benzyloxymethyl)-1-(tert-butyldiphenylsiloxy)ethyl-1-(tributylstannyl)allene with N-(tert-butoxycarbonyl)-2-iodoaniline directly produced the corresponding 2-vinylindole derivative, which was independently transformed into natural (-)-goniomitine and unnatural (+)-goniomitine via the cross-metathesis with chiral oxazolopiperidone lactams. The antiproliferative activity of the synthesized natural (-)-goniomitine in Mock and MDCK/MDR1 cells showed them to be more potent to retard cell growth than unnatural (+)-goniomitine.

Total Synthesis of (±)-Meloscine

The total synthesis of (±)-meloscine was completed in a highly stereoselective manner starting from the known 4-(2-aminophenyl)-2,3-dihydro-N-methoxycarbonylpyrrole. The crucial step in this total synthesis involves the efficient construction of the tetracyclic framework of the target natural product by the intramolecular Pauson-Khand reaction.

Regioselective and stereospecific formation of 2-ethynyl-3-hydroxytetrahydropyran derivatives via 6-endo ring closure

Abstract Efficient access to tetrahydropyran derivatives via highly regio- and stereoselective 6-endo tet mode ring opening of an epoxide by an internal hydroxy group has been developed. Cobalt complexes, derived from trans -4,5-epoxy-6-heptyn-1-ols and dicobalt octacarbonyl were treated with a catalytic amount of BF 3 ·OEt 2 in CH 2 Cl 2 at −78°C to afford cis -2-ethynyl-3-hydroxytetrahydropyran derivatives in a highly regio- and stereoselective manner. Similar treatment of cis -4,5-epoxides provided the corresponding trans -tetrahydropyrans selectively.

Rhodium(I)‐Catalyzed Intramolecular Carbonylative [2+2+1] Cycloaddition of Bis(allene)s: Bicyclo[6.3.0]undecadienones and Bicyclo[5.3.0]decadienones

No templates needed: The title reaction makes it easy to construct the bicyclo[6.3.0]undecadienone framework in high yields (see scheme). A template effect is not required to achieve this ring-closing reaction efficiently. The present method can be applied to the construction of bicyclo[5.3.0] and bicyclo[4.3.0] ring systems. Ts = p-toluenesulfonyl.

Studies on total syntheses of antitumor styryllactones: Stereoselective total syntheses of (+)-goniofufurone, (+)-goniobutenolide A, and (−)-goniobutenolide B

Abstract A highly stereoselective aldol reaction of the aldehyde 11, derived from (+)-tricarbonyl(η6-2-trimethylsilylbenzaldehyde)chromium(0) complex (4), with 2-trimethysilyloxyfuran afforded the γ-lactone derivative 13. The γ-lactone 13 was subsequently converted into three antitumor styryllactones, (+)-goniofufurone, (+)-goniobutenolide A, and (−)-goniobutenolide B.

Csp3–Csp3 and Csp3–H Bond Activation of 1,1-Disubstituted Cyclopentane

The unprecedented C(sp(3))-C(sp(3)) bond cleavage of unactivated cyclopentane has been achieved. Rh(I)-catalyzed cycloaddition of allenylcyclopentane-alkynes produced in situ the 9-cyclopentyl-8-rhodabicyclo[4.3.0]nona-1,6-diene intermediates, which subsequently underwent [7+2] cycloaddition via β-C elimination, affording bicyclo[7.4.0]tridecatriene derivatives in good yields. Changing the Rh(I) catalyst effected the Cγ-H bond activation of the common 9-cyclopentyl-8-rhodabicyclo[4.3.0]nona-1,6-diene intermediate to produce the novel spiro[2.4]heptane skeleton in a site-selective manner.

Formal synthesis of (+)-nakadomarin A.

The formal synthesis of (+)-nakadomarin A was completed. The significant points of this synthesis are the highly stereoselective formation of the diazatricyclo[6.4.0.0(1,5)]dodecane skeleton (A, B, and D rings) based on the Pauson-Khand reaction and novel furan ring (C ring) formation, using the vinyl residue of the Pauson-Khand product.