Keiko Yamamoto

Showa Pharmaceutical University, Machida, Tōkyō, Japan

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Publications (84)300.43 Total impact

  • Keiko Yamamoto, Yasuaki Anami, Toshimasa Itoh
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    ABSTRACT: The first determination of the X-ray crystal structure of the ligand binding domain (LBD) of the vitamin D receptor (VDR) complexed with 1α,25-dihydroxyvitamin D3 was reported in 2000. Since then several dozen crystal structures of VDR accommodating various ligands have been presented. Almost all of these complexes display the canonical active conformation observed in the VDR-LBD/1α,25- dihydroxyvitamin D3 complex, and all have quite similar ligand binding pocket (LBP) architectures. To develop new VDR ligands as therapeutic agents, it is important to separate the various biological activities of 1α,25- dihydroxyvitamin D3, such as calcium regulation, cell differentiation and anti-proliferation, and immune modulation. We focused on the structure of the LBP and discovered that vitamin D analogs with a branched side chain induce structural rearrangement of the amino acid residues lining the LBP. These analogs formed an additional cavity in the LBP for accommodation of the side chain and thus altered the structure of the LBP. Interestingly, the ligands showed agonistic, partial agonistic, or antagonistic activity depending upon the structure of the side chain. These results indicate that ligands which alter the pocket structure open a new perspective for the development of VDR ligands exhibiting a specific biological activity.
    Current Topics in Medicinal Chemistry 11/2014; 14(21). · 3.45 Impact Factor
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    ABSTRACT: Polychlorinated dibenzo-p-dioxins (PCDDs) and coplanar polychlorinated biphenyls (PCBs) contribute to dioxin toxicity in humans and wildlife after bioaccumulation through the food chain from the environment. The authors examined human and rat cytochrome P450 (CYP)-dependent metabolism of PCDDs and PCBs. A number of human CYP isoforms belonging to the CYP1 and CYP2 families showed remarkable activities toward low-chlorinated PCDDs. In particular, human CYP1A1, CYP1A2, and CYP1B1 showed high activities toward monoCDDs, diCDDs, and triCDDs but no detectable activity toward 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-tetraCDD). Large amino acids located at putative substrate-recognition sites and the F-G loop in rat CYP1A1 contributed to the successful metabolism of 2,3,7,8-tetraCDD. Rat, but not human, CYP1A1 metabolized 3,3',4,4',5-pentachlorobiphenyl (CB126) to two hydroxylated metabolites. These metabolites are probably less toxic than is CB126, due to their higher solubility. Homology models of human and rat CYP1A1s and CB126 docking studies indicated that two amino acid differences in the CB126-binding cavity were important for CB126 metabolism. In this review, the importance of CYPs in the metabolism of dioxins and PCBs in mammals and the species-based differences between humans and rats are described. In addition, the authors reveal the molecular mechanism behind the binding modes of dioxins and PCBs in the heme pocket of CYPs.
    International Journal of Molecular Sciences 08/2014; 15(8):14044-14057. · 2.34 Impact Factor
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    ABSTRACT: We are continuing to study the structural basis of vitamin D receptor (VDR) agonism and antagonism by using 22S-alkyl vitamin D analogues. Here we report the synthesis and biological evaluation of 22R-alkyl analogues and the X-ray crystallographic analysis of vitamin D receptor ligand-binding domain (VDR-LBD) complexed with a 22R-analogue. VDR-LBD complexed with the partial agonist 8a showed that 8a binds to VDR-LBD with two conformations, one of which is the antagonist/VDR-LBD complex structure and the other is the agonist/VDR-LBD complex structure. The results indicate that the partial agonist activity of 8a depends on the sum of antagonistic and agonistic activities caused by the antagonist and agonist binding conformers, respectively. The structural basis observed here must be applicable to the partial agonism of other ligand-dependent nuclear receptors. This is the first report describing the trapping of a conformational subset of the ligand and the nuclear receptor in a single crystal.
    Journal of Medicinal Chemistry 04/2014; · 5.48 Impact Factor
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    ABSTRACT: The potency of 25-hydroxyvitamin D3 (25(OH)D3 ) is increased by several fold through its metabolism into 1α,25-dihydroxyvitamin D3 (1α,25(OH)2 D3 ) by cytochrome P450 27B1 (CYP27B1). Thus, the pivotal role of 1α-hydroxylation in the activation of vitamin D compounds is well known. Here, we examined the metabolism of 25-hydroxy-16-ene-23-yne-vitamin D3 (25(OH)-16-ene-23-yne-D3 ), a synthetic analog of 25(OH)D3 in a cell-free system and demonstrated that 25(OH)-16-ene-23-yne-D3 is neither activated by cytochrome CYP27B1 nor inactivated by cytochrome P450 24A1 (CYP24A1). These findings were also confirmed in immortalized normal human prostate epithelial cells (PZ-HPV-7) which are known to express both CYP27B1 and CYP24A1, indicating that the structural modifications featured in 25(OH)-16-ene-23-yne-D3 enable the analog to resist the actions of both CYP27B1 and CYP24A1. To provide intelligible structure-function information, we also performed molecular docking analysis between the analog and CYP27B1. Furthermore, 25(OH)-16-ene-23-yne-D3 was found to suppress the growth of PZ-HPV-7 cells with a potency equivalent to 1α,25(OH)2 D3 . The antiproliferative activity of 25(OH)-16-ene-23-yne-D3 was found to be vitamin D receptor (VDR)-dependent as it failed to inhibit the growth of mammary tumor cells derived from VDR-knockout mice. Furthermore, stable introduction of VDR into VDR-knockout cells restored the growth inhibition by 25(OH)-16-ene-23-yne-D3 . Thus, we identified 25-hydroxy-16-ene-23-yne-vitamin D3 as a novel non-1α-hydroxylated vitamin D analog which is equipotent to 1α,25(OH)2 D3 in its antiproliferative activity. We now propose that the low potency of the intrinsic VDR-mediated activities of 25(OH)D3 can be augmented to the level of 1α,25(OH)2 D3 without its activation through 1α-hydroxylation by CYP27B1, but by simply preventing its inactivation by CYP24A1. J. Cell. Biochem. 9999: XX-XX, 2014. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 02/2014; · 3.37 Impact Factor
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    ABSTRACT: Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) is a zinc-containing carboxypeptidase and significantly inhibits fibrinolysis. TAFIa inhibitors are thus expected to act as profibrinolytic agents. We recently reported the design and synthesis of selenium-containing inhibitors of TAFIa and their inhibitory activity. Here we report the crystal structures of potent selenium-, sulfur- and phosphinic acid-containing inhibitors bound to porcine pancreatic carboxypeptidase B (ppCPB). ppCPB is a TAFIa homolog and is surrogate TAFIa for crystallographic analysis. Crystal structures of ppCPB complexed with selenium compound 1a, its sulfur analog 2 and phosphinic acid derivative EF6265 were determined at 1.70, 2.15 and 1.90 Å resolution, respectively. Each inhibitor binds to the active site of ppCPB in a similar manner to that observed for previously reported inhibitors. Thus, in complexes, selenium, sulfur and phosphinic acid oxygen coordinate to zinc in ppCPB. This is the first observation and report of selenium coordinating to zinc in CPB.
    Journal of Medicinal Chemistry 09/2013; · 5.48 Impact Factor
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    ABSTRACT: Increasing evidence has accumulated to suggest that vitamin D may reduce the risk of cancer through its biologically active metabolite, 1α,25(OH)2D3, which inhibits proliferation and angiogenesis, induces differentiation and apoptosis, and regulates many other cellular functions. Thus, it is plausible to assume that rapid clearance of 1α,25(OH)2D3 by highly expressed CYP24A1 could interrupt the normal physiology of cells and might be one cause of cancer initiation and progression. In fact, enhancement of CYP24A1 expression has been reported in literature for many cancers. Based on these findings, CYP24A1-specific inhibitors and vitamin D analogs which are resistant to CYP24A1-dependent catabolism might be useful for cancer treatment. CYP24A1-specific inhibitor VID400, which is an azole compound, markedly enhanced and prolonged the antiproliferative activity of 1α,25(OH)2D3 in the human keratinocytes. Likewise, CYP24A1-resistant analogs such as 2α-(3-hydroxypropoxy)- 1α,25(OH)2D3 (O2C3) and its C2-epimer ED-71 (Eldecalcitol), and 19nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3 (MART-10) showed potent biological effects. Our in vivo studies using rats revealed that MART-10 had a low calcemic effect, which is a suitable property as an anticancer drug. Much lower affinity of MART-10 for vitamin D binding protein (DBP) as compared with 1α,25(OH)2D3 may be related to its more potent cellular activities. Based on these results, we conclude that (1) high affinity for VDR, (2) resistance to CYP24A1-dependent catabolism, (3) low affinity for DBP, and (4) low calcemic effect may be required for designing potent vitamin D analogs for cancer treatment.
    Anti-cancer agents in medicinal chemistry 07/2013;
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    ABSTRACT: Dioxins, including polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans, and coplanar polychlorinated biphenyls, are known to be metabolized by enzymes such as cytochrome (CYP) P450, angular dioxygenase, lignin peroxidase, and dehalogenase. It is noted that all of these enzymes have metal ions in their active centers, and the enzyme systems except for peroxidase each have a distinct electron transport chain. Among these enzyme systems, we have focused on cytochrome P450-dependent metabolism of dioxins from the viewpoint of practical use for bioremediation. Mammalian and fungal cytochromes P450 showed remarkable activity toward low-chlorinated PCDDs. In particular, mammalian cytochromes P450 belonging to the CYP1 family showed high activity. Rat CYP1A1 showed high activity toward 2,3,7-trichloro-dibenzo-p-dioxin but no detectable activity for 2,3,7,8-tetrachloro-dibenzo-p-dioxin (2,3,7,8-TCDD). On the basis of these results, we assumed that enlarging the space of the substrate-binding pocket of rat CYP1A1 might generate TCDD-metabolizing enzyme. Large-sized amino acids located at putative substrate-recognition sites and F-G loop were substituted for alanine by site-directed mutagenesis. Finally, we successfully generated 2,3,7,8-TCDD-metabolizing enzyme by site-directed mutagenesis of rat CYP1A1. We hope that recombinant microorganisms harboring genetically engineered cytochrome P450 will be used for bioremediation of soil contaminated with PCDDs, polychlorinated dibenzofurans, and coplanar polychlorinated biphenyls in the future.
    Biotechnology and Applied Biochemistry 01/2013; 60(1):65-70. · 1.35 Impact Factor
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    ABSTRACT: Available therapies for thromboembolic disorders include thrombolytics, anticoagulants, and antiplatelets, but these are associated with complications such as bleeding. To develop an alternative drug which is clinically safe, we focused on activated thrombin-activatable fibrinolysis inhibitor (TAFIa) as the target molecule. TAFIa is a zinc-containing carboxypeptidase that significantly inhibits fibrinolysis. Here we designed and synthesized selenium-containing compounds 5-13 to discover novel TAFIa inhibitors having a superior zinc-coordinating group. Compounds 5-13 significantly inhibited TAFIa activity (IC(50) 2.2 × 10(-12) M - 2.6 × 10(-6) M). We found that selenol is a better functional group than thiol for coordinating to zinc at the active site of TAFIa. Furthermore, compound 12, which has an amino-chloro-pyridine ring, was found to be a potent and selective TAFIa inhibitor that lacks carboxypeptidase N inhibitory activity. Therefore, compound 12 is a promising candidate for the treatment of thromboembolic disorders. This is the first report of a selenium-containing inhibitor for TAFIa.
    Journal of Medicinal Chemistry 08/2012; 55(17):7696-705. · 5.48 Impact Factor
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    ABSTRACT: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen that is activated by thrombin in plasma. In fibrinolytic processes, carboxy-terminal lysine (Lys) residues in partially degraded fibrin are important sites for plasminogen binding and activation, and an active form of TAFI (TAFIa) inhibits fibrinolysis by eliminating these residues proteolytically. We synthesized DD2 [7-Amino-2-(sulfanylmethyl)heptanoic acid], a Lys analogue containing sulfur, as an inhibitor of TAFIa and investigated its pharmacological profile and pathophysiological role in thrombolysis via in vitro and in vivo studies. DD2 specifically inhibited plasma TAFIa activity with an apparent IC(50) (50% inhibitory concentration) value of 3.4×10(-8)M under the present experimental condition and enhanced tissue plasminogen activator-mediated clot lysis in a concentration-dependent manner. In order to study tissue factor (TF)-induced microthrombosis in an animal model, rats were given intravenous injection (2.5mg/kg and higher) or oral administration (10mg/kg and higher) of DD2. This attenuated TF-induced glomerular fibrin deposition and increased the plasma levels of fibrin degradation products and D-dimer in a dose-dependent manner. A DD2 dose approximately 4X higher than the dose used in intravenous injections was required to achieve an equivalent thrombolytic effect to that seen following oral administration. Moreover, the oral absorption efficiency of DD2 into the vasculature was 29.8%. These results indicate that both intravenous and oral administration of DD2 enhanced endogenous fibrinolysis and reduced thrombi in a TF-induced microthrombosis model.
    Thrombosis Research 07/2012; 130(4):e222-8. · 2.43 Impact Factor
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    ABSTRACT: Sesamin and episesamin are two epimeric lignans that are found in refined sesame oil. Commercially available sesamin supplements contain both sesamin and episesamin at an approximate 1:1 ratio. Our previous study clarified the sequential metabolism of sesamin by cytochrome P450 (P450) and UDP-glucuronosyltransferase in human liver. In addition, we revealed that sesamin caused a mechanism-based inhibition (MBI) of CYP2C9, the P450 enzyme responsible for sesamin monocatecholization. In the present study, we compared the metabolism and the MBI of episesamin with those of sesamin. Episesamin was first metabolized to the two epimers of monocatechol, S- and R-monocatechols in human liver microsomes. The P450 enzymes responsible for S- and R-monocatechol formation were CYP2C9 and CYP1A2, respectively. The contribution of CYP2C9 was much larger than that of CYP1A2 in sesamin metabolism, whereas the contribution of CYP2C9 was almost equal to that of CYP1A2 in episesamin metabolism. Docking of episesamin to the active site of CYP1A2 explained the stereoselectivity in CYP1A2-dependent episesamin monocatecholization. Similar to sesamin, the episesamin S- and R-monocatechols were further metabolized to dicatechol, glucuronide, and methylate metabolites in human liver; however, the contribution of each reaction was significantly different between sesamin and episesamin. The liver microsomes from CYP2C19 ultra-rapid metabolizers showed a significant amount of episesamin dicatechol. In this study, we have revealed significantly different metabolism by P450, UDP-glucuronosyltransferase, and catechol-O-methyltransferase for sesamin and episesamin, resulting in different biological effects.
    Drug metabolism and disposition: the biological fate of chemicals 06/2012; 40(10):1917-26. · 3.74 Impact Factor
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    ABSTRACT: Previously, we reported that 22S-butyl-25,26,27-trinor-1α,24-dihydroxyvitamin D(3)2 represents a new class of antagonist for the vitamin D receptor (VDR). The crystal structure of the ligand-binding domain (LBD) of VDR complexed with 2 showed the formation of a butyl pocket to accommodate the 22-butyl group and insufficient interactions between ligand 2 and the C-terminus of VDR. Here, we designed and synthesized new analogues 5a-c and evaluated their biological activities to probe whether agonistic activity is recovered when the analogue restores interactions with the C-terminus of VDR. Analogues 5a-c exhibited full agonistic activity in transactivation. Interestingly, 5c, which bears a 24-diethyl group, completely recovered agonistic activity, although 3c and 4c act as an antagonist and a weak agonist, respectively. The crystal structures of VDR-LBD complexed with 3a, 4a, 5a, and 5c were solved, and the results confirmed that butyl pocket formation in VDR strongly affects the agonistic or antagonistic behaviors of ligands.
    Journal of Medicinal Chemistry 04/2012; 55(9):4373-81. · 5.48 Impact Factor
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    ABSTRACT: The active form of vitamin D, 1α,25-dihydroxyvitamin D [1α,25(OH)(2)D], interacts with vitamin D receptor (VDR) and induces antiproliferative, anti-invasive, proapoptotic and pro-differentiation activities in prostate cancer cells. Three cytochrome P-450 (CYP) hydroxylases are responsible for vitamin D synthesis and degradation, including vitamin D-25-hydroxylase (25-OHase) in the liver, and 25(OH)D-1α-hydroxylase (1α-OHase) or CYP27B1, and 25(OH)D-24-hydroxylase (24-OHase) or CYP24A1 in the kidneys. However, it is now recognized that CYP27B1 and CYP24A1 are also expressed in many tissues and cells, including the prostate. Although at least six CYP enzymes have been identified with 25-OHase activity, the two major ones are CYP27A1 and CYP2R1, and both are expressed in the prostate, with CYP2R1 as the predominate type. This indicates that prostate tissue has the ability to activate and inactivate vitamin D in an autocrine/paracrine fashion. Recent evidence indicates that 25-hydroxyvitamin D [25(OH)D] and its analogs can bind to VDR as agonists, without converting them to 1α,25(OH)(2)D or the corresponding 1α-hydroxylated metabolites, to modulate gene expressions that will lead to cell growth arrest and other antitumor activities. This finding suggests that the circulating levels of 25(OH)D, and the autocrine synthesis of 25(OH)D may play an important role in regulating the growth of prostate cancer. Thus, in addition to 1α,25(OH)(2)D analogs, the presence of CYP2R1, CYP27B1 and CYP24A1 in the prostate suggests that the analogs of vitamin D and 25(OH)D, especially those that are resistant to CYP24A1 degradation, can be developed and used for the prevention and treatment of prostate cancer.
    Anticancer research 01/2012; 32(1):291-8. · 1.87 Impact Factor
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    ABSTRACT: The active form of vitamin D(3), 1α,25-dihydroxyvitamin D(3)(1α,25(OH)(2)D(3)), has anti-proliferative and anti-invasive activities in prostate cancer cells. Because of 1α,25(OH)(2)D(3) therapeutic potential in treating cancers, numerous analogues have been synthesized with an attempt to increase anti-proliferative and/or decrease calcemic properties. Among these analogues, 19-nor-1α,25(OH)(2)D(2) while being less calcemic has equivalent potency as 1α,25(OH)(2)D(3) in several in vitro and in vivo systems. We recently showed that 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)(2)D(3) (MART-10) was at least 500-fold and 10-fold more active than 1α,25(OH)(2)D(3) in inhibiting the proliferation of an immortalized normal prostate PZ-HPV-7 cells and the invasion of androgen insensitive PC-3 prostate cancer cells, respectively. In this study, we further investigated the effects of MART-10 and 1α,25(OH)(2)D(3) on the dose- and time-dependent induction of CYP24A1 gene expression in PC-3 prostate cancer cells. We found that MART-10 induced CYP24A1 gene expression at a lower concentration with a longer duration compared to 1α,25(OH)(2)D(3), suggesting that MART-10 is less susceptible to CYP24A1 degradation. Molecular docking model of human CYP24A1 and MART-10 indicates that its side chain is far away from the heme ion and is less likely to be hydroxylated by the enzyme. Furthermore, MART-10 was a more potent inhibitor of PC-3 cell proliferation and invasion compared to 1α,25(OH)(2)D(3). In addition, MART-10 down-regulated matrix metalloproteinase-9 (MMP-9) expression which could be one mechanism whereby MART-10 influences cancer cell invasion. Finally, we observed that subcutaneous administration of MART-10 up-regulated the CYP24A1 mRNA expression in rat kidneys without affecting their plasma calcium levels. Thus, our findings demonstrate that MART-10 is biologically active in vivo and may be an effective vitamin D analogue for clinical trials to treat prostate cancer.
    The Journal of steroid biochemistry and molecular biology 09/2011; 127(3-5):269-75. · 3.98 Impact Factor
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    ABSTRACT: Coplanar polychlorinated biphenyls included in dioxin-like compounds are bio-accumulated and adversely affect wildlife and human health. Although many researchers have studied the metabolism of PCBs, there have been few reports of the in vitro metabolism of 3,3',4,4',5-pentachlorobiphenyl (PCB126), despite the fact that it has the highest toxicity among PCB congeners. Cytochrome P450 (CYP) 1A1 proteins can metabolize some dioxins and PCBs by hydroxylation, but the activities of human and rat CYP1A1 proteins are very different. The mechanism remains unclear. From our results, rat CYP1A1 metabolized PCB126 into 4-OH-3,3',4',5-tetrachlorobiphenyl and 4-OH-3,3',4',5,5'-pentachlorobiphenyl, but human CYP1A1 did not metabolize. Homology models of the two CYP proteins, and docking studies, showed that differences in the amino acid residues forming their substrate-binding cavities led to differences in the size and shape of the cavities; only the cavity of rat CYP1A1 allowed PCB126 close enough to the haem to be metabolized. Comparison of the amino acid residues of other mammalian CYP1A1 proteins suggested that rats have a unique metabolism of xenobiotics. Our results suggest that it is necessary to be careful in human extrapolation of toxicity data estimated by using the rat as an experimental animal, especially in the case of compounds metabolized by CYP1A1.
    Journal of Biochemistry 03/2011; 149(4):487-94. · 3.07 Impact Factor
  • Toshimasa Itoh, Ayako Tomiyasu, Keiko Yamamoto
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    ABSTRACT: Tetracosahexaenoic acid (C(24):6n-3, THA, 3) is an essential biosynthetic precursor in mammals of docosahexaenoic acid (C(22):6n-3, DHA, 1), the end-product of the metabolism of n-3 fatty acids. THA 3 is present in commercially valuable fishes, such as flathead flounder. Tricosahexaenoic acid (C(23):6n-3, TrHA, 2), an odd-numbered-chain fatty acid, has been identified from marine organisms such as the dinoflagellate, Amphidinium carterae. To date, few studies have examined THA 3 and TrHA 2 due to difficulties in detecting and identifying these compounds, so their chemical and biological properties remain poorly characterized. Only one methodology for the chemical synthesis of THA 3 has been presented, and no method for the synthesis of TrHA 2 has been reported. We report here the efficient synthesis of THA 3 in four steps in 56% overall yield, and the synthesis of TrHA 2 in six steps in 48% overall yield. We also present the synthesis of Δ(2)-THA 4, an intermediate of β-oxidation of THA 3 to DHA 1, in three steps in 73% overall yield.
    Lipids 02/2011; 46(5):455-61. · 2.56 Impact Factor
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    ABSTRACT: Cytochrome P450 (CYP) 1B1 catalyzes 17beta-estradiol (E(2)) to predominantly carcinogenic 4-hydroxy-E(2), whereas CYP1A1 and 1A2 convert E(2) to non-carcinogenic 2-hydroxy-E(2). Hence, selective inhibition of CYP1B1 is recognized to be beneficial for the prevention of E(2) related breast cancer. In this study, we first evaluated the structure-property relationship of 18 major flavonoids on inhibiting enzymatic activity of CYP1A1, 1A2 and 1B1 by using an ethoxyresorufin O-deethylation assay. Flavones and flavonols indicated relatively strong inhibitory effects on CYP1s compared with flavanone that does not have the double bond between C-positions 2 and 3 on the C-ring. Flavonoids used in this study selectively inhibited CYP1B1 activity. In particular, methoxy types of flavones and flavonols such as chrysoeriol and isorhamnetin showed strong and selective inhibition against CYP1B1. To understand why selective inhibition was observed, we carried out a molecular docking analysis of these methoxyflavonoids with the 2-3 double bond and CYP1s. The results suggested that chrysoeriol and isorhamnetin fit well into the active site of CYP1B1, but do not fit into the active site of CYP1A2 and 1A1 because of steric collisions between the methoxy substituent of these methoxyflavonoids and Ser-122 in CYP1A1 and Thr-124 in CYP1A2. In conclusion, our results demonstrate: (1) strong inhibitory effects of flavonoids on CYP1 activities require the 2-3 double bond on the C-ring; (2) methoxyflavonoids with the 2-3 double bond had strong and selective inhibition against CYP1B1, suggesting chemopreventive flavonoids for E(2) related breast cancer; and (3) binding specificity of these methoxyflavonoids is based on the interactions between the methoxy groups and specific CYP1s residues.
    Bioorganic & medicinal chemistry 09/2010; 18(17):6310-5. · 2.82 Impact Factor
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    ABSTRACT: We previously reported that 22S-butyl-25,26,27-trinor-1alpha,24-dihydroxyvitamin D(3) 2 was a potent VDR antagonist. The X-ray crystal structure of the ligand binding domain of VDR complexed with 2 indicated that this ligand induces an extra cavity within the ligand-binding pocket. The structure also showed that the ligand forms only poor hydrophobic interactions with helix 12 of the protein. Here, to study the effects of the induction of the extra cavity and of insufficient interactions with helix 12 on antagonism, we designed and synthesized a series of vitamin D(3) analogues with or without a 22-alkyl substituent and evaluated their biological potency. We found that the 22-butyl analogues 3c and 5c act as full antagonists, the 22-ethyl analogues 3b, 4b, 5b, and 22-butyl analogue 4c act as partial agonists, and the others (3a, 4a, 5a, 6a, 6b, and 6c) act as full agonists for VDR. It is intriguing that 6c is a potent agonist for VDR, whereas its 26,27-dinor analogue 5c is a potent antagonist. Analogue 6c recruited coactivator SRC-1 well, but 5c did not. These results indicate that a combination of induction of the extra cavity and insufficient hydrophobic interactions with helix 12 is important for VDR antagonism in this class of ligands.
    Journal of Medicinal Chemistry 08/2010; 53(15):5813-26. · 5.48 Impact Factor
  • Keiko Yamamoto, Hiroyuki Masuno, Sachiko Yamada
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    ABSTRACT: 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 07/2010; 32(31).
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    ABSTRACT: The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a direct pharmacological target for drugs that enhance insulin sensitivity and are used clinically for the treatment of type II diabetes. Because the specificity of ligand recognition is lower for PPARgamma than for other nuclear receptors, PPARgamma can bind a larger variety of ligand types. In order to elucidate why the ligand recognition of PPARgamma is so flexible, we performed correlated fragment molecular orbital calculations for complexes of PPARgamma and each of two distinctive ligands, rosiglitazone and farglitazar. We found quite different patterns of ligand binding for these two ligands. The ligand-binding system of rosiglitazone, a drug in common clinical use, is based mainly on local electrostatic interactions around the thiazolidine ring, whereas both electrostatic interactions and van der Waals dispersion interactions with hydrophobic residues are required for the binding of farglitazar to PPARgamma. We suggest that the development of novel ligands will require adequately hydrophobic pharmacophores.
    Bioorganic & medicinal chemistry letters 06/2010; 20(11):3344-7. · 2.65 Impact Factor
  • Toshimasa Itoh, Nobuko Yoshimoto, Keiko Yamamoto
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    ABSTRACT: 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 05/2010; 41(20).

Publication Stats

1k Citations
300.43 Total Impact Points

Institutions

  • 2008–2012
    • Showa Pharmaceutical University
      Machida, Tōkyō, Japan
  • 2006–2012
    • Toyama Prefectural University
      • • Department of Biotechnology
      • • Faculty of Engineering
      Toyama-shi, Toyama-ken, Japan
  • 2010
    • Showa University
      Shinagawa, Tōkyō, Japan
  • 1990–2008
    • Tokyo Medical and Dental University
      • • Department of Biomedical Science (SBS)
      • • Institute of Biomaterials and Bioengineering
      • • Department of Materials Science and Bioengineering
      • • Institute for Medical and Dental Engineering
      Edo, Tōkyō, Japan
  • 2006–2007
    • Kyoto University
      • Division of Food Science and Biotechnology
      Kyoto, Kyoto-fu, Japan
  • 1987
    • Teikyo University
      • Faculty of Pharmaceutical Sciences
      Edo, Tōkyō, Japan