Takumi Ogawa

Tohoku Pharmaceutical University, Sendai-shi, Miyagi, Japan

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Publications (10)24.16 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We designed and synthesized novel m-carborane-containing selective estrogen receptor modulator (SERM) candidates using previously reported m-carborane-containing ER partial agonist 1 as the lead compound. Biological activities were evaluated by means of ERα competitive binding assay and MCF-7 cell proliferation assay. Re-positioning the N,N-dimethylaminoethyloxy group at the para position of 1 to the meta position enhanced the ERα-binding affinity, and 4c showed the highest relative binding affinity (RBA: 83 vs 17β-estradiol=100) among the tested compounds. Compound 4b showed the most potent ER-agonist activity (EC50: 1.4nM) and the lowest maximal efficacy (Emax: 50%) in MCF-7 cell proliferation assay. Inhibition of 0.1nM 17β-estradiol-induced MCF-7 cell proliferation by 4b (IC50: 0.4μM) was at least 10 times more potent than that of the lead compound 1. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & medicinal chemistry letters 06/2015; DOI:10.1016/j.bmcl.2015.05.083 · 2.33 Impact Factor
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    ABSTRACT: We previously discovered m-carborane-containing estrogen receptor (ER) modulator 4, which exhibits weak ER-agonistic and antagonistic activities in transactivation assays. With the aim of developing novel ER partial agonists, we designed and synthesized various analogues of 4 with a bent-core structure, that is, pseudo cyclic structure (5), tetrahydropyrimidinone (6), m-benzene (7), adamantane (8), and 9,10-dimethyl-m-carborane (9), in place of the m-carborane moiety. Compound 9 showed greater binding affinity than 4 in ER-binding assay using [6,7-(3)H]-17β-estradiol and was a more effective partial agonist than 4 in MCF-7 cell proliferation assay. It appears to be a promising candidate as a selective ER modulator (SERM).
    Bioorganic & Medicinal Chemistry 07/2014; 22(13). DOI:10.1016/j.bmc.2014.04.022 · 2.95 Impact Factor
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    ABSTRACT: The two subtypes of estrogen receptor (ER), ERα and ERβ, differ greatly in expression pattern and biological functions, and ERβ-selective ligands candidates to treat immune-related disorders. ERβ-selective ligands have mostly been designed based the idea of introducing a substituent that interferes sterically with the ligand's interaction with Met421 to selectively decrease the affinity for ERα (the equivalent residue in ERβ is Ile373). Therefore, we designed and synthesized a series of carboranyl phenol derivatives bearing an aliphatic substituent as candidate ERβ-selective ligands. Introduction of a longer aliphatic substituent into the carboranyl moiety enhanced the ERβ selectivity of o-carboranyl phenol derivatives 4, but not m-carboranyl bisphenol derivatives 5. Compound 4c showed 7.4-fold ERβ selectivity in ER-binding assay and exhibited moderate estrogenic activity in cell proliferation assay using MCF-7 cell line.
    Chemical & pharmaceutical bulletin 04/2014; 62(4):386-91. DOI:10.1248/cpb.c13-00796 · 1.38 Impact Factor
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    ABSTRACT: We previously showed that fluorination of the carborane-containing selective estrogen receptor modulator (SERM) BE360 altered the agonist/antagonist activity balance and the estrogen receptor (ER) α/β subtype selectivity. Here, we designed and synthesized a series of fluorinated carboranyl phenols as candidate ERβ-selective ligands. Introduction of a fluorine atom onto the carborane cage commonly reduced the binding affinity for ERα, to an extent that depended on the other substituents present. The B-fluorinated m-carboranyl phenol 4a showed fourfold more potent ERβ-binding affinity than the parent non-fluorinated compound 7. 1-Iodo-9-fluoro-m-carboranyl phenol 4f showed high ERβ-binding affinity with an ERβ/ERα selectivity ratio of 8.2. Among the compounds tested, 6 showed the highest ERβ selectivity (10.1-fold) and the highest ER-agonistic activity (EC50: 5.1 × 10−10 M) in MCF-7 cell proliferation assay.
    Bioorganic & medicinal chemistry letters 12/2013; 23(24):6555–6558. DOI:10.1016/j.bmcl.2013.10.067 · 2.33 Impact Factor
  • Kiminori Ohta, Takumi Ogawa, Yasuyuki Endo
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    ABSTRACT: We previously identified o-carborane bisphenol BE360 (4) as a selective estrogen receptor modulator (SERM), which ameliorated bone loss without inducing estrogenic action in uterus of OVX and ORX mice. Here, we synthesized a fluorinated derivative, B-fluorinated o-carborane bisphenol BE310 (5) by means of S(N)Ar reaction. Compound 5 was a partial ER agonist, like 4, with little change of ERα and ERβ selectivity as compared with 4. However, its agonistic activity was 40 times weaker than that of 4. Thus, 5 is a novel SERM candidate with potential for reduced estrogenic side effects, and in vivo evaluation as an anti-osteoporosis agent seems warranted.
    Bioorganic & medicinal chemistry letters 05/2012; 22(14):4728-30. DOI:10.1016/j.bmcl.2012.05.068 · 2.33 Impact Factor
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    ABSTRACT: Novel carborane-containing estrogen receptor (ER) modulators, carbamate and thiocarbamate derivatives 5 and 6, were designed and synthesized based upon the m-carborane bisphenol skeleton. Their activities were evaluated by competitive binding assay with recombinant human ERalpha, transcriptional activation assay and cell proliferation assay. All test compounds dose-dependently bound to human ERalpha and showed potent estrogenic activity. The binding affinities of thiocarbamates 6a and 6b are higher than those of the alkyl carbamates 5a-5d and are similar to that of the phenyl carbamate 5e. The binding affinity was well correlated with the acidity of the NH proton, indicating the existence of an interaction between the NH proton and amino acid residue(s) of the ERalpha ligand binding domain. The amino acid residue(s) interacting with the NH proton appears to be different from Asp351, which is known to play an important role in the expression of antiestrogenic activity. The side chain of the m-carborane bisphenol structure strictly controls the balance of estrogenic and antiestrogenic activities, and the (thio)carbamates can be classified as an agonist group.
    Bioorganic & medicinal chemistry 12/2009; 17(23):7958-63. DOI:10.1016/j.bmc.2009.10.018 · 2.95 Impact Factor
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    ABSTRACT: Carboranes are a class of carbon-containing polyhedral boron-cluster compounds with globular geometry and hydrophobic surface that interact with hormone receptors. Estrogen deficiency results in marked bone loss due to increased osteoclastic bone resorption in females, but estrogen replacement therapy is not generally used for postmenopausal osteoporosis due to the risk of uterine cancer. We synthesized a novel carborane compound BE360 to clarify its anti-osteoporosis activity. BE360 showed a high binding affinity to estrogen receptors (ER), ERalpha and ERbeta. In ovariectomized (OVX) mice, femoral bone volume was markedly reduced and BE360 dose-dependently restored bone loss in OVX mice. However, BE360 did not exhibit any estrogenic activity in the uterus. BE360 also restored bone loss in orchidectomized mice without androgenic action in the sex organs. Therefore, BE360 is a novel selective estrogen receptor modulator (SERM) that may offer a new therapy option for osteoporosis.
    Biochemical and Biophysical Research Communications 02/2009; 380(2):218-22. DOI:10.1016/j.bbrc.2009.01.033 · 2.28 Impact Factor
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    ABSTRACT: p-Carborane bisphenols and their derivatives were prepared and evaluated for binding affinity to estrogen receptor alpha. Their estrogenic activity was evaluated by means of transcriptional assay and cell proliferation assay using MCF-7 cell lines. 1,12-Bis(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 4a showed potent estrogenic activity, approaching that of 17beta-estradiol, in transactivation assay. The activity of isomers 5a and 6a was drastically affected by the change in the position of one of the hydroxyl groups; 6a (ortho-OH in one ring) was about 1000 times less potent than 4a. Modification of this hydroxyl group with alkyl groups decreased the estrogenic activity in all isomers. Compound 4a also showed potent MCF-7 cell proliferation-enhancing activity.
    Bioorganic & medicinal chemistry 02/2009; 17(3):1109-17. DOI:10.1016/j.bmc.2008.12.044 · 2.95 Impact Factor
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    ABSTRACT: Novel diphenylamine-type estrogen receptor ligands were designed and synthesized, and their biological activities were evaluated by means of binding assays for estrogen receptor-alpha and -beta and cell proliferation assay using MCF-7 cells. Compounds 4f, 11b, 12c, and 8 showed moderate estrogenic activities. We propose that the diphenylamine skeleton may be a privileged structure for various nuclear receptor ligands, including RAR, RXR, and AR ligands.
    Bioorganic & medicinal chemistry letters 09/2008; 18(18):5050-3. DOI:10.1016/j.bmcl.2008.08.004 · 2.33 Impact Factor
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    ABSTRACT: A series of m-carborane derivatives was prepared based upon the structures of antiestrogenic drugs and their activities were evaluated by estrogen receptor alpha (ERalpha) binding assay and transactivation assay using human breast cancer cell line, MCF-7 cells. The m-carborane bisphenol 5 exhibited about a thousand times more potent ER agonistic activity than the o-carborane bisphenol 11. The m-carborane bisphenol structure appears to be a favorable hydrophobic pharmacophore for the development of novel selective estrogen receptor modulators (SERMs).
    Bioorganic & Medicinal Chemistry Letters 09/2006; 16(15):3943-6. DOI:10.1016/j.bmcl.2006.05.032 · 2.33 Impact Factor