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Synthesis and evaluation of analogues of estrone-3-O-sulfamate as potent steroid sulfatase inhibitors


Reference:

Woo, L. W. L., Leblond, B., Purohit, A. and Potter, B. V. L., 2012. Synthesis and evaluation of analogues of estrone-3-O-sulfamate as potent steroid sulfatase inhibitors. Bioorganic and Medicinal Chemistry, 20 (8), pp. 2506-2519.

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    Official URL:

    http://dx.doi.org/10.1016/j.bmc.2012.03.007

    Abstract

    Estrone sulfamate (EMATE) is a potent irreversible inhibitor of steroid sulfatase (STS). In order to further expand SAR, the compound was substituted at the 2- and/or 4-positions and its 17-carbonyl group was also removed. The following general order of potency against STS in two in vitro systems is observed for the derivatives: The 4-NO 2 > 2-halogens, 2-cyano > EMATE (unsubstituted) > 17-deoxyEMATE > 2-NO 2 > 4-bromo > 2-(2-propenyl), 2-n-propyl > 4-(2-propenyl), 4-n-propyl > 2,4-(2-propenyl) = 2,4-di-n-propyl. There is a clear advantage in potency to place an electron-withdrawing substituent on the A-ring with halogens preferred at the 2-position, but nitro at the 4-position. Substitution with 2-propenyl or n-propyl at the 2- and/or 4-position of EMATE, and also removal of the 17-carbonyl group are detrimental to potency. Three cyclic sulfamates designed are not STS inhibitors. This further confirms that a free or N-unsubstituted sulfamate group (H 2NSO 2O-) is a prerequisite for potent and irreversible inhibition of STS as shown by inhibitors like EMATE and Irosustat. The most potent derivative synthesized is 4-nitroEMATE (2), whose IC 50s in placental microsomes and MCF-7 cells are respectively 0.8 nM and 0.01 nM.

    Details

    Item Type Articles
    CreatorsWoo, L. W. L., Leblond, B., Purohit, A. and Potter, B. V. L.
    DOI10.1016/j.bmc.2012.03.007
    DepartmentsFaculty of Science > Pharmacy & Pharmacology
    Publisher StatementPotter_BMC_2012_20_8_2506_ii.pdf: NOTICE: this is the author’s version of a work that was accepted for publication in Bioorganic & Medicinal Chemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Bioorganic & Medicinal Chemistry, vol 20, issue 8, 2012, DOI 10.1016/j.bmc.2012.03.007; Potter_BMC_2012_20_8_2506_ii.doc: NOTICE: this is the author’s version of a work that was accepted for publication in Bioorganic & Medicinal Chemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Bioorganic & Medicinal Chemistry, vol 20, issue 8, 2012, DOI 10.1016/j.bmc.2012.03.007
    RefereedYes
    StatusPublished
    ID Code29308

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