PDBsum entry 3c7p

Lyase

PDB id: 3c7p

Contents

Protein chain

258 a.a.

Ligands

POF

MBO

GOL

Metals

_ZN

_CL

Waters ×282

References listed in PDB file

Key reference

• Title: Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-Generation agent, In vitro and in vivo activities, Molecular modeling, And protein crystallography.
• Authors: L.W.Woo, D.S.Fischer, C.M.Sharland, M.Trusselle, P.A.Foster, S.K.Chander, A.Di fiore, C.T.Supuran, G.De simone, A.Purohit, M.J.Reed, B.V.Potter.
• Ref.: Mol Cancer Ther, 2008, 7, 2435-2444. [DOI no: 10.1158/1535-7163.MCT-08-0195]
• PubMed id: 18723489

Abstract

An improved steroid sulfatase inhibitor was prepared by replacing the N-propyl group of the second-generation steroid-like inhibitor (2) with a N-3,3,3-trifluoropropyl group to give (10). This compound is 5-fold more potent in vitro, completely inhibits rat liver steroid sulfatase activity after a single oral dose of 0.5 mg/kg, and exhibits a significantly longer duration of inhibition over (2). These biological properties are attributed to the increased lipophilicity and metabolic stability of (10) rendered by its trifluoropropyl group and also the potential H-bonding between its fluorine atom(s) and Arg(98) in the active site of human steroid sulfatase. Like other sulfamates, (10) is expected to be sequestered, and transported by, erythrocytes in vivo because it inhibits human carbonic anhydrase II (hCAII) potently (IC(50), 3 nmol/L). A congener (4), which possesses a N-(pyridin-3-ylmethyl) substituent, is even more active (IC(50), 0.1 nmol/L). To rationalize this, the hCAII-(4) adduct, obtained by cocrystallization, reveals not only the sulfamate group and the backbone of (4) interacting with the catalytic site and the associated hydrophobic pocket, respectively, but also the potential H-bonding between the N-(pyridin-3-ylmethyl) group and Nepsilon(2) of Gln(136). Like (2), both (10) and its phenolic precursor (9) are non-estrogenic using a uterine weight gain assay. In summary, a highly potent, long-acting, and nonestrogenic steroid sulfatase inhibitor was designed with hCAII inhibitory properties that should positively influence in vivo behavior. Compound (10) and other related inhibitors of this structural class further expand the armory of steroid sulfatase inhibitors against hormone-dependent breast cancer.

Secondary reference #1

• Title: 2-Substituted estradiol bis-Sulfamates, Multitargeted antitumor agents: synthesis, In vitro sar, Protein crystallography, And in vivo activity.
• Authors: M.P.Leese, B.Leblond, A.Smith, S.P.Newman, A.Di fiore, G.De simone, C.T.Supuran, A.Purohit, M.J.Reed, B.V.Potter.
• Ref.: J Med Chem, 2006, 49, 7683-7696. [DOI no: 10.1021/jm060705x]
• PubMed id: 17181151

Secondary reference #2

• Title: Structure-Activity relationships of c-17 cyano-Substituted estratrienes as anticancer agents.
• Authors: M.P.Leese, F.L.Jourdan, K.Gaukroger, M.F.Mahon, S.P.Newman, P.A.Foster, C.Stengel, S.Regis-Lydi, E.Ferrandis, A.Di fiore, G.De simone, C.T.Supuran, A.Purohit, M.J.Reed, B.V.Potter.
• Ref.: J Med Chem, 2008, 51, 1295-1308.
• PubMed id: 18260615

Note In the PDB file this reference is annotated as "TO BE PUBLISHED". The citation details given above were identified by an automated search of PubMed on title and author names, giving a percentage match of 92%.