Determination of the absolute configuration of aromatase and dual aromatase-sulfatase inhibitors by vibrational and electronic circular dichroism spectra analysis.

The absolute configuration of a newly designed, letrozole-based chiral aromatase inhibitor that could not be defined by crystallographic techniques has been determined by means of vibrational and electronic circular dichroism and by optical rotation measurements combined with density functional theory calculations on possible conformers. The same absolute configurational assignment can be applied to the individual enantiomeric sulfamate esters, which are derived from the corresponding enantiomers of the chirally separated parent phenols, based on the similarity of the ECD spectrum of the sulfamate derivative to that of its phenolic precursor. The two enantiomeric sulfamate esters studied here are the first examples of nonsteroidal dual aromatase-sulfatase inhibitor whose activities have been evaluated on optically resolved enantiomers.

[1]  B. Potter,et al.  Chiral aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole template: synthesis, absolute configuration, and in vitro activity. , 2008, Journal of medicinal chemistry.

[2]  B. Potter,et al.  Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity. , 2007, Organic & biomolecular chemistry.

[3]  B. Potter,et al.  Dual aromatase-steroid sulfatase inhibitors. , 2007, Journal of medicinal chemistry.

[4]  A. Hansen,et al.  Natural Chiroptical Spectroscopy: Theory and Computations , 2007 .

[5]  P. Stephens,et al.  Are the absolute configurations of 2-(1-hydroxyethyl)-chromen-4-one and its 6-bromo derivative determined by X-ray crystallography correct? A vibrational circular dichroism study of their acetate derivatives , 2005 .

[6]  B. Potter,et al.  A letrozole-based dual aromatase–sulphatase inhibitor with in vivo activity , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[7]  P. Polavarapu,et al.  Peer Reviewed: Chiral Analysis Using Mid-IR Vibrational CD Spectroscopy , 2004 .

[8]  Stefan Grimme,et al.  Systematic Investigation of Modern Quantum Chemical Methods to Predict Electronic Circular Dichroism Spectra , 2003 .

[9]  L. Nafie,et al.  Vibrational Optical Activity Theory , 2002 .

[10]  A. Brodie.  Aromatase inhibitors in breast cancer , 2002, Trends in Endocrinology & Metabolism.

[11]  M. Frisch,et al.  Hartree−Fock and Density Functional Theory ab Initio Calculation of Optical Rotation Using GIAOs: Basis Set Dependence , 2000 .

[12]  C. Rosini,et al.  Determination of the Absolute Configuration of 1-Arylethane-1,2-diols by a Nonempirical Analysis of the CD Spectra of Their 4-Biphenylboronates , 1999 .

[13]  P. Stephens,et al.  Determination of absolute configuration using circular dichroism: Tröger’s Base revisited using vibrational circular dichroism , 1999 .

[14]  P. Wipf,et al.  Theory-Assisted Determination of Absolute Stereochemistry for Complex Natural Products via Computation of Molar Rotation Angles , 1998 .

[15]  P. Polavarapu.  AB INITIO MOLECULAR OPTICAL ROTATIONS AND ABSOLUTE CONFIGURATIONS , 1997 .

[16]  M. Frisch,et al.  Ab initio calculation of atomic axial tensors and vibrational rotational strengths using density functional theory , 1996 .

[17]  P. Stephens.  Theory of vibrational circular dichroism , 1985 .

[18]  P. Stephens,et al.  Vibrational Circular Dichroism , 1976 .

[19]  K. Mislow.  Introduction to stereochemistry , 1966 .