QSAR Modeling of alpha-Campholenic Derivatives with Sandalwood Odor

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for a series of 44 synthetic alpha-campholenic derivatives with sandalwood odor. These compounds have complex stereochemistry as they contain up to five chiral atoms. To address stereospecificity of odor intensity, a 3D-QSAR method was developed, which does not require spatial alignment of molecules. In this method, compounds are represented as derivatives of several common structural templates with several substituents, which are numbered according to their relative spatial positions in the molecule. Both wholistic and substituent descriptors calculated with the TSAR software were used as independent variables. Based on published experimental data of sandalwood odor intensities, two discrete scales of the odor intensity with equal or unequal intervals between the threshold values were developed. The data set was divided into a training set of 38 compounds and a test set of six compounds. To build QSAR models, a stepwise multiple linear regression method was used. The best model was obtained using the unequal scale of odor intensity: for the training set, the leave one out cross-validated R(2) (q(2)) was 0.80, the correlation coefficient R between actual and predicted odor intensities was 0.93, and the correlation coefficient for the test set was 0.95. The QSAR models developed in this study contribute to the better understanding of structural, electronic, and lipophilic properties responsible for sandalwood odor. Furthermore, the QSAR approach reported herein can be applied to other data sets that include compounds with complex stereochemistry.

[1]  Didier Villemin,et al.  Application of neural networks to structure–sandalwood odour relationships , 1997 .

[2]  A. Verloop,et al.  Development and Application of New Steric Substituent Parameters in Drug Design , 1976 .

[3]  M. Laska,et al.  Olfactory discrimination ability of human subjects for ten pairs of enantiomers. , 1999, Chemical senses.

[4]  Johann Gasteiger,et al.  The comparison of geometric and electronic properties of molecular surfaces by neural networks: Application to the analysis of corticosteroid-binding globulin activity of steroids , 1996, J. Comput. Aided Mol. Des..

[5]  L. Buck,et al.  Combinatorial Receptor Codes for Odors , 1999, Cell.

[6]  R. Axel,et al.  A novel multigene family may encode odorant receptors: A molecular basis for odor recognition , 1991, Cell.

[7]  H. Wiener.  Structural determination of paraffin boiling points. , 1947, Journal of the American Chemical Society.

[8]  B D Silverman,et al.  Comparative molecular moment analysis (CoMMA): 3D-QSAR without molecular superposition. , 1996, Journal of medicinal chemistry.

[9]  P. Broto,et al.  Molecular structures: perception, autocorrelation descriptor and sar studies. Autocorrelation descriptor , 1984 .

[10]  Peter Wolschann,et al.  ON THE ODOR OF THE ENANTIOMERS OF MADROL , 1997 .

[11]  M. Hennig,et al.  SYNTHESIS AND STRUCTURE ELUCIDATION OF A NEW POTENT SANDALWOOD-OIL SUBSTITUTE , 1998 .

[12]  Terry E. Acree,et al.  Odor thresholds of the stereoisomers of methyl jasmonate , 1985 .

[13]  J. Gasteiger,et al.  Autocorrelation of Molecular Surface Properties for Modeling Corticosteroid Binding Globulin and Cytosolic Ah Receptor Activity by Neural Networks , 1995 .

[14]  Stephan Wnendt,et al.  Thalidomide's chirality , 1997, Nature.

[15]  Wilson H. De Camp,et al.  The FDA perspective on the development of stereoisomers. , 1989 .

[16]  F. Zufall,et al.  Central Role of the CNGA4 Channel Subunit in Ca2+-Calmodulin-Dependent Odor Adaptation , 2001, Science.

[17]  L. Vuataz,et al.  The taste ofl- andd-amino acids , 1965, Experientia.

[18]  S. Pickett,et al.  GRid-INdependent descriptors (GRIND): a novel class of alignment-independent three-dimensional molecular descriptors. , 2000, Journal of medicinal chemistry.

[19]  Karl H. Schulte‐Elte,et al.  Zur Stereochemie der Geruchswahrnehmung von 1-Dekalon-Derivaten und ihren oxaanalogen Verbindungen , 1976 .

[20]  Peter Wolschann,et al.  Conformational Parameters of the Sandalwood‐Odor Activity: Conformational calculations on sandalwood odor , 1994 .

[21]  Karen J. Rossiter,et al.  Structure−Odor Relationships , 1996 .

[22]  H. A. Kuiper,et al.  Chirality in synthetic agrochemicals: bioactivity and safety consideration 0f IUPAC Reports on Pesticides (37) , 1997 .

[23]  Cristian G. Bologa,et al.  QSAR for Cycloaliphatic Alcohols with Qualitatively Defined Sandalwood Odour Characteristics , 1999 .

[24]  Lutz Weber,et al.  Synthese, Struktur und Reaktionen von α‐Campholenepoxiden , 1993 .

[25]  G. Fráter,et al.  Chiral recognition of sandalwood odorants. , 2000, Enantiomer.

[26]  Linda B. Buck,et al.  Genetic tracing reveals a stereotyped sensory map in the olfactory cortex , 2001, Nature.

[27]  M. Laska,et al.  Olfactory discrimination ability for aromatic odorants as a function of oxygen moiety. , 2002, Chemical senses.

[28]  Stephan Frings,et al.  Ca2+ permeation in cyclic nucleotide‐gated channels , 1999, The EMBO journal.

[29]  Peter Wolschann,et al.  Synthesis and olfactoric activity of side-chain modified β-santalol analogues , 2001 .

[30]  A. Tropsha,et al.  Beware of q2! , 2002, Journal of molecular graphics & modelling.

[31]  M. Laska,et al.  Trigeminal perception of odorant quality in congenitally anosmic subjects. , 1997, Chemical senses.

[32]  Lemont B. Kier,et al.  A Shape Index from Molecular Graphs , 1985 .

[33]  Susan S. Schiffman,et al.  Influence of chirality of amino acids on the growth of perceived taste intensity with concentration , 1982, Physiology & Behavior.

[34]  Christian Chapuis,et al.  Catalysis in the preparation of fragrances and flavours , 2001 .

[35]  Roger L. Snowden,et al.  Stereoselective Syntheses of (±)-epi-β-Santalene and (±)-epi-β-Santalol , 1981 .

[36]  Karl H. Schulte‐Elte,et al.  Diastereoselektivität der Geruchswahrnehmung von Alkoholen der Iononreihe , 1985 .

[37]  M. Randic.  Characterization of molecular branching , 1975 .

[38]  J. Bradley,et al.  Facilitation of Calmodulin-Mediated Odor Adaptation by cAMP-Gated Channel Subunits , 2001, Science.

[39]  Peter Wolschann,et al.  Synthesis and olfactoric activity of keto-β-santalol and methoxy-β-santalol , 1998 .