A Structure-Activity Study of Taxol, Taxotere, and Derivatives Using the Electronic Indices Methodology (EIM)

Among the new families of effective anticancer drugs, the natural product paclitaxel (Taxol/Bristol-Myers-Squibb) and its semisynthetic derivative docetaxel (Taxotere/Rhone-Poulenc Rorer) are probably the most promising agents under investigation. Surprisingly considering their importance no detailed quantum mechanical studies have been carried out for these drugs. In this work we report the first structure--activity relationship (SAR) studies for 20 taxoid structures using molecular descriptors from all-electron quantum methods. The used methods were the pattern-recognition Principal Component Analysis (PCA), Hierarchical Clustering Analysis (HCA), and the recently developed Electronic Indices Methodology (EIM). The combined use of EIM with PCA/HCA methodologies was able to correctly classify active and inactive taxoids with 100% of accuracy using only a few "universal" quantum molecular descriptors. It was possible to identify the electronic features defining active molecules. This information can be used to select and design new active compounds. The combined use of EIM with PCA/HCA can be a new and very efficient tool in the field of computer assisted drug design.

[1]  Galvão,et al.  Theoretical Approach to Identify Carcinogenic Activity of Polycyclic Aromatic Hydrocarbons. , 1996, Physical review letters.

[2]  D. Guénard,et al.  Relationships between the structure of taxol analogues and their antimitotic activity. , 1991, Journal of medicinal chemistry.

[3]  K. Nicolaou,et al.  Total synthesis of taxol , 1994, Nature.

[4]  D. Galvão,et al.  A semiempirical study on the electronic structure of 10-deacetylbaccatin-III. , 2002, Journal of molecular graphics & modelling.

[5]  D. Galvão,et al.  Structure–activity relationship (SAR) studies of the tripos benchmark steroids , 2002 .

[6]  Eamonn F. Healy,et al.  Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model , 1985 .

[7]  P. Giannakakou,et al.  Synthesis and biological evaluation of 2-acyl analogues of paclitaxel (Taxol). , 1998, Journal of medicinal chemistry.

[8]  D. Galvão,et al.  Structure–carcinogenic activity relationship studies of polycyclic aromatic hydrocarbons (PAHs) with pattern-recognition methods , 2001 .

[9]  Liliana Y. A. Dávila,et al.  Applicability of MNDO techniques AM1 and PM3 to ring‐structured polymers , 2002, J. Comput. Chem..

[10]  J. Snyder,et al.  The Conformations of Taxol in Chloroform , 2000 .

[11]  Y. Takahata,et al.  Structure-Activity Relationship Studies of Carcinogenic Activity of Polycyclic Aromatic Hydrocarbons Using Calculated Molecular Descriptors with Principal Component Analysis and Neural Network Methods , 1999, J. Chem. Inf. Comput. Sci..

[12]  A. Benesi,et al.  Characterization of taxol in methylene chloride by nmr spectroscopy , 1992 .

[13]  J. Stewart.  Optimization of parameters for semiempirical methods I. Method , 1989 .

[14]  F. Chu,et al.  Comparative molecular field analysis of a series of paclitaxel analogues. , 1997, Journal of medicinal chemistry.

[15]  T. Isaksson,et al.  Multivariate techniques in the analysis of meat quality. , 1996, Meat science.

[16]  A. McPhail,et al.  Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. , 1971, Journal of the American Chemical Society.

[17]  Rainer E. Martin,et al.  PM3 geometry optimization and CNDO/S‐CI computation of UV/Vis spectra of large organic structures: Program description and application to poly(triacetylene) hexamer and taxotere , 1999 .

[18]  C. Song,et al.  Synthesis, biological activity and receptor-based 3-D QSAR study of 3'-N-substituted-3'-N-debenzoylpaclitaxel analogues. , 2002, Bioorganic & medicinal chemistry.

[19]  Qi Gao,et al.  The “hydrophobic collapse” conformation of paclitaxel (Taxol®) has been observed in a non-aqueous environment: Crystal structure of 10-deacetyl-7-epitaxol , 1996 .

[20]  M. F. Budyka,et al.  Computer modeling of C2 cluster addition to fullerene C60 , 2002 .

[21]  I. Ojima,et al.  New photoaffinity analogs of paclitaxel. , 1999, Bioorganic & medicinal chemistry letters.

[22]  T. Sugimura,et al.  Multistep carcinogenesis: a 1992 perspective. , 1992, Science.

[23]  Rosana Vendrame,et al.  Identifying Relevant Molecular Descriptors Related to Carcinogenic Activity of Polycyclic Aromatic Hydrocarbons (PAHs) Using Pattern Recognition Methods , 2002, J. Chem. Inf. Comput. Sci..

[24]  D. Galvão,et al.  Electronic indices from semi-empirical calculations to identify carcinogenic activity of polycyclic aromatic hydrocarbons , 2000 .

[25]  D. Rusinska-Roszak,et al.  PM3 CONFORMATIONS OF C-13 TAXOL SIDE CHAIN METHYL ESTER , 1995 .

[26]  D. Mastropaolo,et al.  Crystal and molecular structure of paclitaxel (taxol). , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Snyder,et al.  The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Structure–activity relationship study of some inhibitors of HIV-1 integrase , 1999 .

[29]  J. Stewart.  Optimization of parameters for semiempirical methods II. Applications , 1989 .

[30]  P. Vrignaud,et al.  Syntheses and structure-activity relationships of the second-generation antitumor taxoids: exceptional activity against drug-resistant cancer cells. , 1996, Journal of medicinal chemistry.

[31]  Rosana Vendrame,et al.  Structure-Activity Relationship Studies of Substituted 17-Acetoxyprogesterone Hormones , 2000, J. Chem. Inf. Comput. Sci..

[32]  H. Williams,et al.  NMR and molecular modeling study of the conformations of taxol and of its side chain methylester in aqueous and non-aqueous solution. , 1993 .

[33]  D. Guénard,et al.  Taxol and taxotere: discovery, chemistry, and structure-activity relationships , 1993 .

[34]  D. Galvão,et al.  Structure–activity study of indolequinones bioreductive alkylating agents , 1999 .