Structure-activity relationship study of rutaecarpine analogous active against central nervous system cancer

Abstract

Com o objetivo de relacionar os descritores geométricos e eletrônicos dos derivados análogos da rutaercarpina com a atividade biológica contra o câncer do sistema nervoso central (CNS), cálculos de química quântica molecular em nível B3LYP/6-31(d) e análise estatística foram realizados para os 21 derivados análogos da rutaecarpina. Dos 86 descritores moleculares calculados, 5 foram selecionados na construção do modelo de análises de componentes principais (PCA). A componente PC1, a qual responde por 46,11% da variância total dos dados, foi capaz sozinha de discriminar completamente os compostos em duas classes: ativos e inativos. Todos os descritores moleculares selecionados pelo modelo PCA são parâmetros eletrônicos. A análise de agrupamento hierárquico (HCA) foi também aplicada aos descritores selecionados pelo modelo PCA. Baseado nos 5 descritores selecionados é possível sugerir novos derivados ativos da rutaercarpina para serem sintetizados. Além disso, um modelo de mínimos quadrados parciais para análise discriminante (PLS-DA) supervisionado foi construído e aplicado com sucesso na discriminação dos análogos à rutaercarpina, o qual foi validado usando um conjunto independente de compostos.In order to relate the geometric and electronic descriptors of the rutaecarpine analogous to their biological activity against cancer of the central nervous system (CNS), molecular quantum chemical calculations at B3LYP/6-31(d) level and statistical analysis were carried out for 21 rutaecarpine analogous. Out of the 86 molecular descriptors calculated, 5 were selected to build the principal component analysis (PCA) model. The PC1 component that accounts for 46.11% of the total variance of the data was alone able to discriminate completely the compounds into two classes: active and inactive. All molecular descriptors selected by PCA model are electronic parameters. The hierarchical cluster analysis (HCA) was also applied on the selected descriptors. Based on the 5 electronic descriptors selected, it is possible to suggest new compounds to be synthesized with activity against CNS cancer. In addition to that, a supervised partial least squares discriminant analysis (PLS-DA) model was built and successfully applied to discriminate rutaecarpine analogues, being validated through an independent test set and considered robust to overfitting.Keywords: central nervous system cancer, quinazoline-beta-carboline-5-one, B3LYP, rutaecarpine analogous Introduction Brain tumors are rare, but their incidence and mortality rates have been increasing over the past decades in several countries, especially among older people.1-3 Although very little about brain tumors is known, it is believed that genetic factors, hormonal and environmental factors are related to the evolution of this disease. 4,5 The central nervous system (CNS) comprises the brain and spinal cord. Patients who experience personality changes, apathy, early dementia, constant headache or even depression can have a brain tumor. 6,7 Data from the American Cancer Society (ACS) sh...

Synthesis, Antimicrobial Activity and Structure-Activity Relationship of Some 5-Arylidene-thiazolidine-2,4-dione Derivatives

“…This procedure has been applied with success in similar works. [32][33][34][35][36][37] By applying PCA procedure on the selected descriptors by Fisher's weight, after many attempts, the best result was obtained with four molecular descriptors: dipole moment (μ), bond angle between atoms 5, 6 and 18 (A 5-6-18 ), partial atomic charge on atom 18 (Q 18 ) and bond orders between atoms 5 and 17 (O 5-17 ).…”

Application of Hartree-Fock Method for Modeling of Bioactive Molecules Using SAR and QSPR

“…In general, reports show that these modifications are made throughout small changes in the leading compound structure, followed by trials in laboratory to quantify the variations in the biological activity due to changes in the molecular structure [91].…”

Potassium tert-Butoxide-Mediated Cascade Synthesis of Rutaecarpine Alkaloid Analogues: Access to Molecular Complexity on Multigram Scales

“…Among them, alkaloid rutaecarpine and its analogues (Figure ), isolated from the Chinese medicinal plant Evodia rutaecarpa, show multiple activities including anti-inflammatory, antitumor, antithrombosis, and antiobesity effects . Some of its analogues display enhanced activity against various tumor cell lines. − …”