Lomustine Analogous Drug Structures for Intervention of Brain and Spinal Cord Tumors: The Benefit of In Silico Substructure Search and Analysis

Lomustine is a nitrosourea anticancer agent shown to be effective for treatment of childhood medulloblastoma. In silico substructure searches produced 17 novel nitrosourea agents analogous to lumustine and retaining activity for DNA alkylation and cytotoxic activity. The mean values for Log P, polar surface area, formula weight, number of oxygens & nitrogens, and rotatable bonds were 2.524, 62.89 Anstroms2, 232.8, 5, and 2, respectively. All 17 agents have formula weight less than 450 and Log P less than 5, two criteria preferred for blood-brain barrier penetration. These agents have a polar surface area less than 90 Angstroms2. Each show zero violations of the Rule of five indicating favorable drug likeness and oral drug activity. Hierarchical cluster analysis indicated that 16 of the novel agents were highly similar to lomustine, save for agent 12 which bears a hydroxylated branched carbon substituent. A total of 17 novel anticancer agents were elucidated having molecular properties very effective for penetrating through the BBB and into the central nervous system. This study shows the effectiveness of in silico search and recognition of anticancer agents that are suitable for the clinical treatment of brain tumors.

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Revisiting the General Solubility Equation: In Silico Prediction of Aqueous Solubility Incorporating the Effect of Topographical Polar Surface Area

Journal of Chemical Information and Modeling ◽

10.1021/ci200387c ◽

2012 ◽

Vol 52 (2) ◽

pp. 420-428 ◽

Cited By ~ 61

Author(s):

Jogoth Ali ◽

Patrick Camilleri ◽

Marc B. Brown ◽

Andrew J. Hutt ◽

Stewart B. Kirton

Keyword(s):

Surface Area ◽

In Silico ◽

Aqueous Solubility ◽

In Silico Prediction ◽

Polar Surface Area ◽

Polar Surface ◽

Solubility Equation

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Topological Polar Surface Area Defines Substrate Transport by Multidrug Resistance Associated Protein 1 (MRP1/ABCC1)

Journal of Medicinal Chemistry ◽

10.1021/jm801389m ◽

2009 ◽

Vol 52 (4) ◽

pp. 1214-1218 ◽

Cited By ~ 42

Author(s):

Janaina Fernandes ◽

Cerli R. Gattass

Keyword(s):

Multidrug Resistance ◽

Surface Area ◽

Polar Surface Area ◽

Substrate Transport ◽

Polar Surface ◽

Topological Polar Surface Area

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Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.5b01962 ◽

2016 ◽

Vol 59 (6) ◽

pp. 2841-2846 ◽

Cited By ~ 17

Author(s):

Steffen V. F. Hansen ◽

Elisabeth Christiansen ◽

Christian Urban ◽

Brian D. Hudson ◽

Claire J. Stocker ◽

...

Keyword(s):

Fatty Acid ◽

Free Fatty Acid ◽

Surface Area ◽

Receptor Agonist ◽

Polar Surface Area ◽

In Vivo Efficacy ◽

Polar Surface

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The effect of the solvent nature on the quinoline derivatives physicochemical characteristics

Butlerov Communications ◽

10.37952/roi-jbc-01/19-60-11-31 ◽

2019 ◽

Vol 60 (11) ◽

pp. 31-39

Author(s):

Vladimir V. Shcherbakov ◽

◽

Svetlana V. Kurbatova ◽

Margarita N. Zemtsova ◽

◽

...

Keyword(s):

Dipole Moment ◽

Surface Area ◽

Chemical Nature ◽

Solvation Energy ◽

Biologically Active ◽

Quinoline Derivatives ◽

Polar Surface Area ◽

Polar Surface ◽

Solvent Nature ◽

Derivatives Of

The influence of the solvent nature on some physicochemical parameters of the quinoline derivatives molecules is investigated. It was noted that a variety of intermolecular interactions arising between the dissolved substance and the solvent and often accompanied by the phenomena of solvation, association, etc. leads to a variety of structural and energy changes in such systems and complicating their description. The most urgent problems of solutions include issues related to the solubility and bioavailability of biologically active compounds and drugs, the study of their ability to dissolve, the permeability of biological barriers, targeted delivery, etc., as well as the problems associated with the study of sorption of organic compounds from aqueous-organic eluents, for example, in liquid chromatography. Derivatives of quinoline (4-carboxy- and 4-aminoquinoline), known as potential drugs with various types of pharmacological action, were used as research objects. Using quantum chemical calculations, the dipole moment of the amino and carboxy derivatives of quinoline was determined, and the data obtained for vacuum and in solvents of various chemical nature were compared. A significant effect of solvent polarity on the dipole moment of quinoline derivatives dissolved in these solvents was found. The values of the solvation energy of quinoline derivatives in solvents of various chemical nature are calculated. It is shown that a change in the solvation energy is determined both by the structure of the molecules of the quinoline derivatives and by the polarity of the solvent. A nonlinear change in the energy of solvation with a change in the polarity of the solvent is established. A comparison is made of the values of the quinoline derivatives molecules polar surface area in solvents of various chemical nature. It was found that the polar surface area of the studied compounds changes slightly with a change in the nature of the solvent.

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