Oncology exploration: charting cancer medicinal chemistry space

Lloyd, David G.; Golfis, Georgia; Knox, Andrew J. S.; Fayne, Darren; Meegan, Mary J.; Oprea, Tudor I.

doi:10.1016/s1359-6446(05)03688-3

Cited by 46 publications

(36 citation statements)

References 46 publications

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“…The Henderson-Hasselbalch equation (Eq 13) describes the activity ratio of neutral form molecules and ionized form molecules. [13] where a d and a n are the ionized molecular form and the neutral molecular form respectively, i is 1 for acids and −1 for bases; pK a is the negative logarithm of the dissociation constant. Therefore [14] The relationship of the activities (a n and a d ) and the total molecular concentration can be expressed by Eq 15 and Eq 16, 28 [15] [ 16] W is the volumetric water fraction, γ the activity coefficient, and K n and K d the sorption coefficients of the neutral and the ionized molecules respectively.…”

Section: Methodsmentioning

confidence: 99%

A Cell-Based Molecular Transport Simulator for Pharmacokinetic Prediction and Cheminformatic Exploration

2006

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In the body, cell monolayers serve as permeability barriers, determining transport of drug molecules from one organ or tissue compartment to another. After oral administration, for example, drug transport across the epithelial cell monolayer lining the lumen of the intestine determines the fraction of drug in the gut that is absorbed by the body. By modeling passive transcellular transport properties in the presence of an apical to basolateral concentration gradient, we demonstrate how a computational, cell-based molecular transport simulator can be used to define a physicochemical property space occupied by molecules with desirable permeability and intracellular retention characteristics. Considering extracellular domains of cell surface receptors located on the opposite side of a cell monolayer as a drug's desired site-of-action, simulation of transcellular transport can be used to define the physicochemical properties of molecules with maximal transcellular permeability but minimal intracellular retention. Arguably, these molecules would possess very desirable features: least likely to exhibit non-specific toxicity, metabolism and side effects associated with high (undesirable) intracellular accumulation; and, most likely to exhibit favorable bioavailability and efficacy associated with maximal rates of transport across cells and minimal intracellular retention, resulting in (desirable) accumulation at the extracellular site-of-action. Calculated permeability predictions showed good correlations with PAMPA, Caco2, and intestinal permeability measurements, without "training" the model and without resorting to statistical regression techniques to "fit" the data. Therefore, cell-based molecular transport simulators could be useful in silico screening tools for chemical genomics and drug discovery.

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Section: Methodsmentioning

confidence: 99%

A Cell-Based Molecular Transport Simulator for Pharmacokinetic Prediction and Cheminformatic Exploration

2006

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“…underlying the observed variables and has been applied to immunologic datasets, analysis of microarrays and drug libraries, clinical investigations to defi ne disease profi les, and analysis of psychologic or psychiatric assessments (11)(12)(13)(14)(15). In psychologic assessments, this analysis can take the form of uncovering the core opinions and attitudes (unobservable factors) that result in the answers given in a questionnaire (observable variables).…”

Section: Neuroradiology: Mr Spectroscopic Imaging Factor Analysis In mentioning

confidence: 99%

Factor Analysis of Proton MR Spectroscopic Imaging Data in HIV Infection: Metabolite-derived Factors Help Identify Infection and Dementia

Mohamed¹,

Lentz²,

Lee³

et al. 2010

Radiology

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Purpose:To develop a relevant pathophysiologic model of human immunodefi ciency virus (HIV)-associated dementia by studying regional variations in metabolite levels measured with magnetic resonance (MR) spectroscopic imaging and their relationship to immunologic measures and cognitive dysfunction. Materials and Methods:This was a HIPAA-compliant, institutional review boardapproved study involving written informed consent. Distributions of N -acetylaspartate (NAA), choline (Cho), and creatine (Cr) concentrations in 94 subjects (20 seronegative controls and 74 HIV-positive subjects; 34 of the HIV-positive subjects having HIV-associated dementia; 63 men, 31 women; mean age, 40 years) were determined with proton (hydrogen 1 [ 1 H]) MR spectroscopic imaging. HIV-positive subjects underwent neuropsychological testing and blood and cerebrospinal fl uid (CSF) analysis. Factor analysis was utilized to determine associations between metabolites across regions. Analysis of variance and t tests were used to isolate differences between cohorts. Results:A "Cho factor" differentiated seronegative controls from HIV-infected cohorts, indicating elevated Cho levels across deep gray and white matter regions of HIV-positive individuals. An "NAA factor" differentiated those with dementia from those without and correlated best with psychomotor and executive function tests. A "Cr factor" indicated Cr elevations correlated with CSF monocyte chemoattractant protein-1 levels. NAA and Cr factor scores were strongly weighted to metabolite changes in white matter regions. Conclusion:These results highlight the importance of white matter involvement in HIV-associated dementia and support the current pathogenesis model of glial cell proliferation in HIV infection, denoted by regional Cho elevations, and neuronal dysfunction and/or death, denoted by NAA decreases, associated with dementia. Factor analysis of MR spectroscopic imaging data is a useful method for determining regional metabolic variations in HIV infection and its neuropsychological correlates.q RSNA, 2010

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“…The limitations of current anticancer drugs and rapid development of drug resistance Pechan, 1991;McCubrey et al, 2006) have highlighted the need for the discovery of new anticancer agents, preferably with novel mechanisms of action. To identify new chemical entities for a more effective treatment of cancer, drug designers can follow many strategies, but the crucial decision is always the selection of a suitable starting point from the vast chemical space (Lloyd et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and anticancer effects of pongamol derivatives on mitogen signaling and cell cycle kinases

et al. 2011

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A series of oxazole and pyrazole derivatives of pongamol (1) were designed and synthesized to examine their anti-cancer activity. The cytotoxicity of these compounds was examined in three different human tumor cell lines, IMR-32, HeLa and Jurkat. Although all compounds tested were quite effective than the pongamol against all the three different types of cancer cell lines examined, the compounds (2), (5), and (6) were found to be the most active compounds of this series.

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Oncology exploration: charting cancer medicinal chemistry space

Cited by 46 publications

References 46 publications

A Cell-Based Molecular Transport Simulator for Pharmacokinetic Prediction and Cheminformatic Exploration

A Cell-Based Molecular Transport Simulator for Pharmacokinetic Prediction and Cheminformatic Exploration

Factor Analysis of Proton MR Spectroscopic Imaging Data in HIV Infection: Metabolite-derived Factors Help Identify Infection and Dementia

Synthesis and anticancer effects of pongamol derivatives on mitogen signaling and cell cycle kinases

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