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The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
CpG islands are located at the 5’-end of genes and occupy around 60% of human gene promoters. Although the majority of CpG sites in the genome are methylated in normal cells, most of the CpG islands remain un-methylated during differentiation and development, as presumably more gene expression occurs during differentiation and development but relatively less gene expression occurs in mature healthy cells. The reduction or ablation of gene expression by DNA methylation is thought to be due to a steric effect which prevents recruitment of regulatory proteins including transcription factors to the DNA. The methylation patterns in the genome are created and maintained by methyltransferase enzymes which transfer methyl groups to DNA bases or proteins such as histones. Methylated bases have also been shown to provide preferred binding sites for methyl-binding domain proteins which are known to repress gene expression through interactions with histone deacetylases (HDACs). In addition to cancer (i.e. carcinogenesis), DNA methylation has also been shown to be associated with a number of key biological processes including genomic imprinting, X-chromosome inactivation, repetitive elements repression, and aging.
Drug Nanocrystals
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
M. Ermelinda S. Eusébio, Ricardo A. E. Castro, Joäo Canotilho
To prevent aggregation, nanocrystallisation must be carried out in the presence of stabilisers [121]. These are adsorbed at the particle surface and stabilisation may be achieved by electrostatic repulsion among particles, by steric effects, or by a combination of both. Electrostatic stabilisers typically include ionic surfactants and polymers (e.g., sodium dodecyl sulphate [122, 123], sodium alginate [54]) [124–126]. For electrostatic stabilisation of nanocrystals, the zeta potential should be in excess of 30 mV [1]. Concerning brain delivery, some authors report that negatively charged particles should be used, as highly positively charged nanoparticles displayed toxicity to the BBB [127]. Electrostatic stabilisation is effective in aqueous media, but problems may arise when converting into dry solid forms. Moreover, stability may also be affected by changes in both pH and ionic strength. Steric stabilisation is not dependent on these effects, although it shows a greater temperature dependency [1], and may be used to prepare nanocrystals both in aqueous and non-aqueous media. For steric stabilisation, non-ionic amphiphilic surfactants or polymers are used (e.g., Tween 80, poloxamers, polyvinyl alcohol, polyvinylpyrrolidone [123–125]). Nanosuspensions may also be made more stable by combining electrostatic and steric effects in the same stabiliser molecule [118] or combining non-ionic and ionic stabilisers [128].
Swarm Intelligence and Evolutionary Algorithms for Drug Design and Development
Published in Sandeep Kumar, Anand Nayyar, Anand Paul, Swarm Intelligence and Evolutionary Algorithms in Healthcare and Drug Development, 2019
The molecular parameters used for making an account for all electronic properties, hydrophobility, steric effect as well as topology can be determined via experimenting practically or theoretically via computational chemistry [53,54].
Benzenesulfonamides with different rigidity-conferring linkers as carbonic anhydrase inhibitors: an insight into the antiproliferative effect on glioblastoma, pancreatic, and breast cancer cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Francesco Liguori, Simone Carradori, Roberto Ronca, Sara Rezzola, Serena Filiberti, Fabrizio Carta, Marta Turati, Claudiu T. Supuran
To better explore the chemical space within the ureido benzenesulfonamide scaffold and to study the feasibility of the synthetic scheme to a larger number of derivatives, we attempted to synthesise a library of compounds characterised by: (i) a primary benzenesulfonamide as ZBG; (ii) an imidazolidin-2-one linker in para or meta position with respect to the sulphonamide function; (iii) a tail characterised by chemical diversity in terms of electronic and steric effects (aliphatic chains, differently substituted aryl groups, benzyl moieties) (Figure 1). The insertion of the cyclic ureido moiety, already reported by Zhang34 and by Mboge et al.33, resulted in particular interest, both from the chemical and pharmacological viewpoints, as controversial results were claimed in some recent works33, according to which sulphonamides, such as SLC-149 and congeners do not show antiproliferative activity and that the CA IX in the used cell lines does not possess a catalytic role in hypoxic tumours33.
In silico evaluation of multispecies toxicity of natural compounds
Published in Drug and Chemical Toxicology, 2021
Sripriya N., Ranjith Kumar M., Ashwin Karthick N., Bhuvaneswari S., Udaya Prakash N. K.
To relate the physiochemical properties to biological activity, relevant descriptors called molecular descriptors (MD) are used. The relevance of molecular descriptors in toxicity prediction depends on the endpoints, concerned biological system and class of chemicals (Balls et al. 2012). More than 2000 molecular descriptors such as molecular volume, shape, dipole moment, the number of atoms, steric effect, refractivity, dissociation constant, electronegativity, octanol/water partition coefficient can be generated and used for in silico predictions (Hansch 1993, Todeschini and Consonni 2008). One such tool in evaluating the toxicity of any compound is Toxicity Evaluation Software Tool (TEST), which integrates and predicts the toxicity based on the compound’s toxic mechanism and critical structural similarities. Thus, the multispecies toxicity of natural compounds was evaluated using QSAR-TEST in this study.
Mechanistic and biological characterisation of novel N 5-substituted paullones targeting the biosynthesis of trypanothione in Leishmania
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Andrea Medeiros, Diego Benítez, Ricarda S. Korn, Vinicius C. Ferreira, Exequiel Barrera, Federico Carrión, Otto Pritsch, Sergio Pantano, Conrad Kunick, Camila I. de Oliveira, Oliver C. F. Orban, Marcelo A. Comini
The kinetic and thermodynamic studies strongly suggest that the binding site of MOL2008 and 20, at least partially, overlaps with that of SP and GSP. GspS is an enzyme capable to catalyse the formation of GSP but not of T(SH)2 due to steric effects that preclude binding of GSP to the enzyme’s active site36. Thus, we reasoned that if occupation of the GSP-binding site by N5-substituted paullones is relevant for TryS inhibition, then GspS should not be inhibited by these compounds. Confirming our hypothesis, GspS from the Kinetoplastid Crithidia fasciculata proved refractory to MOL2008, which caused a minor inhibition (20%) of the enzyme at the highest concentration tested of 300 µM (see Supplementary Information for details about protein preparation and enzymatic assay). This concentration is 2000-fold higher than that needed to produce 50% inhibition of LiTryS (Table 1).