Modeling of Purine Derivatives Transport across Cell Membranes Based on Their Partition Coefficient Determination and Quantum Chemical Calculations

Abstract

Mercaptopurine (6-MP), thioguanine (6-TG), and azathioprine (AZA) are purine antimetabolites introduced as anticancer or immunosuppressive drugs decades ago. Methylated AZA, called MAZA, is among the investigational drugs. The present study compares MAZA to the widely recognized drugs AZA, 6-MP, and 6-TG with respect to the ability of being transported across cell membranes. The obtained octanol/water phases partition coefficients and results of quantum chemical calculations predict the following sequence of hydrophobicity: MAZA > AZA > 6-TG > 6-MP.

The interactome: Predicting the protein-protein interactions in cells

“…Proper selection of the protein domain is necessary [102][103][104][105][106][107][108]. In addition to pure chemical data [109][110][111][112][113][114][115][116] in the context of the Drug Discovery [117][118][119][120][121][122][123][124][125][126][127], there is also a need for some knowledge on protein-protein interactions, the high quality structural prediction of proteins [2,[128][129][130][131][132][133][134][135][136] and their inhibitors, and a detailed understanding of how those inhibitors affect the molecular recognition between proteins. The development of theoretical methods for function annotation clearly shows that a detailed analysis of local characteristics of the protein chain can significantly improve accuracy.…”

Synthesis and Anti-tumor Activities of Novel [1,2,4]triazolo[1,5-a]pyrimidines

“…The clinical application of 6-mercaptopurine [1] and thioguanine [2] in cancer treatment and the development of potent purine based CDK inhibitors, such as Purvalanols [3,4], Olomoucine [3] and Roscovitine [5], together with other findings based on the purine scaffold, have largely inspired and directed parallel developments in the chemistry and anti-tumor research of related heterocyclic analogs, including pyrrolo-pyrimidines [6], pyrazolo-pyrimidines [7,8], imidazo-pyridines [9], triazolo-pyrimidines [10], pyrazolo-pyridazines [11] and imidazo-pyrazines [12]. [1,2,4]Triazolo [1,5-a]pyrimidines, a subtype of purine bioisosteric analogs, were also reported to possess potential anti-tumor activities, especially those bearing functional groups at C-5, C-6 or C-7 positions [13][14][15]. However, substitutions at the C-2 position seemed to be less attractive.…”

“…However, substitutions at the C-2 position seemed to be less attractive. Recently, some [1,2,4]triazolo [1,5-a]pyrimidines bearing functional group at C-2 and C-7 positions, were disclosed for their good antiproliferative ability [16,17], which greatly encouraged us to explore more potent analogs of such structures. Therefore, we carried out a series of modifications upon the [1,2,4]triazolo [1,5-a]pyrimidine scaffold by introducing functional groups into C-2 and C-7 positions.…”

“…Therefore, we carried out a series of modifications upon the [1,2,4]triazolo [1,5-a]pyrimidine scaffold by introducing functional groups into C-2 and C-7 positions. Herein, we report the synthesis and in vitro anti-tumor evaluation of a new series of 7-anilino-5-methyl-2-(3-((5-(substituted-aminomethyl)furan-2-yl)methylthio)propyl) [1,2,4]triazol [1,5-a]pyrimidines (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Synthesis and Biological Evaluation of New 4β-5-Fu-substituted 4'-Demethylepipodophyllotoxin Derivatives

“…Natural L-amino acids are good pharmacophore carriers as well as good kinetophores, so we sought to combine demethyepipodophyllotoxin (an inhibitor of topoisomerase II) and 5-FU (a nucleoside antimetabolite) through a peptide bond derived from a natural L-amino acid. At the same time, the significance of a drug's lipophilicity has widely been recognized by many researchers working in the drug discovery and drug design fields [31,32]. The absorption, distribution, metabolism, excretion and toxicity of a drug are closely related with its lipophilicity, so this property must be considered in the rational design of anticancer drugs [33,34].…”