Synthesis, Crystal Structure, and Biological Evaluation of Novel 5-Hydroxymethylpyrimidines.

Marcin Stolarczyk,Aleksandra Mikołajczyk,Iwona Bryndal,Agnieszka Matera-Witkiewicz,Aleksandra Wolska,Anna Pyra,Magdalena Krupińska

doi:10.3390/ma14226916

Marcin Stolarczyk, Aleksandra Mikołajczyk + Show 5 more

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https://doi.org/10.3390/ma14226916

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Abstract

Pyrimidine displays a wide array of bioactivities, and thence, it is still considered a potent unit of new drug research. Its derivative, 5-hydroxymethylpyrimidine, can be found as a scaffold of nontypical nitrogen bases in DNA and as a core of some natural bioactive compounds. In this study, we obtained a series of 5-hydroxymethylpyrimidines that vary in the 4-position by the reduction of proper esters. All compounds were characterized by spectroscopic analysis, and single-crystal X-ray diffraction was performed for some of them. Biological investigations estimated cytotoxic properties against normal (RPTEC) and cancer (HeLa, HepaRG, Caco-2, AGS, A172) cell lines. It was found that the derivatives with an aliphatic amino group at the 4-position are generally less toxic to normal cells than those with a benzylsulfanyl group. Moreover, compounds with bulky constituents exhibit better anticancer properties, though at a moderate level. The specific compounds were chosen due to their most promising IC50 concentration for in silico study. Furthermore, antimicrobial activity tests were performed against six strains of bacteria and one fungus. They demonstrated that only derivatives with at least three carbon chain amino groups at the 4-position have weak antibacterial properties, and only the derivative with 4-benzylsulfanyl constituent exhibits any antifungal action.

Highlights

The pyrimidine ring is a well-known and established constituent of many synthetic drugs commonly used in medicine that demonstrate a variety of pharmacological activities, especially antimicrobial and antineoplastic [1]
We reported that 5-hydroxymethylpyrimidine with a a tetrasulfide bridge at the 4-position has interesting antibacterial and antifungal proptetrasulfide bridge at the 4-position has interesting antibacterial and antifungal properties
In the continuation foregoing research, we present the results the cytotoxic and antimicrobial studyofofour a series of 5-hydroxymethylpyrimidines thatofvary in the 4and antimicrobial study of a series of

Summary

Introduction

The pyrimidine ring is a well-known and established constituent of many synthetic drugs commonly used in medicine that demonstrate a variety of pharmacological activities, especially antimicrobial (e.g., trimethoprim, pyrimethamine, zidovudine, flucytosine) and antineoplastic (e.g., fluorouracil, gemcitabine, cytarabine) [1]. It is still among the leading compounds investigated by medicinal chemists for practical clinical applications of its derivatives [2]. It is ubiquitous in nature due to the presence of nitrogenous bases in DNA and RNA. Modifications in the structures of nucleobases include the process of methylation at the 5-position of the pyrimidine ring and further oxidation of this group by TET (ten-eleven translocation) family proteins [4] to form 5-hydroxymethylcytosine (hmC)

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