Synthesis, structural, conformational and DFT studies of N-3 and O-4 alkylated regioisomers of 5-(hydroxypropyl)pyrimidine

Because of the great pharmacological potential of the pyrimidine motif, novel C-5 substituted N-3 acyclic and O-4 acyclic pyrimidine derivatives were prepared as an interesting class of compounds for biological evaluation. Introduction of the 2,3-dihydroxypropyl (DHP) and penciclovir (PCV)-like side chains to 2-methoxypyrimidin-4-one (2) afforded a mixture of N- and O-acyclic pyrimidine nucleosides in the ratio of 54: 29 (3:4) and 57:21 (5:6) with N-3 isomer being dominant. Distinction between N- and O-alkylated pyrimidine moiety was deduced from extensive experimental FT-IR, HPLC-MS and 1D (H-1, C-13) and 2D (COSY, HMQC and HMBC) NMR analyses. The N-, O-regioisomers were also examined by computational method at density functional theory (DFT) RB3LYP/6-31G(d), 6-31G** and 6-31+G* levels. DFT global chemical reactivity descriptors (total energy, chemical hardness, electronic chemical potential and electrophilicity) were calculated for the isomers and used to predict and describe their relative stability and reactivity. The chemical reactivity indices were related to the C-2-N-3-C-4 bond angle. Theoretical predictions can be used to compare chemical reactivity and stability with future biological evaluation and behaviour of these compounds.This is the peer-reviewed version of the following article: Salihovic, M.; Osmanović, A.; Špirtović-Halilović, S.; Roca, S.; Mescic, A.; Vujisić, L. V.; Trifunović, S. S.; Završnik, D.; Sofic, E. Synthesis, Structural, Conformational and DFT Studies of N-3 and O-4 Alkylated Regioisomers of 5-(Hydroxypropyl)Pyrimidine. Journal of Molecular Structure 2015, 1091, 170–176. [https://doi.org/10.1016/j.molstruc.2015.02.078

Therapeutic Perspective of Vitamin C and Its Derivatives

l-Ascorbic acid (ASA), vitamin C, is a ubiquitous carbohydrate-like compound that has an essential role in a number of cellular processes, such as collagen synthesis, cellular oxidation, and various hydroxylation reactions. ASA is a biomolecule of critical importance for protection of cellular components against oxidative damage caused by toxic free radicals and other reactive oxygen species (ROS) that are involved in the development of various types of chronic diseases. Vitamin C has a switchover role from being an antioxidant in physiological conditions to a prooxidant under pathologic conditions. Moreover, some l-ascorbic acid derivatives exhibit strong and selective antitumor and antiviral activity. This review emphasizes the advances on diverse and potent biological profiles of l-ascorbic acid and its derivatives, and their perspective in the development of new bioactive chemical entities in the future. The work is primarily addressed at antioxidant, anticancer, and antiviral potencies of l-ascorbic acid and compounds containing its butenolide structural motif

C-5 Hydroxyethyl and Hydroxypropyl Acyclonucleosides as Substrates for Thymidine Kinase of Herpes Simplex Virus Type 1 (HSV-1 TK): Syntheses and Biological Evaluation

The efficient syntheses of 5-(2-hydroxyethyl)- and 5-(3-hydroxypropyl)-substituted pyrimidine derivatives bearing 2,3-dihydroxypropyl, acyclovir-, ganciclovir- and penciclovir-like side chains are reported. A synthetic approach that included the alkylation of an N-anionic-5-substituted pyrimidine intermediate (method A) provided the target acyclonucleosides in significantly higher overall yields in comparison to those obtained by method B using sylilation reaction. The phosphorylation assays of novel compounds as potential substrates for thymidine kinase of herpes simplex virus type 1 (HSV-1 TK) showed that solely pyrimidine 5-substituted acyclonucleosides with a penciclovir-like side chain acted as a fraudulent substrates of HSV-1 TK. Moreover, the uracil derivative with penciclovir-like side chain with less bulky 2-hydroxyethyl substituent at C-5 proved to be a better substrate than the corresponding one with a 3-hydroxypropyl substituent. Therefore, this acyclonucleoside was selected as a lead compound for the development of a positron emission tomography HSV-1 TK activity imaging agent.ISSN:1420-304

Green solvent-free synthesis of new N-heterocycle-L-ascorbic acid hybrids and their antiproliferative evaluation

The authors’ aim was to improve the application of copper-catalyzed azide-alkyne cycloaddition in the synthesis of hybrids containing biologically significant nucleobases and L-ascorbic acid scaffolds by introducing an environmentally friendly and waste-free ball mill. Results: Two series of hybrids with a purine, pyrrolo[2,3-d]pyrimidine or 5-substituted pyrimidine attached to 2,3-dibenzyl-L-ascorbic acid via a hydroxyethyl- (15a–23a) or ethylidene-1,2,3-triazolyl (15b–23b) bridge were prepared by ball milling and conventional synthesis. The unsaturated 6-chloroadenine L-ascorbic acid derivative 16b can be highlighted as a lead compound and showed strong antiproliferative activity against HepG2 (hepatocellular carcinoma) and SW620 (colorectal adenocarcinoma) cells. Conclusion: Mechanochemical synthesis was superior in terms of sustainability, reaction rate and yield, highlighting the advantageous applications of ball milling over classical reactions

Green solvent-free synthesis of new N-heterocycle-L-ascorbic acid hybrids and their antiproliferative evaluation

The authors’ aim was to improve the application of copper-catalyzed azide-alkyne cycloaddition in the synthesis of hybrids containing biologically significant nucleobases and L-ascorbic acid scaffolds by introducing an environmentally friendly and waste-free ball mill. Results: Two series of hybrids with a purine, pyrrolo[2,3-d]pyrimidine or 5-substituted pyrimidine attached to 2,3-dibenzyl-L-ascorbic acid via a hydroxyethyl- (15a–23a) or ethylidene-1,2,3-triazolyl (15b–23b) bridge were prepared by ball milling and conventional synthesis. The unsaturated 6-chloroadenine L-ascorbic acid derivative 16b can be highlighted as a lead compound and showed strong antiproliferative activity against HepG2 (hepatocellular carcinoma) and SW620 (colorectal adenocarcinoma) cells. Conclusion: Mechanochemical synthesis was superior in terms of sustainability, reaction rate and yield, highlighting the advantageous applications of ball milling over classical reactions

Synthesis and Biological Evaluation of a New Acyclic Pyrimidine Derivative as a Probe for Imaging Herpes Simplex Virus Type 1 Thymidine Kinase Gene Expression

With the idea of finding a more selective radiotracer for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression by means of positron emission tomography (PET), a novel [18F]fluorine radiolabeled pyrimidine with 4-hydroxy-3-(hydroxymethyl)butyl side chain at N-1 (HHB-5-[18F]FEP) was prepared and evaluated as a potential PET probe. Unlabeled reference compound, HHB-5-FEP, was synthesized via a five-step reaction sequence starting from 5-(2-acetoxyethyl)-4-methoxypyrimidin-2-one. The radiosynthesis of HHB-[18F]-FEP was accomplished by nucleophilic radiofluorination of a tosylate precursor using [18F]fluoride-cryptate complex in 45% ± 4 (n = 4) radiochemical yields and high purity (>99%). The biological evaluation indicated the feasibility of using HHB-5-[18F]FEP as a PET radiotracer for monitoring HSV1-tk expression in vivo