Design, Synthesis, and Biological Evaluation of Unconventional Aminopyrimidine, Aminopurine, and Amino‐1,3,5‐triazine Methyloxynucleosides

Abstract

Herein we describe a class of unconventional nucleosides (methyloxynucleosides) that combine unconventional nucleobases such as substituted aminopyrimidines, aminopurines, or aminotriazines with unusual sugars in their structures. The allitollyl or altritollyl derivatives were pursued as ribonucleoside mimics, whereas the tetrahydrofuran analogues were pursued as their dideoxynucleoside analogues. The compounds showed poor, if any, activity against a broad range of RNA and DNA viruses, including human immunodeficiency virus (HIV). This inactivity may be due to lack of an efficient metabolic conversion into their corresponding 5'-triphosphates and poor affinity for their target enzymes (DNA/RNA polymerases). Several compounds showed cytostatic activity against proliferating human CD4(+) T-lymphocyte CEM cells and against several other tumor cell lines, including murine leukemia L1210 and human prostate PC3, kidney CAKI-1, and cervical carcinoma HeLa cells. A few compounds were inhibitory to Moloney murine sarcoma virus (MSV) in C3H/3T3 cell cultures, with the 2,6-diaminotri-O-benzyl-D-allitolyl- and -D-altritolyl pyrimidine analogues being the most potent among them. This series of unconventional nucleosides may represent a novel family of potential antiproliferative agents.

Exploration of the Chemistry and Biological Properties of Pyrimidine as a Privilege Pharmacophore in Therapeutics

“…2-(4-methyl-5-nitro-6-(pyrrolidin-1-yl)-pyrimidin-2-ylamino)-3-phenylpropanoic acid (Fig. 39) exhibited antiviral activity with IC 50 of 73 μg mLG 1 (Danesh et al, 2015) while 2,4diaminopyrimidine derivative (IC 50 = 13 μg mLG 1 ) was the most effective among the series screened by Fernandez-Cureses et al (2015). Other recently reported pyrimidines with promising antiviral activities in Fig.…”

Synthesis of Diaminopyrimidine Sulfonate Derivatives and Exploration of Their Structural and Quantum Chemical Insights via SC-XRD and the DFT Approach

“…5 Whatever the origin of pyrimidine occurrence, whether natural or synthesized, it has proved to be privileged for therapeutics as remarkable pharmacophores. Some of the fused heterocyclic ring systems are potential antibacterial (5-amino-thiazolo [4,5d]pyrimidine), 6 antifungal (pyrrolo [2,3-d]pyrimidines), 7 anti-viral (2,4-diaminopyrimidinederivative), 8 anticancer (pyrazolopyrimidine), 9 anti-inflammatory and analgesic (N-(4-hydroxy-6-tosyl-5,6,7,8-tetrahydropyrido [4,3-d]pyrimidin-2-yl)isonicotinamide), 10 and antimalarial (sulfadiazine) agents, as shown in Figure 1. These heterocyclic compounds are highly recognized chemical building blocks with significant medicinal applications.…”

Conservation of antiviral activity and improved selectivity in PMEO-DAPym upon pyrimidine to triazine scaffold hopping

“…Chloro-substituted triazines are not very reactive and substitution of the chlorine atom by alcohols requires strong reaction conditions (Afonso et al, 2006). The synthesis of PMEO-5-aza-DAPym (19, Scheme 1) was initially attempted following a procedure similar to our described method for the synthesis of amino-1,3,5-triazine methyloxynucleosides (Fernández-Cureses et al, 2015). Treatment of 6-chloro-2,4-diamino-1,3,5-triazine (17) with an excess of phosphonate 18 (Naperville et al, 1999), in the presence of sodium hydride under microwave irradiation at 100 °C (Scheme 1) failed to produce the desired phosphonate 19 and led to a complex reaction mixture that could not be identified.…”