Design, synthesis, and biological evaluation of unconventional aminopyrimidine, aminopurine, and amino-1,3,5-triazine methyloxynucleosides

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.S.d.C. thanks the Spanish Ministry of Science and Innovation for a postdoctoral Juan de la Cierva contract (JDC-MICINN). The authors also thank the Spanish MINECO (SAF2012-39760-C02), the Comunidad de Madrid (BIPEDD-2-CM S-2010/BMD-2457), and KU Leuven (GOA No. 10/014) for financial support, and Ms. Lizette van Berckelaer and Ms. Leen Ingels (KU Leuven) for dedicated technical assistancePeer Reviewe