title: 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.
authors.affiliation: Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid (Spain).
authors.forename: Gloria
authors.initials: G
authors.lastname: Fernández-Cureses
authors.forename: Sonia
authors.initials: S
authors.lastname: de Castro
authors.forename: María-Luisa
authors.initials: ML
authors.lastname: Jimeno
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008980:Moloney murine sarcoma virus / Q000187:drug effects; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011687:Purines; D011743:Pyrimidines; D014227:Triazines; C030986:pyrimidine; C030985:purine
keywords: antiproliferation; drug design; medicinal chemistry; nucleosides; nucleotides