New carbocyclic N(6)-substituted adenine and pyrimidine nucleoside analogues with a bicyclo[2.2.1]heptane fragment as sugar moiety; synthesis, antiviral, anticancer activity and X-ray crystallography

Constantin I Tănase; Constantin Drăghici; Ana Cojocaru; Anastasia V Galochkina; Jana R Orshanskaya; Vladimir V Zarubaev; Sergiu Shova; Cristian Enache; Maria Maganu

doi:10.1016/j.bmc.2015.08.033

New carbocyclic N(6)-substituted adenine and pyrimidine nucleoside analogues with a bicyclo[2.2.1]heptane fragment as sugar moiety; synthesis, antiviral, anticancer activity and X-ray crystallography

Bioorg Med Chem. 2015 Oct 1;23(19):6346-54. doi: 10.1016/j.bmc.2015.08.033. Epub 2015 Sep 1.

Authors

Constantin I Tănase¹, Constantin Drăghici², Ana Cojocaru³, Anastasia V Galochkina⁴, Jana R Orshanskaya⁵, Vladimir V Zarubaev⁶, Sergiu Shova⁷, Cristian Enache⁸, Maria Maganu²

Affiliations

¹ National Institute for Chemical-Pharmaceutical Research and Development, 112 Vitan Av., 031299 Bucharest 3, Romania. Electronic address: cvtanase@gmail.com.
² Organic Chemistry Center 'C.D.Neniţescu, 202 B Splaiul Independentei, Bucharest 060023, Romania.
³ National Institute for Chemical-Pharmaceutical Research and Development, 112 Vitan Av., 031299 Bucharest 3, Romania.
⁴ Influenza Research Institute, Dept. Chemotherapy, 15/17 Prof. Popova Str., St. Petersburg 197376, Russian Federation. Electronic address: nastyagalochkina@yandex.ru.
⁵ Influenza Research Institute, Dept. Chemotherapy, 15/17 Prof. Popova Str., St. Petersburg 197376, Russian Federation. Electronic address: deina89@mail.ru.
⁶ Influenza Research Institute, Dept. Chemotherapy, 15/17 Prof. Popova Str., St. Petersburg 197376, Russian Federation. Electronic address: zarubaev@influenza.spb.ru.
⁷ Institute of Macromolecular Chemistry 'Petru Poni', Iasi, Romania.
⁸ Central Laboratory for Phytosanitary Quarantine, 11, Voluntari Blvd., 077190 Voluntari, Romania.

PMID: 26361736
DOI: 10.1016/j.bmc.2015.08.033

Abstract

New nucleoside analogues with an optically active bicyclo[2.2.1]heptane skeleton as sugar moiety and 6-substituted adenine were synthesized by alkylation of 6-chloropurine intermediate. Thymine and uracil analogs were synthesized by building the pyrimidine ring on amine 1. X-ray crystallography confirmed an exo-coupling of the thymine to the ring and an L configuration of the nucleoside analogue. The library of compounds was tested for their inhibitory activity against influenza virus A∖California/07/09 (H1N1)pdm09 and coxsackievirus B4 in cell culture. Compounds 13a and 13d are the most promising for their antiviral activity against influenza, and compound 3c against coxsackievirus B4. Compounds 3b and 3g were tested for anticancer activity.

Keywords: Anticancer; Antiviral activity; Bicyclo[2.2.1]heptane nucleosides; Chloropurine; Pyrimidine nucleosides; X-ray-crystallography.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenine Nucleotides / chemistry*
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Antiviral Agents / chemical synthesis*
Antiviral Agents / pharmacology
Bridged Bicyclo Compounds / chemistry*
Cell Line, Tumor
Cell Survival / drug effects
Chlorocebus aethiops
Crystallography, X-Ray
Dogs
Drug Screening Assays, Antitumor
Enterovirus B, Human / drug effects
Humans
Influenza A Virus, H1N1 Subtype / drug effects
Madin Darby Canine Kidney Cells
Molecular Conformation
Pyrimidine Nucleosides / chemistry*
Structure-Activity Relationship
Vero Cells

Substances

Adenine Nucleotides
Antineoplastic Agents
Antiviral Agents
Bridged Bicyclo Compounds
Pyrimidine Nucleosides
bicyclo(2.2.1)heptene