Synthesis and cytostatic activity of 7-arylsulfanyl-7-deazapurine bases and ribonucleosides †

576 | Med. Chem. Commun., 2015, 6, 576–580 This journal is © The R a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Flemingovo nam. 2, CZ-16610 Prague 6, Czech Republic. E-mail: hocek@uochb.cas.cz; Tel: +42


Introduction
Several base-modified purine nucleosides are important antitumor agents. 1 Also diverse substituted purine and deazapurine bases exert cytostatic effects, typically through inhibition of kinases and other ATP-or GTP-dependent enzymes. 2 Recently, we have discovered new types of nucleoside cytostatics: 6-hetaryl-7-deazapurine, 3 7-hetaryl-7-deazaadenine 4 and 6-substituted 7-hetaryl-7-deazapurine 5 ribonucleosides.They all showed cytostatic effects at nanomolar concentrations and their mechanism of action is not yet fully understood.They are inhibitors of adenosine kinases, 6,7 but they are substrates at the same time and are phosphorylated to nucleoside triphosphates which then interfere with RNA synthesis or are incorporated to DNA and RNA.In all three series, the most active were derivatives bearing thiophene or furan (Chart 1).
C-H activation reactions are increasingly popular methods in organic synthesis 8 and were also applied in purines and deazapurines.In addition to relatively common and useful C-H arylations of purines reported by us 9 and by others, 10 we have recently reported C-H borylation 11 and C-H sulfenylation 12 of 7-deazapurines.The latter method gave access to 7-arylsulfanyl-7-deazapurine bases, 12 which can be considered extended thia-analogues of 7-aryl-7-deazapurines that are components of the abovementioned nucleoside cytostatics. 4,5Therefore, we decided to prepare a series of 7-phenylsulfanyl-and 7-Ĳ2-thienyl)sulfanyl-7-deazapurine bases and ribonucleosides for screening of their anticancer activity.These extended analogues should show whether the direct conjugation of the (het)aryl group at position 7 is needed for the cytostatic activity of this class of 7-deazapurine nucleosides, 4,5 and in principle, they can also be metabolized to other sulfur-containing nucleosides.
On the other hand, direct methoxylation of 1a-2a by reaction with NaOMe in MeOH was not successful.Therefore, we first protected the NH at position 9 by a SEM group and then the methoxylation of 5a or 6a by MeONa proceeded quantitatively to give intermediates 5h and 6h.Final cleavage of the SEM groups by TFA afforded the desired 6-methoxy-7deazapurines 1h and 2h in high yields (Scheme 3).
In addition, all compounds were also tested on antiviral activity (HCV 1B and 2A replicon and RSV), antimicrobial activity (panel of gram-positive and gram-negative bacteria) and antifungal activity (several strains of Candida species) but did not show any significant activity in these assays.

Conclusions
In conclusion, we have developed a facile methodology for the synthesis of a series of 7-Ĳhet)arylsulfanyl-7-deazapurine bases and nucleosides bearing diverse substituents at position 6.It was based on Cu-catalysed C-H sulfenylation of 6-chloro-7-deazapurine followed by glycosidation and/or cross-coupling or nucleophilic substitutions.While the ribonucleoside analogues were almost entirely inactive, most of the 7-Ĳthienylsulfanyl)-7-deazapurine bases showed significant cytostatic activities.

substituents at position 6
showed significant cytostatic effects at micromolar concentrations.The most active were 6-hetaryl-(2b and 2c) and 6-methylamino and -dimethylamino (2e and 2f) derivatives having IC 50 values in the low micromolar range.Compounds 2e and 2f were non-toxic to BJ and MRC-5 fibroblasts showing a promising therapeutic index.

Table 2
Yields of the transformations of 7-deazapurine nucleosides

Table 3
Cytostatic activities of selected compounds