Potential Orally-Active Heparin-Like Compounds: Synthesis and Anticoagulant Activity

According to World Health Organization, cardiovascular diseases are the first cause of death worldwide. Although health improved in the last decades, lifestyle changes led to an increased incidence of cardiovascular diseases. Currently, the available antithrombotic drugs are associated with significant drawbacks that limit their use and the development of more advantageous drugs with less secondary effects is necessary. A new class of polysulfated small-molecules with anticoagulant and antiplatelet activities was discovered in our group.^{1, 2} However, these polysulfated derivatives showed poor antithrombotic efficacy by in vivo oral administration in mice, predicted to be due to poor absorption in the gastrointestinal (GI) tract.^{2, 3} The main aim of this work was to improve the oral bioavailability of these compounds. In order to get new optimized analogues two strategies were considered: i) obtaining conjugates with bile acids and ii) introduction of a triazole ring.

Naringin-deoxycholic acid conjugate was obtained through a crosslinking reaction using 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoro borate (TBTU) as coupling reagent. Triazole linked xanthone glycoside was obtained through a copper(I)-catalyzed alkyne-azide cycloaddition following by O- and N-deacetylation. Sulfation was successfully achieved with triethylamine-sulfur trioxide adduct under microwave irradiation.

The three sulfated derivatives were screened for anticoagulant activity using the three classic clotting times: activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). All the sulfated compounds prolonged the clotting times and the most active compound was the persulfated naringin-deoxycholic acid conjugate, exhibiting a double concentration value on the APTT (APTT₂) in the micromolar range (around 44 µM). These new optimized analogues with anticoagulant activity are expected to cross the GI tract membranes after oral administration.

References

1. Correia-da-Silva, M.; Sousa, E.; Duarte, B.; Marques, F.; Cunha-Ribeiro, L. M.; Pinto, M. M. M. Eur. J. Med. Chem. 2011, 46, 2347-2358.
2. Correia-da-Silva, M.; Sousa, E.; Duarte, B.; Marques, F.; Carvalho, F.; Cunha-Ribeiro, L. M.; Pinto, M. M. J. Med. Chem. 2011, 54, 5373-84.
3. Correia-da-Silva, M.; Sousa, E.; Duarte, B.; Marques, F.; Carvalho, F.; Cunha-Ribeiro, L. M.; Pinto, M. M. J. Med. Chem. 2011, 54, 95-106.

 Acknowledgments: This research was partially supported by ERDF through the COMPETE and national funds through FCT, under the project PEst-C/MAR/LA0015/2013.