A series of hybrid compounds based on natural products—bile acids and dihydroartemisinin—were prepared by different synthetic methodologies and investigated for their in vitro biological activity against HL‐60 leukemia and HepG2 hepatocellular carcinoma cell lines. Most of these hybrids presented significantly improved antiproliferative activities with respect to dihydroartemisinin and the parent bile acid. The two most potent hybrids of the series exhibited a 10.5‐ and 15.4‐fold increase in cytotoxic activity respect to dihydroartemisinin alone in HL‐60 and HepG2 cells, respectively. Strong evidence that an ursodeoxycholic acid hybrid induced apoptosis was obtained by flow cytometric analysis and western blot analysis.

Herein we report a study on the synthesis and biological evaluation of a library of nucleoside-bile acid conjugates prepared by combining 2′-deoxyadenosine, 2′-deoxyguanosine, 2′-deoxyuridine as well as adenosine and guanosine derivatives with cheno-, urso-, nor-cheno-, nor-urso- and taurourso-desoxycholic acid derivatives by means of the click reaction. The new nucleoside-bile acid conjugates incorporating a triazole moiety were tested in vitro against leukemic K562 and HCT116 colon carcinoma, as well as on normal fibroblast cells. Six compounds displayed interesting anti-proliferative activity against the selected cancer lines and no cytotoxic effects against normal fibroblasts. A possible structure activity relationship was also investigated.

This contribution reports the synthesis of some novel bioconjugates with anticancer activity and able to release nitric oxide (NO) under visible light excitation. The 4-nitro-2-(trifluoromethyl)aniline derivative, a suitable NO photodonor, was conjugated with 2′-deoxyadenosine and urso-and cheno-deoxycholic acid derivatives, through a thioalkylic chain or the 4-alkyl-1,2,3-triazole moiety. Photochemical experiments demonstrated the effective release of NO from 2′-deoxyadenosine and ursodeoxycholic acid conjugates under the exclusive control of visible light inputs. Studies for the in vitro antiproliferative activity against leukemic K562 and colon carcinoma HCT116 cell lines are reported for all the compounds as well as a case study of photocytotoxicity against HCT116.KEYWORDS: NO photorelease, 2′-deoxyadenosine conjugates, bile acid conjugates, photochemotherapeutics T he biological relevance of nitric oxide (NO) in many bioregulatory systems such as neurotransmission, vasodilatation, hormone secretion, and immune stimulation is nowadays well-established.1,2 Recent studies demonstrated that NO is a very efficient antimicrobial and antioxidant agent that can be employed to tackle bacterial infections and cardiovascular diseases. 3,4 Moreover NO can be used as an anticancer agent or as a chemosensitizer enhancing the effect of traditional cancer therapies. 3−7 In this view, some conventional drugs may be in principle modified with a NO releasing moiety in order to produce synergistic effects due to the combined active species. Although several therapies are based on the regulation of NO synthase activity responsible for the endogenous NO concentration, 7−9 there is an increasing interest in innovative therapies based on exogenous NO releasing agents. 10 The effect of a NO releasing drug is strongly related to the concentration and dose of NO delivered. For instance, NO concentrations in the micromolar range inhibit the growth of tumor cells, whereas picomolar NO concentrations encourage cell proliferation. 11−13Strategies to control the NO release can be based on the use of an external trigger that allow the NO release under a specific stimulus (luminous, chemical, or electrochemical).14,15 Among these, light is the most appealing due to its peculiar advantages of not perturbing the physiological values of parameters such as temperature, pH, and ionic strength, fundamental prerequisites for biomedical applications. 16 These unique features make photoactivated NO donors (photocages) a powerful arsenal in the burgeoning field of nanomedicine with intriguing potential to tackle cancer diseases in a noninvasive way. 17−20 In the last years we have developed a number of molecular and supramolecular systems with anticancer activity based on the 1-nitro-2-(trifluoromethyl)aniline as suitable photocage releasing NO upon irradiation with visible light. 16,17,21−23 The mechanism of NO release involves a nitro-to-nitrite photorearrangement followed by the rupture of the O−NO bond with formation of NO and a phen...

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A series of glycomimetics of UDP-GlcNAc, in which the β-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring, has been synthesized by the application of different click-chemistry procedures. Their affinities for human O-GlcNAc transferase (hOGT) have been evaluated and studied both spectroscopically and computationally. The binding epitopes of the best ligands have been determined in solution by means of saturation transfer difference (STD) NMR spectroscopy. Experimental, spectroscopic, and computational results are in agreement, pointing out the essential role of the binding of β-phosphate. We have found that the loss of interactions from the β-phosphate can be counterbalanced by the presence of hydrophobic groups at a pyrroline ring acting as a surrogate of the carbohydrate unit. Two of the prepared glycomimetics show inhibition at a micromolar level.