NO Photoreleaser-Deoxyadenosine and -Bile Acid Derivative Bioconjugates as Novel Potential Photochemotherapeutics

Abstract

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...

Evaluation of the Anticancer Activity of a Bile Acid-Dihydroartemisinin Hybrid Ursodeoxycholic-Dihydroartemisinin in Hepatocellular Carcinoma Cells

“…UDCA is a remarkable molecule exhibiting both anti-and pro-apoptotic properties toward different cell types depending on the conditions (Goossens and Bailly, 2019). We also reported on the selective cytotoxicity of several UDCA-based conjugates (Navacchia et al, 2016;Navacchia et al, 2017). In general, normal cells have a slower growth rate that may in part account for the lower sensitivity to anticancer drugs.…”

Bile Acid Conjugates with Anticancer Activity: Most Recent Research

“…Improved cytotoxicity and cytoselectivity. [48] BA-TAM Condensation 4T1, MCF-7, T47D. Better inhibition.…”

“…[51] BA-Aryl/heteroaryl Condensation MDA-MB-231, U87. Comparable/better cytotoxicity than Cisplatin and Doxorubicin [52] Upon irradiation with visible light, 1-nitro-2-(trifluoromethyl)aniline alkyne, a nitic oxide (NO) photodonor molecule, is able to generate NO radicals [48]. NO can be used as an anticancer agent or as a chemosensitizer to enhance the effect of traditional cancer therapies [53,54].…”

Nanoscale lipid vesicles functionalized with a nitro-aniline derivative for photoinduced nitric oxide (NO) delivery

“…Recently, 4-nitro-3-(triuoromethyl)aniline (NTA) based NO donors chemically incorporated into calixarene, Pt-nanoparticle and cellulose modied NO donors have been reported [17][18][19] However, NO-releasing nano-scaffolds containing NTA with good biocompatibility and stability in physiological media are rarely reported. 20,21 This prompted us to investigate the NO releasing behaviour of NTA in a nanoscale vesicle surface. Vesicles are site specic and provide an opportunity to modulate the NO-release behaviour of NTA.…”