Abstract
A series of 2-deoxy-2-iodo-α-d-mannopyranosylbenzotriazoles was synthesized using the benzyl, 4,6-benzylidene and acetyl protected D-glucal in the presence of N-iodosuccinimide (NIS). Subsequent removal of the iodine at the C-2 position using tributyltin hydride under free radical conditions afforded the 2-deoxy-α-d-glucopyranosylbenzotriazoles in moderate to high yields. This method was extended to the preparation of substituted 2-deoxy-β-d-glucopyranosylimidazoles as well. The stereoselectivity of the addition reaction and the effect of the protecting group and temperature on anomer distribution of the benzotriazole series were also investigated. The anticancer properties of the newly synthesized compounds were evaluated in a series of viability studies using HeLa (human cervical adenocarcinoma), human breast and lung cancer cell lines. The N-[3,4,6-tri-O-benzyl-2-deoxy-α-d-glucopyranosyl]-1H-benzotriazole and the N-[3,4,6-tri-O-acetyl-2-deoxy-α-d-glucopyranosyl]-2H-benzotriazole were found to be the most potent cancer cell inhibitors at 20 µM concentrations across all four cell lines.
Highlights
Benzotriazoles are a versatile class of heterocycles with a wide range of applications and usages including antibacterial [1], antiviral [2] and antiparasitic [3], among others [4]
While the mechanism of action of the ribose derivatives is well-documented [9], little is known about the mode of action of N-glycosyl benzotriazoles
Our results suggest that the benzyl protected 1H-2-deoxy-α-D-glucopyranosylbenzotriazole 5 was the most potent of all compounds and is capable of complete inhibition of cell viability at 100 μ M and by 92% (8% survival) at 10 μ M concentration
Summary
Benzotriazoles are a versatile class of heterocycles with a wide range of applications and usages including antibacterial [1], antiviral [2] and antiparasitic [3], among others [4]. Compounds containing the benzotriazole moiety have been reported to possess powerful effects in inhibiting cell proliferation and arresting cancer development. Interest in the generation of 2-deoxy analogs of compound I arose from the abundance of reports on the biological activity displayed by 2-deoxy-D-glucose. By the benzotriazole anion from the bottom face of the three membered ring iodonium ion 27 give rise to the 2-deoxy-2-iodo-α-mannose isomers 21a and 21b. Our results suggest that the benzyl protected 1H-2-deoxy-α-D-glucopyranosylbenzotriazole 5 was the most potent of all compounds and is capable of complete inhibition of cell viability at 100 μ M and by 92% (8% survival) at 10 μ M concentration. Our results show that the isomer 6b is as effective as compound 5 in killing our cancer cell lines at 100 μ M, even with the acetyl protecting group present. HeLa cell viatbhielrietywsatsuldesiesst.hCanel5l%s wsuerrveivtraelartaetedawcriotshseailtlhceerllalinDeMs tSesOtecdoantt2r0olμ(Mdafoshr ecodmlipnoeu)nodr 5 and the synthesized compoleusns dthsaant2a4%cofnocrecnotmraptoiounndof6b10. 0ThμeMeff(ebcltaicvkenbeasrsso)fobro1th0 cμoMmp(ogurenydsb5arasn)d. 6b decreased as concentrations were lowered to 10 μM and 1 μM
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