Search

Abstract: Gemcitabine (GEM) is a nucleoside analog agent against a wide variety of tumors. To overcome its limitation of rapid metabolism in vivo that results in short circulation time and poor antitumor efficacy, a novel prodrug (CLA–GEM conjugate) has been developed through the covalent coupling of conjugated linoleic acid (CLA) to N4-amino group of GEM. The chemical structure of CLA–GEM conjugate was identified by NMR, FTIR and other methods. From in vitro tests, it was demonstrated that the linkage with CLA increased the plasma stability of GEM as well as the antitumor activity against human breast tumor cells (MCF-7). Importantly, it also altered the transport pattern of GEM across cell membrane (MCF-7 and MDA-MB-231), evidenced by the little effect of nucleoside transporter inhibitors (NBMPR and dipyridamole) on the IC50 values of CLA–GEM, instead of the great effect on that of unmodified GEM. In vivo pharmacokinetic study showed that the CLA–GEM conjugate had a longer plasma half-life and a higher bioavailability compared to that of unmodified GEM. Significant stronger antitumor activity was observed in the nude mice xenografted MCF-7 breast tumor after treated with CLA–GEM than that of unmodified GEM, while no significant body weight loss was found in all treatments. In conclusion, the novel CLA–GEM conjugate prepared in this study would be a promising prodrug of gemcitabine for future clinical use. [Copyright &y& Elsevier]

Abstract: Two types of neamine derivatives, neamine-dinucleotide conjugates 8a–g and neamine-PNA conjugates 12a–c and 14a–d, were synthesized. Compound 8a–g were synthesized by the condensation of azido-neamine with dinucleotide-5′-carboxylic acids, followed by reduction and deprotection. Compound 12a–c and 14a–d were synthesized by the similar strategy. The binding affinities of conjugates 8a–g, 12a–c, and 14a–d towards 16S RNA, 18S RNA, and TAR RNA were evaluated by SPR. It indicates that conjugates 12a–c and 14a–d interact with 16S, 18S RNA at the same level as that of neamine, 14a and 14d show about twofold binding affinities to TAR RNA compared to that of neamine. However, the neamine-dinucleotide conjugates 8a–g exhibit very weak binding affinities to 16S, 18S, and TAR RNA, computer modelling results that negative–negative electrostatic repulsion of phosphate group in compound 8a–g and RNA leads to a sharp decrease of the binding affinities compared with that of neamine, neamine-nucleoside and neamine-PNA conjugates. [Copyright &y& Elsevier]