Treatment of castration-resistant prostate cancer (CRPC) remains challenging due to the development of drug resistance. The Warburg effect describes the ability of cancer cells to consume larger amounts of glucose compared to normal tissues. We identified derivatives of natural 1,4-naphthoquinones to be active in CRPC and further synthetically modified them via glucose conjugation to increase selectivity by Warburg effect targeting. Mechanisms of action were examined by quantitative proteomics followed by bioinformatical analysis and target validation. Four synthesized molecules revealed the highest selectivity towards human CRPC cells, which correlated with higher GLUT-1 activity and expression. The compounds were able to induce pro-apoptotic signs and to inhibit the pro-survival processes and mechanisms of drug resistance (i.e., AR-signaling and autophagy). Proteome analysis suggested a disruption of the mitochondria/oxidative phosphorylation, which was validated by further functional analysis: thus, mitochondria depolarization, elevated levels of cytotoxic ROS, an increase of Bax/Bcl-2 ratio as well as release of mitochondrial AIF and cytochrome C to cytoplasm were observed. In conclusion, glucose-conjugated 1,4-naphthoquinones show potent activity and selectivity in human CRPC exerted via mitochondrial targeting. The compounds can overcome drug resistance against current standard therapies and suppress pro-survival mechanisms. This unique combination of properties makes them new promising candidates for the treatment of CRPC.
The cytotoxicity of natural glycosides from Ginseng, semisynthetic analogues and related triterpenes of the dammarane series, isolated from the leaves of the Far-East species of the genus Betula was studied in order to elucidate structure-activity relationships. Some of the compounds studied were active against the human lung carcinoma GLC4 and adenocarcinoma COLO 320 cell lines. The natural glycosides displayed the lowest cytotoxicity. The triterpenes of the dammarane series used as starting aglycones for semisynthetic derivatives were moderately cytotoxic. The dammarane triterpenes possessing keto groups and their semisynthetic glucosides were the most active compounds tested. Cytotoxic effects of the dammarane glucosides were inversely proportional both to the number of sugars attached to the aglycones and to the number of hydroxy groups of the aglycones. The type of side chain and the configuration of the hydroxy group at C-3 in aglycones did not have a significant influence on the cytotoxicity.
One of the methods for studying the relationship between the chemical structure of compounds and their biological activity consists of the synthesis of compounds with a given structure and an investigation of their biological properties. In order to evaluate the influence of an additional 6D-OH group in panaxatriol on the biological activity of its semi-synthetic glycosides [1, 2], it became necessary to synthesize the corresponding panaxadiol monoglucosides. Panaxadiol (3E,12E-dihydroxy-20R,25-epoxydammarane) (1) is the acid-hydrolysis product of the glycoside fraction of Panax ginseng C. A. Meyer root. Its molecule has no C-6 hydroxyl, in contrast with panaxatriol [3][4][5]. Exhaustive glycosylation of 1 was performed previously under conditions of the ortho-ester method [6]. However, proof of the structures and purities of the isomeric monoglucosides was not given. 1: R 1 = R 2 = H; 4: R 1 = Ac, R 2 = H; 5: R 1 = GlcAc 4 , R 2 = H 6: R 1 = H, R 2 = GlcAc 4 ; 7: R = GlcAc 4 ; 8: R 1 = Glc, R 2 = H 9: R 1 = H, R 2 = Glc; 10: R = Glc O Br AcOThe molecule of 1 has two hydroxyls on C-3 and C-12, the reactivity of which depends on the glycosylation conditions. A strong intramolecular H-bond (IMHB) between the 12E-OH proton and the O atom of the tetrahydropyran ring [3][4][5] increases the nucleophilicity of the 12E-OH O atom and makes it possible to glycosylate it regioselectively [7,8].
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