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Abstract: Design of an efficient site-specific drug delivery system based on degradable functional polymers still remains challenging. In this work, we synthesized and characterized three degradable functional polyesters belonging to the poly(malic acid) family: the poly(benzyl malate) (PMLABe), the poly(ethylene glycol)-b-poly(benzyl malate) (PEG42-b-PMLABe), the biotin-poly(ethylene glycol)-b-poly(benzyl malate) (Biot-PEG62-PMLABe). Starting from these building blocks, we were able to prepare the corresponding well-defined degradable functional nanoparticles whose toxicity was evaluated in vitro on normal and cancer cell lines. Results have evidenced that the prepared nanoparticles did not show any significant cytotoxicity even at high concentrations. A model anti-cancer drug (doxorubicin, Dox) or a fluorescent probe (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine, DiD oil) has been encapsulated into PMLABe, PEG42-PMLABe or Biot-PEG62-PMLABe based nanoparticles in order to evaluate, respectively, the in vitro cytotoxicity of Dox-loaded nanoparticles on normal and cancer cell lines and the ligand (biotin) effect on cellular uptake in vitro using mmt 060562 cell line. Dox-loaded PMLABe, PEG42-PMLABe or Biot-PEG62-PMLABe nanoparticles showed an in vitro cytotoxicity similar to that of free Dox. Moreover, the DiD oil loaded Biot-PEG62-PMLABe based nanoparticles showed a better in vitro cellular uptake than ligand-free DiD oil loaded nanoparticles. Both results evidence the great potential of such degradable functional poly(malic acid) derivatives for the design of highly efficient site-specific anti-cancer nanovectors. [Copyright &y& Elsevier]

Background/Aims: Coumarins are natural compounds found in many plants that possess medical value by itself and its modified derivatives. Method: Six novel coumarin derivatives were synthesized and examined for their potential anticancer cytotoxicity. Result: Among the 6 derivatives, 3,5-dimethyl-7H-furo[3,2-g]chromen-7-one (DMFC) presented the strongest cytotoxicity against human hepatoma HepG2 cells in vitro with an IC50 value of 8.46 ± 0.28 μM in a 48-hour treatment. Further experiments revealed that DMFC induced apoptosis in HepG2 cells through both extrinsic and intrinsic apoptotic pathways in a p53-dependent manner. Mechanistically, DMFC activated caspases 3, 8 and 9, depolarized mitochondrial membrane potential and induced cytochrome c and apoptosis-inducing factor release. DMFC-induced apoptosis was also characterized by DNA fragmentation, phosphatidylserine externalization and sub-G1 peak in DNA histograms. Moreover, both caspase 8 and 9 inhibitors suppressed the apoptosis induced by DMFC. Western blot analyses revealed that DMFC also significantly increased the expression levels of p53, Fas death receptor, Fas-associated death domain protein and proapoptotic Bcl-2 family members such as Bax, Bad and tBid, as well as decreased the levels of pro-survival members such as Bcl-2 and Bcl-xl. Conclusion: DMFC is potentially an effective therapeutic agent in liver cancer therapy. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

[Display omitted] • Various acridone derivatives were synthesized and evaluated for anticancer activity. • C4 exhibited potent activity against Hep-G2 cells with IC 50 value of 6.29 ± 0.93 μM. • C4 could specifically bind to and destabilize Kras gene promoter i-motif structure. • C4 down-regulated Kras gene expression possibly through its promoter i-motif. • C4 induced cell apoptosis possibly related to its effect on mitochondrial dysfunction. Two series of novel acridone derivatives were designed and synthesized, with their anticancer activity evaluated. Most of these compounds showed potent antiproliferative activity against cancer cell lines. Among them, compound C4 with dual 1,2,3-triazol moieties exhibited the most potent activity against Hep-G2 cells with IC 50 value determined to be 6.29 ± 0.93 μM. Subsequent experiments showed that C4 could bind to and destabilize Kras gene promoter i-motif structure without significant interaction with its corresponding G-quadruplex. C4 could down-regulate Kras expression in Hep-G2 cells, possibly due to its interaction with the Kras i-motif. Further cellular studies indicated that C4 could induce apoptosis of Hep-G2 cells, possibly related to its effect on mitochondrial dysfunction. These results indicated that C4 could be further developed as a promising anticancer agent. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs resulting in low intracellular drug concentrations. It is one of the noteworthy problems in malignant tumor clinical therapeutics. So P-gp protein is one of the ideal targets to solve MDR. Based on the lead compound 5m obtained from our previous work, a series of furan derivatives featuring alkyl-substituted phenols and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were designed and synthesized as reversal agents against P-gp in this paper. Compound 16 containing isopropoxy possessed good potency against P-gp mediated MDR in MCF-7/ADR (IC 50 (doxorubicin) = 0.73 μM, RF = 69.6 with 5 μM 16 treated). Western blot results and Rh123 accumulation assays showed that 16 effectively inhibited P-gp efflux function but not its expression. The preliminary structure–activity relationship and docking studies demonstrated that compound 16 would be a potential P-gp inhibitor. Most worthy of mention is that compound 16 has achieved satisfactory results in combination with a variety of anti-tumor drugs, such as doxorubicin, paclitaxel, and vincristine. This study forwards a hopeful P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance setting the basis for further studies. [Display omitted] • Eighteen 5-alkoxyphenyl-2-(6,7-dimethoxy-1,2,3,4-tetrahydroiso- quinolinecarboxamide)furan derivatives were designed and synthesized. • Title compounds were tested as reversal agents against P-glycoprotein mediated multidrug resistance in MCF-7/ADR cells. • SARs demonstrated that the alkoxy-substituent effect was key in enhancing the P-gp inhibitory activity and corroborated by docking study. • P-gp efflux function was abrogated effectively by compound 16 without down-regulating P-gp expression. • >60 fold increase in intracellular concentration was achieved for doxorubicin and vincristine. [ABSTRACT FROM AUTHOR]