Use of chelating ligands to tune the reactive site of half-sandwich ruthenium(II)-arene anticancer complexes

We show that the chelating ligand XY in Ru(II) anticancer complexes of the type [Ru(eta6-arene)(XY)Cl]n+ has a major influence on the rate and extent of aquation, the pKa of the aqua adduct, and the rate and selectivity of binding to nucleobases. Replacement of neutral ethylenediamine (en) by anionic acetylacetonate (acac) as the chelating ligand increases the rate and extent of hydrolysis, the pKa of the aqua complex (from 8.25 to 9.41 for arene=p-cymene), and changes the nucleobase specificity. For the complexes containing the hydrogen-bond donor en, there is exclusive binding to N7 of guanine in competitive nucleobase reactions, and in the absence of guanine, binding to cytosine or thymine but not to adenine. In contrast, when XY is the hydrogen-bond acceptor acac, the overall affinity for adenosine (N7 and N1 binding) is comparable to that for guanosine, but there is little binding to cytidine or thymidine.     

How to exploit different endocytosis pathways to allow selective delivery of anticancer drugs to cancer cells over healthy cells

It was recently shown that it is possible to exploit the nanoparticle shape to selectively target endocytosis pathways found in cancer and not healthy cells. It is important to understand and compare the endocytosis pathways of nanoparticles in both cancer and healthy cells to restrict the healthy cells from taking up anticancer drugs to help reduce the side effects for patients. Here, the clathrin-mediated endocytosis inhibitor, hydroxychloroquine, and the anticancer drug, doxorubicin, are loaded into the same mesoporous silica nanorods. The use of nanorods was found to restrict the uptake by healthy cells but allowed cancer cells to take up the nanorods via the macropinocytosis pathway. Furthermore, it is shown that the nanorods can selectively deliver doxorubicin to the nucleus of breast cancer cells and to the cytoplasm of pancreatic cancer cells. The dual-drug-loaded nanorods were able to selectively kill the breast cancer cells in the presence of healthy breast cells. This study opens exciting possibilities of targeting cancer cells based on the material shape rather than targeting antibodies.

It was recently shown that it is possible to exploit the nanoparticle shape to selectively target endocytosis pathways found in cancer and not healthy cells.     

Tumor-homing poly-siRNA/glycol chitosan self-cross-linked nanoparticles for systemic siRNA delivery in cancer treatment

The condensed version: Thiolated glycol chitosan can form stable nanoparticles with polymerized siRNAs through charge-charge interactions and self-cross-linking (see scheme). This poly-siRNA/glycol chitosan nanoparticles (psi-TGC) provided sufficient in?vivo stability for systemic delivery of siRNAs. Knockdown of tumor proteins by psi-TGC resulted in a reduction in tumor size and vascularization.     

Mitochondrial mode of action of a thymidine-based cisplatin analogue breaks resistance in cancer cells

Cisplatin analogue complexes with platinum(II) and palladium(II) starting from 3',5'-diamino-3',5'-dideoxy-thymidines were synthesized, both with the D-erythro- and D-threo configurations. Complexes of the general formula [MCl(2)L] were obtained and characterized. NMR spectroscopic measurements and single crystal X-ray structure analysis showed that the metal centers are coordinated to the ligands by the amino groups in 3'- and 5'-positions and not through the thymine moiety. All ligands and complexes showed no significant in vitro activities except thymiplatin (cis-dichloro(3',5'-diamino-3',5'-dideoxy-D-threo-thymidine)platinum(II)). Detailed in vitro studies on the apoptosis pathway in lymphoma (BJAB), leukemia (NALM-6), and melanoma cells (Mel-HO) as well as on transfected or resistant cell lines were carried out. Thymiplatin significantly induced an apoptotic response, which was found to be associated with the loss of mitochondrial membrane potential and with caspase activation. The activity was shown to be independent of Fas-associated protein with death domain (FADD), but dependent on Bcl-2 expression. As a consequence, for thymiplatin a mitochondrial mode of action could be assigned. Moreover, the compound showed activity in cells resistant to common drugs, such as daunorubicin and vincristin, and showed synergistic effects with doxorubicin, vincristin, cytarabin, and daunorubicin.     

Towards a total synthesis of the new anticancer agent mensacarcin: synthesis of the carbocyclic core

A synthesis of the carbocyclic core associated with the new anticancer agent mensacarcin (1) is reported. The strategy involves the synthesis of several novel highly substituted aromatic compounds, such as 12 and 23. The lithium derivative of 12 readily engages in a nucleophilic addition to benzaldehyde 4 to provide the diphenylcarbinol rac-15. The analogous benzyl ether rac-16 undergoes an intramolecular Heck reaction to provide the required tetrahydroanthracene rac-17, which can be transformed into the key tricyclic methyl ether rac-20. In a second approach, the lithium derivative of 21 is added to the hexasubstituted benzaldehyde 23 to give the diphenylcarbinol rac-35. Subsequent methylation to rac-36 followed by an intramolecular Heck reaction provides tricycle rac-37. Similarly, the oxidised compound 40 provides an electronically more suitable intramolecular Heck partner to afford compound 41. Further transformations of these substrates leads to rac-43, which incorporates the core structure of mensacarcin (1).     

On the hydrolysis mechanism of the second-generation anticancer drug carboplatin

The hydrolysis reaction mechanisms of carboplatin, a second-generation anticancer drug, have been explored by combining density functional theory (DFT) with the conductor-like dielectric continuum model (CPCM) approach. The decomposition of carboplatin in water is expected to take place through a biphasic mechanism with a ring-opening process followed by the loss of the malonato ligand. We have investigated this reaction in water and acid conditions and established that the number of protons present in the malonato ligand has a direct effect on the energetics of this system. Close observation of the optimised structures revealed a necessary systematic water molecule in the vicinity of the amino groups of carboplatin. For this reason we have also investigated this reaction with an explicit water molecule. From the computed potential-energy surfaces it is established that the water hydrolysis takes place with an activation barrier of 30 kcal mol(-1), confirming the very slow reaction observed experimentally. The decomposition of carboplatin upon acidification was also investigated and we have computed a 21 kcal mol(-1) barrier to be overcome (experimental value 23 kcal mol(-1)). We have also established that the rate-limiting process is the first hydration, and ascertained the importance of a water molecule close to the two amine groups in lowering the activation barriers for the ring-opening reaction.     

Ruthenation of duplex and single-stranded d(CGGCCG) by organometallic anticancer complexes

We have studied the interaction of the organometallic anticancer ruthenium(II) complexes [(eta(6)-p-cymene)Ru(en)Cl][PF(6)] (1) and [(eta(6)-biphenyl)Ru(en)Cl][PF(6)] (2) (en=ethylenediamine) with the single-stranded (ss) DNA hexamer d(CGGCCG) (I) and the duplex d(CGGCCG)(2) (II) by HPLC, ESI-MS, and one- and two-dimensional (1)H and (15)N NMR spectroscopy. For ss-DNA, all three G's are readily ruthenated with [(eta(6)-arene)Ru(en)](2+), but for duplex DNA there is preferential ruthenation of G3 and G6, and no binding to G2 was detected. For monoruthenated duplexes, N7 ruthenation of G is accompanied by strong hydrogen bonding between G-O6 and en-NH for the p-cymene adducts. Intercalation of the non-coordinated phenyl ring between G3 and C4 or G6 and C5 was detected in the biphenyl adducts of mono- and diruthenated duplexes, together with weakening of the G-O6NH-en hydrogen bonding. The arene ligand plays a major role in distorting the duplex either through steric interactions (p-cymene) or through intercalation (biphenyl).     

A new Dy(III)-based metal-organic framework with polar pores for pH-controlled anticancer drug delivery and inhibiting human osteosarcoma cells

Anticancer drug delivery is considered as the most common and patient acceptable drug administration with reduced side effects. In general, an ideal drug carrier for anticancer drug delivery should have high drug loading capacity, good biocompatibility, and avoid drug delivery in normal tissue (neutral conditions) and promoting the drug release in cancerous tissue (acidic condition). Herein, we synthesize a new porous Dy(III)-based metal-organic framework, [Dy(HABA)(ABA)](DMA)₄] (1, H₂ABA = 4,4'-azanediyldibenzoic acid, DMA = N,N-dimethylacetamide) with uncoordinated N donor sites in the porous surroundings using a bent polycarboxylic acid linker under solvothermal conditions. The structure of the obtained crystalline product has been determined by X-ray single-crystal diffraction, elemental analysis, TGA, XRD, and gas sorption measurement. Due to the suitable window size and polar atom functionalized 1D channels, the activated 1 (1a) was used for anticancer drug 5-Fu loading. A moderately high drug loading and pH-dependent drug-release behavior could be observed for 1a. Furthermore, as demonstrated by the MTT assay, this drug/MOF composite shows low cytotoxicity, good biocompatibility, and anticancer activity against human osteosarcoma cell lines MG63.