Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a surge for new chemotherapeutic drugs. More specifically, the discovery of new drug candidates able to overcome severe side effects, the occurrence of resistance and the inefficacy toward metastatic tumours is highly desirable. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely [Ru(DIP)2(sq)]PF6 (Ru-sq) (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated to the catecholate moiety. Several pieces of experimental evidence (e.g., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrate that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of Ru-sq was then scrutinised in vitro and in vivo, and the results highlight the tremendous potential of this complex as a chemotherapeutic agent against cancer. Ru-sq was notably found have a much higher cytotoxic activity than cisplatin on several cell lines (i.e. in the nanomolar range), and, contrary to cisplatin, to have mitochondrial disfunction as one of its modes of action. The multicellular targets of Ru-sq could potentially be the key to overcome one of the main drawbacks of cisplatin i.e. the occurrence of resistance. Moreover, Ru-sq exhibited impressing activity on Multi Cellular Tumour Spheroids (MCTS) model, leading to a growth inhibition of the tumour even 13 days after treatment (20 μM). Very importantly, using two different in vivo models, it could be demonstrated that this compound is extremely well-tolerated by mice and has a very promising activity, curing, in some cases, tumour-bearing mice.<br>

No abstract

Four diruthenium trithiolato chlorambucil conjugates have been prepared via Steglich esterification from chlorambucil and the corresponding trithiolato precursors. All conjugates are highly cytotoxic towards human ovarian A2780 and A2780cisR cancer cell lines with IC50 values in the nanomolar range. The conjugates exhibit selectivity towards A2780 cells as compared to non-cancerous HEK293 cells, while being only slightly selective for RF24 and A2780cisR cells. In vivo, the conjugate [10]BF4 suppressed the growth of a solid Ehrlich tumor in immunocompetent NMRI mice but did not prolong their overall survival. The reactivity of the chlorambucil conjugates with glutathione, a potential target of the dinuclear ruthenium motive, and with the 2-deoxyguanosine 5'-monophosphate (dGMP-a model target of chlorambucil) was studied by mass spectrometry and NMR spectroscopy. The conjugates did not show catalytic activity for the oxidation of glutathione nor binding to nucleotides, indicating that glutathione oxidation and DNA alkylation are not key mechanisms of action. Four highly cytotoxic diruthenium trithiolato chlorambucil conjugates have been prepared. All conjugates exhibit selectivity towards A2780 cells as compared to HEK293 cells, while being only slightly active in RF24 and A2780cisR cells. In vivo, the best candidate suppressed the growth of a solid Ehrlich tumor in immunocompetent NMRI mice but did not prolong their overall survival.

No abstract

It is documented that deficient fucosylation may play an important role in the pathogenesis of cancer. Since the supplementation ofL-fucosecouldrestorefucosylationinbothin vitro and in vivoconditions,ourintentwastoexaminetheeffectofintraperitoneal administration of L-fucose and L-rhamnose (a similar deoxysaccharide) on tumour growth, mitotic activity and metastatic setting ofasolidformofEhrlichcarcinomaaswellasonthesurvivalrateoftumourbearingmice.BothL-fucoseandL-rhamnoseexerted a significant suppressive effect on tumour growth (P<0.05). After 10 days of therapy, the greatest inhibition of tumour growth expressedasapercentageofcontrolswasobservedinL-rhamnoseatadoseof3g/kg/day(by62%)andL-fucoseatadoseof 5g/kg/day(by47%).Moreover,themitoticindexdecreasedwithincreasingdosesofL-fucoseandL-rhamnose.Prolongedsurvivalof tumourbearingmicewasobservedafter14consecutivedaysofdailyadministeringL-rhamnose.Itsoptimaldosewasestimatedto be3.64g/kg/day.L-Fucose,however,displayedonlyaslighteffectonthesurvivalofthemice.OurresultssuggestthatL-fucoseand especiallyL-rhamnosehaveanticancerpotential.Thisstudyisthefirsttodemonstratethetumour-inhibitoryeffectofL-rhamnose.