Functional bisphosphonate synthesis for the development of new anti-resorption bone drug candidates

Herein we present the synthesis of b-mono and b-bis-substituted vinylidenebisphosphonate esters bearing a carboxylic ester moiety to be used as building blocks for further functionalizations. Reactions of these new bisphosphonate scaffolds through hydrogenation of the unsaturated CQC bond and through metal mediated addition of aryl boronic acids and indoles provide a wide range of new bisphosphonate products as potential leads to contrast osteoporosis

Recent Advances in Bioconjugated Transition Metal Complexes for Cancer Therapy

The introduction of biologically relevant organic moieties in the coordination sphere of transition metal complexes has recently become a well-established strategy to increase the selectivity and biocompatibility of metallodrugs. In this review, the major advances achieved in this area of research in the last three years are described in detail. Particular attention is given to the metal complexes bearing the main biomolecules of life: carbohydrates, lipids, nucleotides, proteins and vitamins. Each paragraph summarizes the synthetic strategy employed to obtain the complexes of interest as well as the most interesting biological results obtained with these potential metallodrugs. Moreover, the structure–activity relationships observed by the different research groups are described and discussed, with the goal of suggesting to the reader the ligand/metal centre combinations that provide the most promising results in the fight against cancer. Some of the compounds examined in this review as well as other bioconjugated metal complexes published in recent decades exhibit interesting selectivity towards cancer cells over normal ones and a specific mode of action. These latter aspects are the basis of what is commonly known as anticancer target therapy

Facile Cu(II) Mediated Addition of Indoles to a New Class of Bisphosphonate Precursors

Thanks to their structural similarity with pyrophosphate, gem-bisphosphonates (BPs) ensure specific bone targeting and are widely employed as drugs for the treatment of bone disorders like osteoporosis, Paget disease and cancer . New recent studies demonstrated the cellular activity of nitrogen containing BP (N-BP) bearing long alkyl chain acting as potent inhibitors of specific enzymes thus leading to inactivation of osteoclasts that are the cells deputed to bone resorption. Herein we present a straightforward synthesis of a new class of β-substituted alkylidene bisphosphates precursors on wich Cu(II) mediated conjugate addition of indoles gave new N-BPs bearing different indolyl derivatives. A modified Knoevenagel condensation of oxalates and aril -ketoesters with methylen-bisphosphate (MBP) was carried out in the presence of TiCl4. The present system provided a facile access to a new class of mono and bi-substituted BP precursors in high yields endowed with an ester moiety. While Cu(II)-catalyzed addition of indoles to the new bis-substituted BP precursors could not be performed, addition to the mono ester substituted BP proceeded readily providing the desired compounds in good yields. It is worth noting that the same reaction on aryl substituted prochiral BPs could not be possible and this further underlines the importance of the newly discovered class of prochiral BPs. The effect of the length of the alkyl chain in the ester moiety was investigated as well. This efficient and versatile synthesis of BPs allowed the preparation of several BP tetraethyl esters that were deprotected removing the ester moieties forming the corresponding bisphosphonic acids that are currently under investigation to assess their activity in the inhibition of the osteoclast activity

Platinum(0)-η²-1,2-(<i>E</i>)ditosylethene Complexes Bearing Phosphine, Isocyanide and <i>N</i>-Heterocyclic Carbene Ligands: Synthesis and Cytotoxicity towards Ovarian and Breast Cancer Cells

A wide range of platinum(0)-η2-(E)-1,2-ditosylethene complexes bearing isocyanide, phosphine and N-heterocyclic carbene ancillary ligands have been prepared with high yields and selectivity. All the novel products underwent thorough characterization using spectroscopic techniques, including NMR and FT-IR analyses. Additionally, for some compounds, the solid-state structures were elucidated through X-ray diffractometry. The synthesized complexes were successively evaluated for their potential as anticancer agents against two ovarian cancer cell lines (A2780 and A2780cis) and one breast cancer cell line (MDA-MB-231). The majority of the compounds displayed promising cytotoxicity within the micromolar range against A2780 and MDA-MB-231 cells, with IC50 values comparable to or even surpassing those of cisplatin. However, only a subset of compounds was cytotoxic against cisplatin-resistant cancer cells (A2780cis). Furthermore, the assessment of antiproliferative activity on MRC-5 normal cells revealed certain compounds to exhibit in vitro selectivity. Notably, complexes 3d, 6a and 6b showed low cytotoxicity towards normal cells (IC50 > 100 µM) while concurrently displaying potent cytotoxicity against cancer cells

Cationic palladium(II)-indenyl complexes bearing phosphines as ancillary ligands: synthesis, and study of indenyl amination and anticancer activity

The reactivity of palladium(ii) indenyl derivatives and their applications are topics relatively less studied, though in recent times these compounds have been used as pre-catalysts able to promote challenging cross-coupling processes. Herein, we propose the first systematic study concerning the nucleophilic attack on the palladium(ii) coordinated indenyl fragment and, for this purpose, we have prepared a library of new Pd-indenyl complexes bearing mono- or bidentate phosphines as spectator ligands, developing specific synthetic strategies. All novel compounds are thoroughly characterized, highlighting that the indenyl ligand presents always a hapticity intermediate between eta(3) and eta(5). Secondary amines have been chosen as nucleophiles for the present study and indenyl amination has been monitored by UV-Vis and NMR spectroscopies, deriving a second order rate law, with dependence on both complex and amine concentrations. The rate-determining step of the process is the initial attack of the amine to the coordinated indenyl fragment, and this conclusion has been supported also by DFT calculations. The determination of second order rate constants has allowed us to assess the impact of the phosphine ligands on the kinetics of the process and identify the steric and electronic descriptors most suitable for predicting the reactivity of these systems. Finally, in vitro tests have proven that these organometallic compounds promote antiproliferative activity towards ovarian cancer cells better than cisplatin and possibly by adopting a different mechanism of action

Indenyl and Allyl Palladate Complexes Bearing N ???Heterocyclic Carbene Ligands: an Easily Accessible Class of New Anticancer Drug Candidates

The mechanochemical syntheses of allyl and indenyl palladate complexes are reported. All compounds were obtained in quantitative yields and microanalytically pure without the need of any workup. These complexes are stable in chlorinated and polar (DMSO or DMSO/H2O solutions) solvents. In chlorinated solvents, they appear as ionic pairs of which crystals suitable for single X-ray diffraction studies have been obtained. Bonding and solvation properties are rationalized through scalar relativistic DFT calculations. Moreover, most complexes showed excellent cytotoxicity towards ovarian cancer cell lines, with IC50 values comparable or lower than cisplatin. The potent anticancer activity of two IPrCl and IPr*-based palladate complexes was examined in a high-grade serous ovarian cancer (HGSOC) patient-derived tumoroid. Moreover, the inhibition of the antioxidant enzyme thioredoxin reductase (TrxR) was noticed, and structure-activity relationships could be derived, suggesting the ROS detoxifying system is involved in the mode of action

The anticancer activity of an air-stable Pd(i)-NHC (NHC = N-heterocyclic carbene) dimer

A new dinuclear Pd(i) complex coordinating two bis(NHC) ligands revealed an unsuspected stability despite the unsaturation of the two metal centres. Even more surprisingly, the compound showed high and selective antiproliferative activity against different cancer cell lines and ovarian cancer tumoroids, and the mechanism of action was different from that of cisplatin