Amide Alkaloids as Privileged Sources of Senomodulators for Therapeutic Purposes in Age-Related Diseases.

Nature is an important source of bioactive compounds and has continuously made a large contribution to the discovery of new drug leads. Particularly, plant-derived compounds have long been identified as highly interesting in the field of aging research and senescence. Many plants contain bioactive compounds that have the potential to influence cellular processes and provide health benefits. Among them, Piper alkaloids have emerged as interesting candidates in the context of age-related diseases and particularly senescence. These compounds have been shown to display a variety of features, including antioxidant, anti-inflammatory, neuroprotective, and other bioactive properties that may help counteracting the effects of cellular aging processes. In the review, we will put the emphasis on piperlongumine and other related derivatives, which belong to the Piper alkaloids, and whose senomodulating potential has emerged during the last several years. We will also provide a survey on their potential in therapeutic perspectives of age-related diseases.

Ruthenium(II) Complex Containing a Redox-Active Semiquinonate Ligand as a Potential Chemotherapeutic Agent: From Synthesis to In Vivo Studies.

Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a search for new chemotherapeutic drugs. Many classes of compounds have been investigated over the years to discover new targets and synergistic mechanisms of action including multicellular targets. 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 with the catecholate moiety. Experimental evidence (e.g., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrates that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of Ru-sq was then scrutinized in vitro and in vivo, and the results highlight the promising potential of this complex as a chemotherapeutic agent against cancer.

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy.

The utilization of photodynamic therapy (PDT) for the treatment of various types of cancer has gained increasing attention over the last decades. Despite the clinical success of approved photosensitizers (PSs), their application is sometimes limited due to poor water solubility, aggregation, photodegradation, and slow clearance from the body. To overcome these drawbacks, research efforts are devoted toward the development of metal complexes and especially Ru(II) polypyridine complexes based on their attractive photophysical and biological properties. Despite the recent research developments, the vast majority of complexes utilize blue or UV-A light to obtain a PDT effect, limiting the penetration depth inside tissues and, therefore, the possibility to treat deep-seated or large tumors. To circumvent these drawbacks, we present the first example of a DFT guided search for efficient PDT PSs with a substantial spectral red shift toward the biological spectral window. Thanks to this design, we have unveiled a Ru(II) polypyridine complex that causes phototoxicity in the very low micromolar to nanomolar range at clinically relevant 595 nm, in monolayer cells as well as in 3D multicellular tumor spheroids.

A Maltol-Containing Ruthenium Polypyridyl Complex as a Potential Anticancer Agent.

Cancer is one of the main causes of death worldwide. Chemotherapy, despite its severe side effects, is to date one of the leading strategies against cancer. Metal-based drugs present several potential advantages when compared to organic compounds and they have gained trust from the scientific community after the approval on the market of the drug cisplatin. Recently, we reported the ruthenium complex ([Ru(DIP)2 (sq)](PF6 ) (where DIP is 4,7-diphenyl-1,10-phenantroline and sq is semiquinonate) with a remarkable potential as chemotherapeutic agent against cancer, both in vitro and in vivo. In this work, we analyse a structurally similar compound, namely [Ru(DIP)2 (mal)](PF6 ), carrying the flavour-enhancing agent approved by the FDA, maltol (mal). To possess an FDA approved ligand is crucial for a complex, whose mechanism of action might include ligand exchange. Herein, we describe the synthesis and characterisation of [Ru(DIP)2 (mal)](PF6 ), its stability in solutions and under conditions that resemble the physiological ones, and its in-depth biological investigation. Cytotoxicity tests on different cell lines in 2D model and on HeLa MultiCellular Tumour Spheroids (MCTS) demonstrated that our compound has higher activity than cisplatin, inspiring further tests. [Ru(DIP)2 (mal)](PF6 ) was efficiently internalised by HeLa cells through a passive transport mechanism and severely affected the mitochondrial metabolism.

Synthesis, characterization, kinetic investigation and biological evaluation of Re(i) di- and tricarbonyl complexes with tertiary phosphine ligands.

Rhenium(i) di- and tri-carbonyl complexes of the form fac-[Re(CO)3(L,L'-Bid)X] and [Re(CO)2(L,L'-Bid)X2], where X = aqua (H2O), methanol (CH3OH), triphenylphosphine (PPh3), 1,3,5-triaza-7-phosphaadamantane (PTA), tricyclohexylphosphine (PCy3) and L,L'-Bid = O,O' bidentate ligands (tropolone = TropH and 3-hydroxyflavone = FlavH) and N,O bidentate ligands (8-hydroxyquinoline = QuinH, 5,7-chloro-8-hydroxyquinoline = diCl-QuinH and quinoline-2,4-dicarboxylic acid = QuinH2), were synthesized and unambiguously characterized by 1H-, 13C-and 31P-NMR, IR, UV/Vis and micro-analysis. The crystal structures of four complexes, namely fac-[Re(CO)3(QuinH)(H2O)]·H2O (5), fac-[Re(CO)3(Quin)(PPh3)] (11), fac-[Re(CO)3(diCl-Quin)(PPh3)] (12) and [Re(CO)2(Trop)(PPh3)2]·2C6H5CH3 (20) were obtained. Re-P bonding distances for 11 and 12 are 2.4948(8) and 2.4908(8) Å, respectively, indicating the effect of the electron-withdrawing substituents of the diCl-Quin- ligand. The second-order rate constants for the substitutions of methanol at 25.1 °C in fac-[Re(CO)3(L,L'-Bid)(CH3OH)] (L,L'-Bid = Trop, Flav and QuinH) type complexes by different entering phosphine ligands (PPh3, PCy3, and PTA) varied between 7.23(7) × 10-5 and 1.32(3) × 10-3 M-1 s-1 and were found to depend on the coordinated bidentate ligand (in general k1 (QuinH) < k1 (Trop) < k1 (Flav)). The toxicity of fac-[Re(CO)3(QuinH)(PTA)], fac-[Re(CO)3(Trop)(PTA)], fac-[Re(CO)3(Trop)(PPh3)] and fac-[Re(CO)3(Flav)(PPh3)] on the cervical cancer HeLa and epithelial RPE-1 cell lines was then evaluated. Complex fac-[Re(CO)3(Flav)(PPh3)] (16) and fac-[Re(CO)3(Trop)(PPh3)] (13) displayed the highest cytotoxicity with IC50 values of 12.21 ± 0.17 µM and 13.35 ± 0.94 µM, respectively in HeLa cells. Interestingly, a small selectivity towards cancer over non-cancerous cells was observed for these compounds (IC50 = 18.41 ± 3.16 µM and >25 µM in RPE-1 cells).