There is a growing interest on dehydroacetic acid DHA derivatives compounds in recent years, due to an establish antibacterial, antifungal, anti-inflammatory and anticancer activities. Several researches were performed on ligand precursor and transition metal complexes derivatives.

Efficient and easy access to a transition metal chelates series with acid DHA as starting materials is reported, the obtained compounds were fully characterized by MP, UV-Vis and FT-IR spectroscopy, several in vitro biological tests were also performed on obtained metal chelates to explore its therapeutically potential in order to continue further investigations and exploring it as new target drugs. In this case, enzymatic activity: as urease inhibitors and antioxidant activities: ABTS free radical scavenging activity, β-carotène linoleic acid bleaching activity, Ferrous ions binding effect, Copper and ferrous chelating activity, gave good values of IC50 for all studied complexes 1-4 in range of 8,20 ±0,39-10,62 ±0,01 μg/mL for urease inhibiting test better than DHA and used standard Thiourea (IC50=11,57±0,68 μg/mL), interesting results are also obtained for compound 2 in ability of chelating ferrous ions with an IC50=14,53±0,92 μg/mL, comparing with tested standard EDTA (CI50=8,80±0,47 μg/mL), for all cited applications complex 4 is mostly a hit, while antimicrobial activity gave better results with free ligand DHA, discussion on molecular structure and predicted structure activity relationship will be given.

In the process of searching for novel compounds with antipsychotic properties, structure-based virtual screening was conducted [1]. Among found dopamine D₂ receptor antagonists, the compound D2AAK3 with 115 nM affinity for D₂ receptor was identified. It also shows nanomolar or low micromolar affinity for D₁, D₃, 5-HT_1A, 5-HT_2A and 5-HT₇ receptors, what makes it a good candidate for a multi-target drug. Interactions of D2AAK3 with its molecular targets at the molecular level were studied in silico by performing homology modeling, molecular docking and molecular dynamics. The main contact of D2AAK3 with all studied receptors is the electrostatic interaction between the proton attached to the nitrogen atom of the ligand and the conserved Asp(3.32), what is typical for orthosteric binding mode in aminergic GPCRs. Behavioral studies [2] performed for D2AAK3 revealed that it decreases amphetamine-induced hyperactivity measured as spontaneous locomotor activity in mice, improves memory consolidation after acute treatment in passive avoidance test and exhibits anxiogenic activity 30 minutes after acute treatment in mice in elevated plus maze (this effect was reversed 60 minutes after administration of D2AAK3). Further optimization of reported compound, toward obtaining molecule with properties resembling atypical antipsychotics, will be conducted.

References:

1. Kaczor AA, Silva AG, Loza MI, Kolb P, Castro M, Poso A (2016) ChemMedChem 11:718-729.
2. Kaczor AA, Targowska-Duda KM, Budzyńska B, Biała G, Silva AG, Castro M (2016) Neurochemistry International 96:84-99.

The antitumor effect of photodynamic therapy (PDT) consists of a combination of direct toxic damage to tumor cells with indirect mechanisms of suppression of tumor vascularization and activation of the immune response. The combination of a photosensitizer (PS) and light in the presence of oxygen leads not only to selective tissue destruction, but also to long-term control over the first cell proliferation. The presence and severity of the above elements of selective destruction largely depends on the properties of the PS. One of the most important directions for increasing the efficiency of PDT is the synthesis of PSs with increased selectivity of accumulation in the pathological site. It has been shown that PSs of the chlorin series have similar selectivity for target cells, low toxicity, and good photophysical properties. Currently, the drug Photoditazin is used for PDT for oncological diseases. Chlorophyll (phytolesterified magnesium porphyrin) is similar in action to bilirubin, which is a candidate molecule responsible for the body's antioxidant defenses.

In this study, it was shown that chlorophyllin is able to accumulate in pathological tissues and influence to the P450 cytochrome. The prooxidative and antiproliferative effects of chlorophyllin as a component of a drug «OXYChlorophyll» was studied in the models «in vitro» and «in vivo». Chlorophyllin provides good absorption, digestibility, stability and accurate transport to target cells. It has been shown to produce antiproliferative effects in Ehrlich's ascites carcinoma (EAC) to the cell line in a dose-dependent manner. Chlorophyllin have been observed to increase the production of reactive oxygen species (ROS) and enzymatic activity of EAC cells, including the production of mitochondrial/whole-cell ROS, and alter the ratio of reduced-to-oxidized glutathione. Importantly that «Chlorophyll OXY»-mediated suppression of EAC cell viability has been replicated in «in vivo» experiments, where its administration a resulted in the reduction of tumor size in mice. In conclusion, this data suggests that chlorophyllin mediated changes on the redox status of cancer cells leads to a decrease in its proliferation.

Funding: The reported study was funded by RFBR, project number 20-33-90185.

Antibody-drug conjugates (ADCs) are used in anticancer therapy with some limitations due to their molecular properties. An alternative to monoclonal antibodies is the affibody, composed of 58 aminoacids, with lower binding affinities, small size, and rapid blood clearance and tissue distribution. We investigated the in vitro efficacy of a novel anti-HER2 ZHER2:2891 affibody conjugated to a cytotoxic drug auristatin E (MMAE) in HER2-positive human cancer cells. Adenocarcinoma cell line SK-BR-3, expressing high levels of HER2, and mammary gland adenocarcinoma MDA-MB-231, expressing basal levels of HER2, were treated with ZHER2:2891DCS-MMAE and trastuzumab (as reference compound).

ZHER2:2891DCS-MMAE induced a significant time-dependent toxic effect in SK-BR-3 cells. A 30% reduction in cell viability was found after 10 min exposure at 7 nM with an IC50 of 80.2 nM. On the contrary, MDA-MB-231 cells were not affected by the affibody complex. The HER2-specific cytotoxic effect of the ZHER2:2891DCS-MMAE has been also confirmed by measuring apoptosis by flow cytometry. In SK-BR-3 cells, increasing concentrations of conjugated affibody, induced cell death after 10 min of treatment with the strongest effect observed after 48 hours. Also, treatment with ZHER2:2891DCS-MMAE reduced (up to 50%) HER2 expression at both mRNA and protein levels in SK-BR-3 cells after 24 hours of treatment.

In conclusion, the cytotoxic conjugate based on the anti-HER2 affibody and MMAE efficiently interacts with HER2 over-expressing cancer cells, allowing the selective and specific delivery of the cytotoxic payload. The basal HER2 expressing cells are not affected most probably due to a lower uptake of drug conjugate. This confirms that affibody may be used to target HER2 overexpressing cells while sparing normal cells.

Cutaneous melanoma (CM) is a public health issue and a major challenge for scientists. At the dawn of the "omics era", we witnessed groundbreaking advances in CM molecular stratification and therapeutic management assisted by genomic profiling and sequencing technologies. However, melanomagenesis is a complex and multifactorial process that cannot be restricted only to genomic aspects, requiring investigation from a multi-omics perspective. The integration of multi-omics data in a physiological and clinical context may provide new clues about the mechanisms of CM initiation, progression, and metastasis, as well as novel biological pathways amenable to targeted therapy. The Cancer Genome Atlas (TCGA) is an important repository of multiple types of omics data, and in particular, for CM, it has been shown that multi-integration can lead to prognosis models with improved prediction performance. Among clinicians and researchers, multi-omics-based-biomarkers are regarded with enthusiasm as they offer new opportunities for clinical trials design and reduce the time and cost of developing new treatments. We present herein how droplet digital PCR (ddPCR), a relatively young omics technology can complement existing approaches in the field to detect multiple types of alterations in both body fluids as well as formalin-fixed tissues harvested from CM patients and how these findings may broaden our vision on CM research, diagnosis, prognosis and therapy in the context of precision medicine.