The global incidence of cancer is rising rapidly and continues to be one of the leading causes of death in the world. Melanoma deserves special attention since it represents one of the fastest growing types of cancer, with advanced metastatic forms presenting high mortality rates due to the development of drug resistance. The aim of this review is to evaluate how the screening of drugs and compounds for melanoma has been performed over the last seven decades. Thus, we performed literature searches to identify melanoma drug screening methods commonly used by research groups during this timeframe.
In vitro
and
in vivo
tests are essential for the development of new drugs; however, incorporation of
in silico
analyses increases the possibility of finding more suitable candidates for subsequent tests.
In silico
techniques, such as molecular docking, represent an important and necessary first step in the screening process. However, these techniques have not been widely used by research groups to date. Our research has shown that the vast majority of research groups still perform
in vitro
and
in vivo
tests, with emphasis on the use of
in vitro
enzymatic tests on melanoma cell lines such as SKMEL and
in vivo
tests using the B16 mouse model. We believe that the union of these three approaches (
in silico, in vitro
, and
in vivo
) is essential for improving the discovery and development of new molecules with potential antimelanoma action. This workflow would provide greater confidence and safety for preclinical trials, which will translate to more successful clinical trials and improve the translatability of new melanoma treatments into clinical practice while minimizing the unnecessary use of laboratory animals under the principles of the 3R's.
Background:
This study presents the synthesis and multi-target behavior of the new 5'-hydroxy-3-(chalcogenyl-triazoyl)-thymidine and the biological evaluation of these compounds as antioxidant and anti-HIV agents.
Objective:
Antiretroviral therapy induces oxidative stress. Based on this, the main objective of this manuscript is the preparation of compounds that combine anti-HIV and antioxidant activities.
Methods:
The compounds were prepared from commercially available AZT, through a copper-catalyzed Huisgen 1,3-dipolar cycloadditions exploiting the AZT azide group and chalcogenyl alkynes.
Results:
The chalcogenium-AZT derivatives were obtained in good yields via click chemistry. The compounds evaluated showed antioxidant and anti-HIV activity. Additionally, in vivo toxicity of this class of compounds was also evaluated and the representative nucleoside did not change the survival, behavior, biochemical hepatic, and renal markers compared to the control mice.
Conclusion:
Data suggest the feasibility of modifying the AZT nucleus with simple organochalcogen fragments, exploring the reactivity of the azide group via 1,3-dipolar Huisgen cycloaddition reaction. The design of these new compounds showed the initially desired biological activities.
Reproductive medicine is a field of science which searches for new alternatives not only to help couples achieve pregnancy and preserve fertility, but also to diagnose and treat diseases which can impair the normal operation of the reproductive tract. Assisted reproductive technology (ART) is a set of methodologies applied to cases related to infertility. Despite being highly practiced worldwide, ART presents some challenges, which still require special attention. Nanotechnology, as a tool for reproductive medicine, has been considered to help overcome some of those impairments. Over recent years, nanotechnology approaches applied to reproductive medicine have provided strategies to improve diagnosis and increase specificity and sensitivity. For in vitro embryo production, studies in non-human models have been used to deliver molecules to gametes and embryos. The exploration of nanotechnology for ART would bring great advances. In this way, experiments in non-human models to test the development and safety of new protocols using nanomaterials are very important for informing potential future employment in humans. This paper presents recent developments in nanotechnology regarding impairments still faced by ART: ovary stimulation, multiple pregnancy, and genetic disorders. New perspectives for further use of nanotechnology in reproductive medicine studies are also discussed.
Background: Trichomonas vaginalis is the causative agent of trichomoniasis, which is one of the most common sexually transmitted diseases worldwide. Trichomoniasis has a high incidence and prevalence and is associated with serious complications such as HIV transmission and acquisition, pelvic inflammatory disease and preterm birth. Although trichomoniasis is treated with oral metronidazole (MTZ), the number of strains resistant to this drug is increasing (2.5-9.6%), leading to treatment failure. Therefore, there is an urgent need to find alternative drugs to combat this disease. Methods: Herein, we report the in vitro and in silico analysis of 12 furanyl N-acylhydrazone derivatives (PFUR 4, a-k) against Trichomonas vaginalis. Trichomonas vaginalis ATCC 30236 isolate was treated with seven concentrations of these compounds to determine the minimum inhibitory concentration (MIC) and 50% inhibitory concentration (IC 50). In addition, compounds that displayed anti-T. vaginalis activity were analyzed using thiobarbituric acid reactive substances (TBARS) assay and molecular docking. Cytotoxicity analysis was also performed in CHO-K1 cells. Results: The compounds PFUR 4a and 4b, at 6.25 µM, induced complete parasite death after 24 h of exposure with IC 50 of 1.69 µM and 1.98 µM, respectively. The results showed that lipid peroxidation is not involved in parasite death. Molecular docking studies predicted strong interactions of PFUR 4a and 4b with T. vaginalis enzymes, purine nucleoside phosphorylase, and lactate dehydrogenase, while only PFUR 4b interacted in silico with thioredoxin reductase and methionine gamma-lyase. PFUR 4a and 4b led to a growth inhibition (< 20%) in CHO-K1 cells that was comparable to the drug of choice, with a promising selectivity index (> 7.4). Conclusions: Our results showed that PFUR 4a and 4b are promising molecules that can be used for the development of new trichomonacidal agents for T. vaginalis.
The screening of potential therapeutic compounds using phenotypic drug discovery (PDD) is being embraced once again by researchers and pharmaceutical companies as an approach to enhance the development of new effective therapeutics. Before the genomics and molecular biology era and the consecutive emergence of targeted-drug discovery approaches, PDD was the most common platform used for drug discovery. PDD, also known as phenotypic screening, consists of screening potential compounds in either in vitro cellular or in vivo animal models to identify compounds resulting in a desirable phenotypic change. Using this approach, the biological targets of the compounds are not taken into consideration. Suitable animal models are crucial for the continued validation and discovery of new drugs, as compounds displaying promising results in phenotypic in vitro cell-based and in vivo small animal model screenings often fail in clinical trials. Indeed, this is mainly a result of differential anatomy, physiology, metabolism, immunology, and genetics between humans and currently used pre-clinical small animal models. In contrast, pigs are more predictive of therapeutic treatment outcomes in humans than rodents. In addition, pigs provide an ideal platform to study cancer due to their similarities with humans at the anatomical, physiological, metabolic, and genetic levels. Here we provide a mini-review on the reemergence of PDD in drug development, highlighting the potential of porcine cancer models for improving pre-clinical drug discovery and testing. We also present precision medicine based genetically defined swine cancer models developed to date and their potential as biomedical models.
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