Current Organic Chemistry - Volume 24, Issue 21, 2020

Peptidic and non-peptidic αvβ6 integrin-binding molecules have been used in the clinic for detection and treatment of tumors expressing αvβ6 integrin, because this protein is expressed in malignant epithelial cells of the oral cavity, pancreas, breast, ovary, colon and stomach carcinomas but it is not expressed in healthy adult tissue except during wound healing and inflammation. This review focuses on the landscape of αvβ6 integrinbinding molecules and their use in cancer treatment and detection, and discusses recent designs for tumor detection, treatment, and immunotherapy. In the last ten years, several reviews about the αvβ6 integrin have been published but no one assessed the landscape of the αvβ6 integrin-binding molecules and their role in cancer detection and treatment. Firstly, this review describes the role of the αvβ6 integrin in normal tissues, how the expression of this protein is correlated with cancer severity and its role in cancer development. Taking into account the potential of αvβ6 integrin-binding molecules in detection and treatment of specific tumors, special attention is given to several high-affinity αvβ6 integrin-binding peptides used for tumor imaging; particularly, the αvβ6-binding peptide NAVPNLRGDLQVLAQKVART [A20FMDV2], derived from the foot and mouth disease virus. This peptide labeled with either 18F, 111In or with 68Ga has been used for PET imaging of αvβ6 integrin-positive tumors. Moreover, αvβ6 integrin-binding peptides have been used for photoacoustic and fluorescence imaging and could potentially be used in clinical application in cancer diagnosis and intraoperative imaging of αvβ6-integrin positive tumors. Additionally, non-peptidic αvβ6-binding molecules have been designed and used in the clinic for the detection and treatment of αvβ6-expressing tumors. Anti-αvβ6 integrin antibodies are another useful tool for selective identification and treatment of αvβ6 (+) tumors. The utility of these αvβ6 integrin-binding molecules as a tool for tumor detection and treatment is discussed, considering specificity, sensitivity and serum stability. Another use of the αvβ6 integrin-binding peptides is to modify the Ad5 cell tropism for inducing oncolytic activity of αvβ6-integrin positive tumor cells by expressing A20FMDV2 peptide within the fiber knob protein (Ad5NULL-A20). The newly designed oncolytic Ad5NULL-A20 virotherapy is promising for local and systemic targeting of αvβ6-overexpressing cancers. Finally, new evidence has emerged, indicating that chimeric antigen receptor (CAR) containing the αvβ6 integrin- binding peptide on top of CD28+CD3 endodomain displays a potent therapeutic activity in a diverse repertoire of solid tumor models.

The characteristics and properties that enable resorcin[4]arenes to self-assemble in order to form derivatives with amino acids with a high potential for application in various fields are reviewed. In particular, resorcin[4]arene synthesis, their characteristics, the variety in the size of cavity, their functional groups, and their applications associated with molecular interactions are described in this study. Also, the types of amino acids that can be recognized by resorcin[4]arenes, their interactions, the techniques that allow the determination of the association constants, and the evaluation of the stoichiometry of the complex formed, are reviewed.

Organometallic complexes are an important class of synthetic reagents and are of great interest due to their versatility and wide biological application. The cationic nature of the coordination nucleus facilitates its interaction with biological molecules such as amino acids, proteins, and nucleic acids. The functionalization of peptides or amino acids with organometallic motifs is a novel strategy for the design and development of molecules with greater biological activity, stability in biological environments, and selectivity for specific targets, which make them valuable tools for designing and obtaining molecules with therapeutic applications. The physicochemical properties of ferrocene make it ideal for drug development, due to its structure, stability in aqueous solutions, redox properties, and low toxicity. In the same way, organotin (IV) derivatives have great potential for drug development because of their multiple biological activities, wide structural versatility, high degree of stability, and low toxicity. However, the synthesis of these drugs based on organometallic molecules containing ferrocene or organotin (IV) is quite complex and represents a challenge nowadays; for this reason, it is necessary to design and implement procedures to obtain molecules with a high degree of purity, in sufficient quantities, and at low cost. This review describes the strategies of synthesis used up to now for the preparation of organometallic amino acids and peptides containing ferrocene or organotin (IV) derivates, as well as their impact on the development of therapeutic agents.

Over the last few years, short peptides have become a powerful tool in basic and applied research, with different uses like diagnostic, antimicrobial peptides, human health promoters or bioactive peptides, therapeutic treatments, templates for peptidomimetic design, and peptide-based vaccines. In this endeavor, different approaches and technologies have been explored, such as bioinformatics, large-scale peptide synthesis, omics sciences, structure-activity relationship studies, and a biophysical approach, among others, seeking to obtain the shortest sequence with the best activity. The advantage of short peptides lies in their stability, ease of production, safety, and low cost. There are many strategies for designing short peptides with biomedical and industrial applications (targeting the structure, length, charge, or polarity) or as a starting point for improving their properties (sequence data base, de novo sequences, templates, or organic scaffolds). In peptide design, it is necessary to keep in mind factors such as the application (peptidomimetic, immunogen, antimicrobial, bioactive, or protein-protein interaction inhibitor), the expected target (membrane cell, nucleus, receptor proteins, or immune system), and particular characteristics (shorter, conformationally constrained, cycled, charged, flexible, polymerized, or pseudopeptides). This review summarizes the different synthetic approaches and strategies used to design new peptide analogs, highlighting the achievements, constraints, and advantages of each.

Glycoproteins and glycopeptides are an interesting focus of research, because of their potential use as therapeutic agents, since they are related to carbohydrate-carbohydrate, carbohydrate-protein, and carbohydrate-lipid interactions, which are commonly involved in biological processes. It has been established that natural glycoconjugates could be an important source of templates for the design and development of molecules with therapeutic applications. However, isolating large quantities of glycoconjugates from biological sources with the required purity is extremely complex, because these molecules are found in heterogeneous environments and in very low concentrations. As an alternative to solving this problem, the chemical synthesis of glycoconjugates has been developed. In this context, several methods for the synthesis of glycopeptides in solution and/or solid-phase have been reported. In most of these methods, glycosylated amino acid derivatives are used as building blocks for both solution and solid-phase synthesis. The synthetic viability of glycoconjugates is a critical parameter for allowing their use as drugs to mitigate the impact of microbial resistance and/or cancer. However, the chemical synthesis of glycoconjugates is a challenge, because these molecules possess multiple reaction sites and have a very specific stereochemistry. Therefore, it is necessary to design and implement synthetic routes, which may involve various protection schemes but can be stereoselective, environmentally friendly, and high-yielding. This review focuses on glycopeptide synthesis by recapitulating the progress made over the last 15 years.

Monitoring the appropriate functions of the brain is a priority when the diagnosis of neurological diseases is carried out. In this regard, there are different analytical techniques to detect neurotransmitters and other molecules with biological activity in the nervous system. Among several analytical procedures, electrochemical techniques are very important since they can be applied in situ, without loss of sensibility and/or minimal handling of samples. In addition, it is also possible to combine them with specific detectors designed on the basis of chemically-modified electrodes in order to improve detection limits by promoting molecular recognition capabilities at their surfaces, thus favoring the development of electrochemical detection in vivo by microelectrodes. In this mini-review, we will describe the major characteristics of this analytical method and its advantages for the detection of neurotransmitters (mostly dopamine) in vivo.

One area of organometallic chemistry that has attracted great interest in recent years is the syntheses, characterization and study of organometallic complexes conjugated to biomolecules with different steric and electronic properties as potential therapeutic agents against cancer and malaria, as antibiotics and as radiopharmaceuticals. This minireview focuses on the unique structural diversity that has recently been discovered in α- amino acids and the reactions of metallocene complexes with peptides having different chemical behavior and potential medical applications. Replacing α-amino acids with metallocene fragments is an effective way of selectively influencing the physicochemical, structural, electrochemical and biological properties of the peptides. Consequently, research in the field of bioorganometallic chemistry offers the opportunity to develop bioactive metal compounds as an innovative and promising approach in the search for pharmacological control of different diseases.