Design of Conjugates Based on Sesquiterpene Lactones with Polyalkoxybenzenes by "Click" Chemistry to Create Potential Anticancer Agents.

Using the methodology of "click" chemistry, a singular method has been developed for the synthesis of unique conjugates based on sesquiterpene lactones: dehydrocostuslactone and alantolactone with polyalkoxybenzenes. To expand the structural range of the resulting conjugates, the length of the 1,2,3-triazole spacer was varied. For all synthesized compounds, the cytotoxic profile was determined on the cell lines of tumor origin (SH-SY5Y, HeLa, Hep-2, A549) and normal Hek 293 cells. It was found that the compounds based on alantolactone 7a-d with a long spacer and substances containing dehydrocostuslactone 10a-d with a short spacer have the greatest toxic effect. The decrease in cell survival under the action of these conjugates may be due to their ability to cause dissipation of the transmembrane potential of mitochondria and inhibit the process of glycolysis, leading to cell death. The obtained results confirm the assumption that the development of conjugates based on sesquiterpene lactones and polyalkoxybenzenes can be considered as a promising strategy for the search for potential antitumor agents.

Synthesis and biological testing of 3,5-bis(arylidene)-4-piperidone conjugates with 2,5-dihydro-5H-1,2-oxaphospholenes.

Using the methodology of "click" chemistry, a series of conjugates of 3,5-bis(benzylidene)-1-(prop-2-yn)piperidin-4-ones with 4-alkyl-3-azidomethyl-2-ethoxy-2,5-dihydro-5H-1,2 oxaphosphol 2-oxides was synthesized. All newly obtained compounds 8-18 were characterized by 1H, 13C, 31P, 19F NMR and IR spectroscopy. The potential antitumor activity of the synthesized conjugates8-18was studied in terms of their ability to influence the viability of variouscancercell lines, including A549, SH-SY5Y, Hep-2, and HeLa. Compound 15, which contains two fluorine atoms in the benzene ring, was shown to be the most promising. The mechanism of the cytotoxic action of this conjugate is supposed to be associated with the ability to inhibit the glycolytic profile of transformed cells.

Benefits and limitations of nanomedicine treatment of brain cancers and age-dependent neurodegenerative disorders.

The treatment of central nervous system (CNS) malignancies, including brain cancers, is limited by a number of obstructions, including the blood-brain barrier (BBB), the heterogeneity and high invasiveness of tumors, the inaccessibility of tissues for early diagnosis and effective surgery, and anti-cancer drug resistance. Therapies employing nanomedicine have been shown to facilitate drug penetration across the BBB and maintain biodistribution and accumulation of therapeutic agents at the desired target site. The application of lipid-, polymer-, or metal-based nanocarriers represents an advanced drug delivery system for a growing group of anti-cancer chemicals. The nanocarrier surface is designed to contain an active ligand (cancer cell marker or antibody)-binding structure which can be modified to target specific cancer cells. Glioblastoma, ependymoma, neuroblastoma, medulloblastoma, and primary CNS lymphomas were recently targeted by easily absorbed nanocarriers. The metal- (such as transferrin drug-loaded systems), polymer- (nanocapsules and nanospheres), or lipid- (such as sulfatide-containing nanoliposomes)-based nano-vehicles were loaded with apoptosis- and/or ferroptosis-stimulating agents and demonstrated promising anti-cancer effects. This review aims to discuss effective nanomedicine approaches designed to overcome the current limitations in the therapy of brain cancers and age-dependent neurodegenerative disorders. To accent current obstacles for successful CNS-based cancer therapy, we discuss nanomedicine perspectives and limitations of nanodrug use associated with the specificity of nervous tissue characteristics and the effects nanocarriers have on cognition.

Perspectives of using microRNA-loaded nanocarriers for epigenetic reprogramming of drug resistant colorectal cancers.

Epigenetic regulation by microRNAs (miRs) demonstrated a promising therapeutic potential of these molecules to regulate genetic activity in different cancers, including colorectal cancers (CRCs). The RNA-based therapy does not change genetic codes in tumor cells but can silence oncogenes and/or reactivate inhibited tumor suppressor genes. In many cancers, specific miRs were shown to promote or stop tumor progression. Among confirmed and powerful epigenetic regulators of colon carcinogenesis and development of resistance are onco-miRs, which include let-7, miR-21, miR-22, miR-23a, miR-27a, miR-34, miR-92, miR-96, miR-125b, miR-135b, miR-182, miR-200c, miR-203, miR-221, miR-421, miR-451, and others. Moreover, various tumor-suppressor miRs (miR-15b-5b, miR-18a, miR-20b, miR-22, miR-96, miR-139-5p, miR-145, miR-149, miR-197, miR-199b, miR-203, miR-214, miR-218, miR-320, miR-375-3p, miR-409-3p, miR-450b-5p, miR-494, miR-577, miR-874, and others) were found silenced in drug-resistant CRCs. Re-expression of tumor suppressor miR is complicated by the chemical nature of miRs that are not long-lasting compounds and require protection from the enzymatic degradation. Several recent studies explored application of miRs using nanocarrier complexes. This study critically describes the most successfully tested nanoparticle complexes used for intracellular delivery of nuclear acids and miRs, including micelles, liposomes, inorganic and polymeric NPs, dendrimers, and aptamers. Nanocarriers shield incorporated miRs and improve the agent stability in circulation. Attachment of antibodies and/or specific peptide or ligands facilitates cell-targeted miR delivery. Addressing in vivo challenges, a broad spectrum of non-toxic materials has been tested and indicated reliable advantages of lipid-based (lipoplexes) and polymer-based liposomes. Recent cutting-edge developments indicated that lipid-based complexes with multiple cargo, including several miRs, are the most effective approach to eradicate drug-resistant tumors. Focusing on CRC-specific miRs, this review provides a guidance and insights towards the most promising direction to achieve dramatic reduction in tumor growth and metastasis using miR-nanocarrier complexes.

Histone modifications in epigenetic regulation of cancer: Perspectives and achieved progress.

Epigenetic changes associated with histone modifications play an important role in the emergence and maintenance of the phenotype of various cancer types. In contrast to direct mutations in the main DNA sequence, these changes are reversible, which makes the development of inhibitors of enzymes of post-translational histone modifications one of the most promising strategies for the creation of anticancer drugs. To date, a wide variety of histone modifications have been found that play an important role in the regulation of chromatin state, gene expression, and other nuclear events. This review examines the main features of the most common and studied epigenetic histone modifications with a proven role in the pathogenesis of a wide range of malignant neoplasms: acetylation / deacetylation and methylation / demethylation of histone proteins, as well as the role of enzymes of the HAT / HDAC and HMT / HDMT families in the development of oncological pathologies. The data on the relationship between histone modifications and certain types of cancer are presented and discussed. Special attention is devoted to the consideration of various strategies for the development of epigenetic inhibitors. The main directions of the development of inhibitors of histone modifications are analyzed and effective strategies for their creation are identified and discussed. The most promising strategy is the use of multitarget drugs, which will affect multiple molecular targets of cancer. A critical analysis of the current status of approved epigenetic anticancer drugs has also been performed.

The Hydroxamic Acids as Potential Anticancer and Neuroprotective Agents.

Hydroxamic acids are a promising class of chemical compounds with proven antitumor potential, primarily due to their ability to inhibit the activity of histone deacetylase enzymes. The analysis of modern experimental data shows a wide range of biological activities of hydroxamic acids, which make them equally worthy candidates for the fight against neuropathologies. A characteristic feature of hydroxamic acids is their ability to act simultaneously on several promising molecular targets for the correction of both neuropathologies and oncological diseases, thereby exhibiting multifunctionality. This review discusses the effect of hydroxamic acids on key parts of cancer and neurodegenerative disorders' pathogenesis. Pathological changes in the processes associated with oxidative stress, the functioning of mitochondria, and the activity of metal enzymes of the class of histone deacetylases, as the main links in the epigenetic regulation of pathological conditions, are such molecular targets.

New Spirocyclic Hydroxamic Acids as Effective Antiproliferative Agents.

AIMS: The main goal of this work is to synthesize new original spirocyclic hydroxamic acids, investigate their cytotoxicity against the panel of tumor cell lines and possible mechanism of action of these active compounds. BACKGROUND: Hydroxamic acids are one of the promising classes of chemical compounds with proven potential anticancer properties. This is manifested in the presence of metal chelating and antioxidant activities, the ability to inhibit histone deacetylase enzymes and a chemosensitizing effect against well known cytostatics. OBJECTIVE: Original spirocyclic hydroxamic acids were synthesized and spectra of their antiproliferative activities were investigated. METHODS: The cytotoxic activities on different tumor lines (SH-SY5Y, HeLa and healthy cells HEK-293) were investigated and determined possible underlying mechanisms of their activity. RESULTS: New original spirocyclic hydroxamic acids were synthesized. These compounds exhibit antiproliferative properties against various tumor cultures cells and also exhibit antioxidant activity, a depolarizing effect on the mitochondrial membrane, inhibit the activity of the histone deacetylase enzyme, and also decrease of basal glycolysis and glycolytic capacity reserve of HeLa and SH-SY5Y tumor cell lines. CONCLUSION: The most promising are compounds 5j-l containing two chlorine atoms as substituents in the quinazoline part of the molecule and hydroxamate function. Therefore, these compounds can be considered as hit compounds for the development on their basis multi-target anticancer agents.

Synthesis and Cytotoxic Activity of Azine Derivatives of 6-Hydroxyxanthanodiene.

BACKGROUND: The conjugates of the sesquiterpene lactone of the eremophilane series of 6- hydroxyxanthanodiene with hydrogenated azines (piperidines and piperazines) have been synthesized and identified by NMR spectrometer. OBJECTIVE: A lactone with an unusual skeleton "6-hydroxyxanthanodiene" was extracted from the plant Elecampane (Inula helenium L) and identified various species with NMR spectrometer. METHODS: The cytotoxic, mitochondrial, and antioxidant activities on different tumor lines such as A549, HCT116, RD and Jurkat were investigated and determined possible mechanisms. RESULTS: The results showed that the most potent compound was IIIi exhibiting highest cytotoxicity against RD cells (IC50 25.23 ± 0.04 µM), depolarized the mitochondrial membrane and was an effective antioxidant (IC50 inhibition of LP 10.68 ± 3.21 µM) without any toxic side effect on healthy cells. CONCLUSION: The conjugates of sesquiterpene lactone 6-hydroxyxanthanodiene III and hydrogenated azines may help to design potential promising anticancer drugs.