Therapeutic Potential of Carnosine and Its Derivatives in the Treatment of Human Diseases.

Despite significant progress in the pathogenesis, diagnosis, treatment, and prevention of cancer and neurodegenerative diseases, their occurrence and mortality are still high around the world. The resistance of cancer cells to the drugs remains a significant problem in oncology today, while in the case of neuro-degenerative diseases, therapies reversing the process are still yet to be found. Furthermore, it is important to seek new chemotherapeutics reversing side effects of currently used drugs or helping them perform their function to inhibit progression of the disease. Carnosine, a dipeptide constisting of ß-alanine and l-histidine, has a variety of functions to mention: antioxidant, antiglycation, and reducing the toxicity of metal ions. It has therefore been proposed to act as a therapeutic agent for many pathological states. The aim of this paper was to find if carnosine and its derivatives can be helpful in treating various diseases. Literature search presented in this review includes review and original papers found in SciFinder, PubMed, and Google Scholar. Searches were based on substantial keywords concerning therapeutic usage of carnosine and its derivatives in several diseases including neurodegenerative disorders and cancer. In this paper, we review articles and find that carnosine and its derivatives are potential therapeutic agents in many diseases including cancer, neurodegenerative diseases, diabetes, and schizophrenia. Carnosine and its derivatives can be used in treating neurodegenerative diseases, cancer, diabetes, or schizophrenia, although their usage is limited. Therefore, there's an urge to synthesize and analyze new substances, overcoming the limitation of carnosine itself.

Synthesis and Cholinesterase Inhibitory Activity of N-Phosphorylated/ N-Tiophosphorylated Tacrine.

BACKGROUND: Alzheimer's disease (AD) is progressive and irreversible neurodegenerative disorder. Current pharmacotherapy is not able to stop progression of the disease and can only improve cognitive functions. Therefore, new drugs are being sought that will slow down the development of the disease. OBJECTIVE: Novel phosphorus and thiophosphorus tacrine derivatives 7-14 were designed, synthesized and their biological activity and molecular modeling was investigated as a new potential anti- Alzheimer's disease (AD) agents. METHODS: 9-Chlorotacrine was treated with propane-1,3-diamine in the presence of sodium iodide to yield N1-(1,2,3,4-tetrahydroacridin-9-yl)propane-1,3-diamine 6. Finally, it was treated with corresponding acid ester or thioester to give phosphorus or thiophosphorus tacrine derivative 7-14. All of the obtained final structures were characterized by 1H NMR, 13C NMR, 31P NMR and MS. RESULTS: The results of the docking studies showed that the newly designed phosphorus and thiophosphorus tacrine analogs, theoretically possess AChE and BChE-binding ability. Kinetic study showed that 8 and 12 in the series proved to be more potent electric eel AChE (eeAChE) and human (hAChE) inhibitors than tacrine, where 8 inhibited eeAChE three times more than the referenced drug. The highest BChE inhibition revealed 11 and 13. The most active compounds against eeAChE, hAChE and BChE showed mixed type of inhibition. CONCLUSION: All new synthesized compound exhibited lower toxicity against neuroblastoma.cell line (SH-SY5Y) in comparison with tacrine. Two analogues in the series, 7 and 9, demonstrated lack of cytotoxicity against hepatocellular cells (hepG2).

Synthesis and biological evaluation of fluorinated N-benzoyl and N-phenylacetoyl derivatives of 3-(4-aminophenyl)-coumarin-7-O-sulfamate as steroid sulfatase inhibitors.

In the present work, we report convenient methods for the synthesis of 3-(4-aminophenyl)-coumarin-7-O-sulfamate derivatives N-acylated with fluorinated analogues of benzoic or phenylacetic acid as steroid sulfatase (STS) inhibitors. The design of these potential STS inhibitors was supported by molecular modeling techniques. Additionally, computational docking methods were used to determine the binding modes of the synthesized inhibitors and to identify potential interactions between inhibitors and amino acid residues located in the active site of STS. The inhibitory effects of the synthesized compounds were tested on STS isolated from human placenta and against estrogen receptor-(ER)-positive MCF-7 and T47D cells, as well as ER-negative MDA-MB-231 and SkBr3 cancer cell lines. In the course of our investigation, compounds 6c and 6j demonstrated the highest inhibitory effect in enzymatic STS assays, both with IC50 values of 0.18 µM (the IC50 value of coumarin-7-O-sulfamate is 1.38 µM, used as a reference). Compound 6j exhibited the highest potency against the MCF-7 and T47D cell lines (15.9 µM and 8.7 µM, respectively). The GI50 values of tamoxifen (used as a reference) were 6.8; 10.6; 15.1; 12.5 µM against MCF-7, T47D, MDA-MB-231 and SkBr3 cancer cell lines, respectively. Despite the slightly lower activity of compounds 1 and 2 (both in enzymatic and cell-based experiments) compared to 6g and 6j, analogues 1 and 2 proved to selectively inhibit the growth of ER- and PR-positive cell lines.