More than 60 serotypes cause a variety of courses and severe clinical signs of infectious diseases. However, there is no specific drug for the treatment of adenoviral diseases. Fluorinated nucleoside sugars chemistry became the basis for the development of promising chemotherapeutic agents with antitumor and antiviral effects. Based on the purine and pyrimidine nucleotide analogs and fluorinated heterocycle molecules a new generation of drugs with anticancer effect was developed.

The reference strain of human adenovirus serotype 5 and monolayer cell line MDBK were used in the experiment. We studied new fluorine-containing compounds 10S-25 (1-S-thio-(1-methylsulfonyl-2-difluoromethyl-vinyl)-2,3,4,6,-tetra-O-acetyl-β-D-glucopyranose), 10S-26 ((S)-2-(ethoxydifluoromethyl)-pyrrolidine hydrochloride), 10S-27(1-(β-D-glucopyranosyl)-4-(hexafluoropropyl)-5-tosyl-1H-1,2,3-triazole),  10S-28 (Dimethyl N,N'-(2,2-difluoropropanedithioyl)bis(L-alaninate)), synthesized in Institute of Organic Chemistry of the NAS of  Ukraine. Antiviral activity and the effect on adenovirus synthesized de novo were investigated.

Cytotoxicity of experimental compounds was within 16 - 637 μg/ml. Antiviral activity was maximal for compound 10S-27 in the concentration of 16 μg/ml (36%). Other experimental compounds had less antiviral activity at all concentrations. However, they had a significant influence on the synthesis of viral offspring. The percentage of virus inhibition titer was in the range of 65-92%. Consequently, the experimental compounds affected the formation of the infectious viral offspring.

An estimated 240 million persons worldwide are chronically infected with hepatitis B virus (HBV). Chronic hepatitis B (CHB) in up to 40% of cases progresses to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma, a leading cause of cancer-related morbidity and mortality worldwide [1]. We are focused on original antiviral strategy intended to suppress the self-assembly process of HBV core (HBc) protein as one of the promising ways to cure CHB without induction of drug resistance. Targeting the capsid protein of HBV and thus interrupting normal capsid formation have been an attractive approach to block the replication of HBV.

Heteroaryldihydropyrimidines (HAPs) were shown to bind the HBV core proteins and misdirect the assembly of the capsid in vitro. We carried out structural optimizations based on HAPs analogue Bay 41-4109 and structure-activity relationship studies [2].

Newly synthesized HAPs 1 and 2 were evaluated for their ability to disrupt the capsid assembly in cell culture, and promising candidates were selected for further evaluation of antiviral activity and discovery of mechanisms of compound action.

Acknowledgments: The author gratefully acknowledges Gunārs and Renāte Duburi for provided scholarship.

References:

[1] World Health Organization (2016) WHO Hepatitis B Fact Sheet (World Health Organization, Geneva)

[2] Qiu, Z. et.al. (2016), Design and Synthesis of Orally Bioavailable 4-Methyl Heteroaryldihydropyrimidine Based Hepatitis B Virus (HBV) Capsid Inhibitors. J. Med. Chem. 59, 7651-7666

Piperlongumine is a natural amide alkaloid isolated from the plant species Piper longum L. It is known to be cytotoxic^[1] and has been reported to selectively kill cancer cells by targeting the stress response to reactive oxygen species (ROS).^[2] The use of small molecules to target cancer by altering cell levels of ROS is emerging area of research and there is huge potential for further exploration in this area.^[3]

Piperlongumine is structurally similar to a number of microtubule-destabilizing agents, including combretastatin A-4 and related chalcones. This project focuses on the effects of piperlongumine on tubulin, a protein that is the main constituent of microtubules. The synthesis of analogues of piperlongumine was carried out to establish a structure-activity relationship for microtubule-destabilizing activity. The novel compounds were screened for their antiproliferative effects in breast cancer cells and normal breast cells. The effect of the piperlongumine analogues on ROS levels was also investigated.

References:

[1]          Bezerra, D. P.; Militao, G. C. G.; de Castro, F. O.; Pessoa, C.; de Moraes, M. O.; Silveira, E. R.; Lima, M. A. S.; Elmiro, F. J. M.; Costa-Lotufo, L. V.,  Toxicology in Vitro 2007, 21, 1-8.

[2]          Raj, L.; Ide, T.; Gurkar, A. U.; Foley, M.; Schenone, M.; Li, X.; Tolliday, N. J.; Golub, T. R.; Carr, S. A.; Shamji, A. F.; Stern, A. M.; Mandinova, A.; Schreiber, S. L.; Lee, S. W., Nature 2011, 475, 231-234.

[3]          Schumacker, P. T., Cancer cell 2006, 10, 175-176.

Estrogen receptor a (ERa) is an important target for the design of drugs such as tamoxifen and fulvestrant. Three series of ER-ligands based on the benzoxepin scaffold structure were synthesised – series I containing an acrylic acid, series II with an acrylamide and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC₅₀ binding values. Series I acrylic acid ligands were generally ERa selective. In particular, a compound (1) featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERa and ERb expression in MCF-7 breast cancer cells. Interestingly, from series III, a phenoxybutyric acid derivative compound (2) was not antiproliferative and selectively downregulated ERb. A docking study of the benzoxepin ligands was undertaken. Compound 1 is a promising lead for development as a clinically relevant SERD, whilst compound 2 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.

Acetylcholinesterase (AChE) is the enzyme that catalyzes the hydrolysis of the neurotransmitter acetylcholine (ACh) into acetic acid and choline, a crucial mechanism for regulation of neurotransmission at synapses in all nervous systems. According to the cholinergic hypothesis, depleted levels of ACh are associated with Alzheimer's disease. As part of a program aimed at preparing new bioactive heterocycles with kinase and AChE inhibition properties, we designed and synthesized a series of (Z)-2-arylidene- and 2-aminomethylene derivatives of thiazolo[3,2-a]pyrimidine by a convenient multicomponent method. The products were fully characterized by 1D- and 2D-NMR, high resolution ESI-MS/MS and single crystal X-ray diffraction analysis, which indicated a consistent Z configuration at the arylidene and amino methylene double bond. Additionally, molecular docking simulations of the series of 2-arylidene/aminomethylene-thiazolo[3,2-a]pyrimidine derivatives to human AChE (PDB ID: 4m0f, chain A) were conducted to investigate the binding mode of those compounds in comparison to Territrem B, used as positive control. The results indicate that some of the test compounds have binding energies to AChE that are comparable, or better, than the positive control, Territrem B. Biological activity studies are underway to assess the activities of the new compounds [1-4].

References:

1. Francis, P.; Palmer, A.; Snape, M.; Wilcock, G. Neurol. Neurosurg. Psychiatry 1999, 66, 137-147.
2. Zhi, H.; Chen, L.; Zhang, L.; Liu, S.-j.; Wan, D. C. C.; Lin, H.; Hu, C. Arkivoc 2008, 13, 266-277.
3. Jin, C.H.; Jun, K.Y.; Lee, E.; Kim, S.; Kwon, Y.; Kim, K.; Na, Y. Med. Chem. 2014, 22, 4553-4565.
4. Cheung, J.; Gary, E. N.; Shiomi, K.; Rosenberry, T. L. ACS Med. Chem. Lett. 2013, 4, 1091-1096.

Alimentary obesity is an important social problem for all developed countries. A variety of factors affects gain of body weight. among which hypodynamia, which is caused by widespread automation. To date, the human diet increases the palm oil content due to its low cost and long shelf life. Detailed research of the effect of excessive amount of palm oil on the body state is very relevant. In the modern world, it is important to search for highly effective and safe medicines for weight loss treatment of metabolic syndrome consequences. 

This work is dedicated to a search for effective and safe  pharmacorrection medications for the first-degree obesity treatment, as the result of excessive consumption of palm oil during a long period of time. 

Our studies have shown that two new compounds containing chalcogenamide groups have the property of reducing weight. The experiment was performed on 24 white non-linear sexually mature rats of both sexes, which weighed 120-180g. The animals were divided into 4 groups. The animals of the intact group were kept on a standard diet of the vivarium of the State Institution «Lugansk State Medical University», LPR. The second group, the control group, has been receiving palm oil at a dose of 30 g/kg to a daily ration for a period of 6 weeks. The rats of the third and fourth groups have been receiving samples of two new organic compounds 1 and 2).The compounds were administered intragastrically at a dose of 2.5 mg/kg for 2 weeks after a six-week high-fat diet. Once every 7 days the rats were weighed to assess the dynamics of changes in their weight.

The body weight of animals had increased by 121% after a six-week high-fat diet. After the first week of pharmacorrection, the  third group showed a decrease in weight by 12.17%, and after the second week the animals lost another 10.75%. During the two-week period of administration of the substance 1 the weight of the rats decreased by a factor of 1,27 and approached the values of the body weight of animals of the intact group. There were no animal deaths in this group, the behavioral reactions of rats were adequate. In the latter days of research the flabbiness of the hair-coat was noted. In the fourth experimental group, the mass decreased by 8.02% during the first two-week period. The death of animals was absent, behavioral reactions were adequate.

The performed studies have shown that substances  1 {3',9'-dibenzyl-6'-selenoxo-3',4',9',10'- tetrahydro-2'H-spiro[cyclohexane-1,12'-[1,3,5,9] tetraaza[7,11]-methano[1,3,5]triazino[1,2-a] [1,5]diazocine]-7',11'(6'H,8'H)-dicarbonitrile} and 2 {4-(2-chlorophenyl)-2-({[3-methyl-2,6-dioxo-7-(2-oxo- 2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl} thio)-5,6,7,8-tetrahydroquinoline-3-carbonitrile} possessed the properties of prospective pharmacorrection medications for alimentary obesity treatment.

Sulfonylureas have been commonly used since the 1950s as antihypoglycemic (e.g., tolbutamide, glipizide, glimepiride) and diuretics drugs (torasemide). Preclinical studies towards antineoplastic activity of sulfonyloureas led to recognize among them a group of diarylsulfonylureas (DSU) (e.g. LY-181984,  Sulofenur and LY‑295501) with activity against a broad spectrum of syngeneic rodent solid tumors and human tumor xenografts [1].

Continuing our previous studies, in which we have shown a significant potential for antitumor activity of 1-(4-substituted pyridine-3-sulfonyl)-3-phenylureas [2], we have undertaken the synthesis and evaluation of cytostatic activity of novel series of N-{[4-(1,2,3-triazol)pyridin-3-yl]sulfonyl}urea derivatives.

To provide easy functionalization of substituent at the position 4 of the pyridinesulfonamide scaffold, which have a significant influence on the antitumor activity [2.3], we started from 4-(2-propyn-1-ylthio/amino)pyridine-3-sulfonamides and, using the copper-catalyzed azide-alkyne cycloaddition (CuAAC), introduced 1,4-disubstituted 1,2,3-triazole ring. The primary sulfonamides thus obtained were next treated  with various isocyanates to give a series of desired sulfonylurea derivatives. The structures of all compounds were confirmed with IR and NMR spectroscopy and elemental analyses.

All compounds were submitted to test their effects on growth of human cancer cell lines: colon cancer HCT-116, breast cancer MCF-7 and cervical cancer HeLa. Cell viability was measured using MTT assay after 72 h of incubation with tested compound in concentration 1 – 100 μM.

References:

1. Pasello G, et al. Oncologist 2013; 18: 1118–1125.
2. Szafrański K, Sławiński J. Molecules. 2015; 20; 12029–12044.
3. Sławiński J, et al. Eur J Med Chem. 2013;69:701–10.

Small libraries of bisbenzimidazoles structurally related to pentamidine have been synthesized and evaluated against different species of parasites. 2,2’-[1,3-Propanediylbis(oxy-1,3-phenylene)]bis-1H-benzimidazole emerged as a potent and selective anti-Trichomonas vaginalis agent from in vitro and in vivo studies. In particular, in vitro under aerobic conditions the compound was more active than metronidazole against both metronidazole-susceptible (C1) and –refractory (085) isolates of Trichomonas vaginalis. In vivo, it cured a subcutaneous mouse model infection using both kinds of isolates.

Radiolabeled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection, we recently developed the fluorine-18-labelled PSMA-ligand [¹⁸F]PSMA-1007 as the next generation radiofluorinated Glu-ureido PSMA inhibitor after [¹⁸F]DCFPyL and [18F]DCFBC. Since radiosynthesis so far has been suffering from rather poor yields, novel procedures for the automated radiosyntheses of [¹⁸F]PSMA-1007 have been developed. We herein report on both the two-step and the novel one-step procedures, which have been performed on different commonly-used radiosynthesisers. Using the novel one-step procedure, the [¹⁸F]PSMA-1007 was produced in good radiochemical yields ranging from 25 to 80% and synthesis times of less than 55 min. Furthermore, upscaling to product activities up to 50 GBq per batch was successfully conducted. All batches passed quality control according to European Pharmacopoeia standards. Therefore, we were able to disclose a new, simple and, at the same time, high yielding production pathway for the next generation PSMA radioligand [¹⁸F]PSMA-1007. Actually, it turned out that the radiosynthesis is as easily realised as the well-known [¹⁸F]FDG synthesis and, thus, transferable to all currently-available radiosynthesisers. Using the new procedures, the clinical daily routine can be sustainably supported in-house even in larger hospitals by a single production batch.

Sixteen (16) new ethyl β-amino benzimidazole acrylate derivatives have been synthesized by using a multi-step strategy such as reductive amination [1], deprotection in acidic media and transamination. The new compounds bear two points of diversity. Indeed, they have been designed from ethyl 3-dimethylamino-2-(1H-benzimidazol-2-yl)acrylate and mono substituted N-Boc diamines. The new benzimidazole derivatives presented a (2E)-s-cis/trans conformation [2,3] associated to a strong polarization of the C-2/C-3 double bond by a push-pull effect.

The sixteen (16) new synthesized compounds were evaluated in biology for their in vitro cytotoxic activity against six representative human tumoral cell lines. Eight (8) of them have a potential activity against some tumoral cell lines which are Huh7-D12, MDA-MB231, NCI-H727, HCT116 and Caco2 (IC₅₀ < 5 μM). Three (3) of the eight (8) bioactive compounds have interesting micromolar inhibition activity on Huh7-D12 (IC₅₀ = 4-5 μM) and Caco2 (IC₅₀ = 3 μM). Therefore, the good results for these three (3) active benzidamidazole derivatives show them as potential cytotoxic agents. Moreover, their structural modification could lead to the generation of promising anticancer agents.

All the compounds were synthesized in moderate to good yields and were also characterized by ¹H and ¹³C NMR.

References

[1]. Bazureau J-P, Draye M (eds) (2011) Ultrasound and microwave: recent advances in organic chemistry. Research Signpost, Kerala. ISBN 978-81-7895-532-2

[2]. Brugidou R, Bazureau JP, Hamelin J, Dahmani Z, Rahmouni M (1999) Stereoselective synthesis of (2E) 3-amino-2-(1H-benzimidazol-2-yl)acrylate and symmetric bis-acrylates by transamination reactions. Het Chem 10: 446-454.

[3]. Rahmouni M, Derdour A, Bazureau JP, Hamelin J (1994) A new route to pyrimido[1,6-a]benzimidazoles: Reactivity of activated 2-benzimidazoles with N-acyl imidates as β-dielectrophiles under microwave irradiation. Tet. Letters 35: 4563-4564.