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Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4

Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME—administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC50) of 58.4 µM, exceeding the activity of fluorouracil (CC50 = 381.2 μM) and equaling the activity of cisplatin (CC50 = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer.

The alternative way of synthesis of valuable 5-amino-3-methylisothiazole and 3-methyl-4-nitroisothiazole has been presented and described. It appeared that new, undescribed 3,3′-dimethyl-4,4′-dinitro-5,5′-bisisothiazole has been produced as a side-product during synthesis. Both experimental and calculated spectral and electronic properties of 3-methyl-4-nitroisothiazole have been extensively researched and discussed. The complete vibrational assignments were made on the basis of potential energy distributions PED. The fully anharmonic infrared and Raman spectra with calculated anharmonic intensities for fundamental bands, overtones as well as combination bands are presented. Vibrational spectra predicted by anharmonic approximation agree very well with experimental data. The stability of molecules of 3-methyl-4-nitroisothiazole arising from hyper conjugative interaction has been estimated using natural bond orbital (NBO 6.0) analysis. The combined frontier molecular orbital and NBO analysis of canonical molecular orbitals was used to predict the most probable sites of 3-methyl-4-nitroisothiazole molecule where single electron can be accepted to and detached from. Measured reduction potential of 3-methyl-4-nitroisothiazole and calculated electron affinity point out that this compound is susceptible to reduction at the similar level of 1-methyl-3-nitropyrazole and this susceptibility is much more than respective 1-methyl-4-nitropyrazole. UV-Vis spectra analysis reveals a nature of valence electron excitation and electron transition of 3-methyl-4-nitroisothiazole. Besides, unambiguous assignment of NMR signal shifts of carbon atoms of isothiazole ring of 3-methyl-4-nitroisothiazole, 5-amino-3-methylisothiazole and intermediate and side products of synthesis was conducted thanks to full detailed analysis of 1H, 13C NMR spectra and their two dimensional (2D) variants. Additionally, molar enthalpy of vaporization (ΔHvap) of 3-methyl-4-nitroisothiazole has been estimated (ΔHvap = 52.2 kJ/mol).

Previous studies demonstrated strong anti-inflammatory properties of isoxazolo[5,4-e]-1,2,4-triazepine (RM33) in vivo. The aim of this investigation was to describe synthesis, determine physicochemical characteristics, evaluate biological activities in murine and human in vitro models, as well as to propose mechanism of action of the compound. The compound was devoid of cell toxicity up to 100 μg/mL against a reference A549 cell line. Likewise, RM33 did not induce apoptosis in these cells. The compound stimulated concanavalin A (ConA)-induced splenocyte proliferation but did not change the secondary humoral immune response in vitro to sheep erythrocytes. Nevertheless, a low suppressive effect was registered on lipopolysaccharide (LPS)-induced splenocyte proliferation and a stronger one on tumor necrosis factor alpha (TNFα) production by rat peritoneal cells. The analysis of signaling pathways elicited by RM33 in nonstimulated resident cells and cell lines revealed changes associated with cell activation. Most importantly, we demonstrated that RM33 enhanced production of cyclooxygenase 2 in LPS-stimulated splenocytes. Based on the previous and herein presented results, we conclude that RM33 is an efficient, nontoxic immune suppressor with prevailing anti-inflammatory action. Additionally, structural studies were carried out with the use of appropriate spectral techniques in order to unequivocally confirm the structure of the RM33 molecule. Unambiguous assignment of NMR chemical shifts of carbon atoms of RM33 was conducted thanks to full detailed analysis of 1H, 13C NMR spectra and their two-dimensional (2D) variants. Comparison between theoretically predicted chemical shifts and experimental ones was also carried out. Additionally, N-deuterated isotopologue of RM33 was synthesized to eliminate potentially disturbing frequencies (such as NH, NH2 deformation vibrations) in the carbonyl region of the IR (infrared) spectrum to confirm the presence of the carbonyl group.

A series of eight novel platinum(II) complexes were synthesized by the reaction of the appropriate 1-methylnitropyrazole derivatives with K2PtCl4 and characterized by elemental analysis, ESI MS spectrometry, 1H NMR, 195Pt NMR, IR and far IR spectroscopy. Thermal isomerization of cis-dichloridobis(1-methyl-4-nitropyrazole)platinum(II) 1 to trans-dichloridobis(1-methyl-4-nitropyrazole)platinum(II) 2 has been presented, and the structure of the compound 2 has been confirmed by X-ray diffraction method. Cytotoxicity of the investigated compounds was examined in vitro on three human cancer cell lines (MCF-7 breast, ES-2 ovarian and A-549 lung adenocarcinomas) and their logP was measured using a shake-flask method. The trans complex 2 showed better antiproliferative activity than cisplatin for all the tested cancer cell lines. Additionally, trans-dichloridobis(1-methyl-5-nitropyrazole)platinum(II) 4 has featured a lower IC50 value than reference cisplatin against MCF-7 cell line. To gain additional information that may facilitate the explanation of the mode of action of tested compounds cellular platinum uptake, stability in L-glutathione solution, influence on cell cycle progression of HL-60 cells and ability to apoptosis induction were determined for compounds 1 and 2.

Here, the Conductor-like Polarizable Continuum Model (CPCM) was used as a less demanding substitute of Periodic Boundary Conditions (PBC) method to attempt to reliably simulate infrared spectra and some structural parameters of solid compound - 5-amino-3-methyl-4-isoxazolecarbohydrazide (HIX). The measured relative electric permittivity of HIX was used as a simplified equivalent of electric intensity generating by other molecules of 5-amino-3-methyl-4-isoxazolecarbohydrazide in crystal structure. The application of CPCM has resulted in better conformity of calculated molecular parameters with experimentally found. Theoretical geometry was compared with data obtained with X-ray crystallography. Comparison of harmonic approximation with anharmonic one, based on the six selected characteristic vibrations, shows that non-scaled harmonic wavenumbers, calculated with CPCM, well correspond to experimental spectra. Additionally, the results point out that anharmonic approximation appeared to be strong sensitive for input geometry and calculation parameters used, so the results are sometimes unreliable, especially for low wavenumbers. Also, the new feasible ways of the synthesis of the titled compound is presented, one of which is particularly easy and highly efficient.

Simple Summary Hematological malignancies are diseases involving the abnormal production of blood cells. The aim of the study is to collect comprehensive information on new drugs used in the treatment of blood cancers which have introduced into therapy in the last decade. The approved drugs were analyzed for their structures and their biological activity mechanisms. Abstract Hematological malignancies, also referred to as blood cancers, are a group of diseases involving abnormal cell growth and persisting in the blood, lymph nodes, or bone marrow. The development of new targeted therapies including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally, Chimeric Antigen Receptor T (CAR-T) cells has improved the clinical outcomes for blood cancers. In this review, we summarized 52 drugs that were divided into small molecule and macromolecule agents, approved by the Food and Drug Administration (FDA) in the period between 2011 and 2021 for the treatment of hematological malignancies. Forty of them have also been approved by the European Medicines Agency (EMA). We analyzed the FDA-approved drugs by investigating both their structures and mechanisms of action. It should be emphasized that the number of targeted drugs was significantly higher (46 drugs) than chemotherapy agents (6 drugs). We highlight recent advances in the design of drugs that are used to treat hematological malignancies, which make them more effective and less toxic.

The synthesis of a series of novel 7-aminooxazolo[5,4-d]pyrimidines 5, transformations during their synthesis and their physicochemical characteristics have been described. Complete detailed spectral analysis of the intermediates 2&ndash, 4, the N&prime, cyanooxazolylacetamidine by-products 7 and final compounds 5 has been carried out using MS, IR, 1D and 2D NMR spectroscopy. Theoretical research was carried out to explain the privileged formation of 7-aminooxazolo[5,4-d]pyrimidines in relation to the possibility of their isomer formation and the related thermodynamic aspects. Additionally, the single-crystal X-ray diffraction analysis for 5h was reported. Ten 7-aminooxazolo[5,4-d]pyrimidines 5 (SCM1&ndash, 10) were biologically tested in vitro to preliminarily evaluate their immunological, antiviral and anticancer activity. Compounds SCM5 and SCM9 showed the best immunoregulatory profile. The compounds displayed low-toxicity and strongly inhibited phytohemagglutinin A-induced proliferation of human peripheral blood lymphocytes and lipopolysaccharide-induced proliferation of mouse splenocytes. Compound SCM9 caused also a moderate suppression of tumor necrosis factor &alpha, (TNF-&alpha, ) production in a human whole blood culture. Of note, the compounds also inhibited the growth of selected tumor cell lines and inhibited replication of human herpes virus type-1 (HHV-1) virus in A-549 cell line. Molecular investigations showed that the compounds exerted differential changes in expression of signaling proteins in Jurkat and WEHI-231 cell lines. The activity of SCM5 is likely associated with elicitation of cell signaling pathways leading to cell apoptosis. The compounds may be of interest in terms of therapeutic utility as inhibitors of autoimmune disorders, virus replication and antitumor agents.

Both experimental and calculated spectral and electronic properties of two isomers 1-methyl-3-nitropyrazole and 1-methyl-5-nitropyrazole have been demonstrated and discussed in details based on normal mode analysis. The fully anharmonic infrared spectra with calculated anharmonic intensities for fundamental bands, overtones and combination bands were also reported. The stability of title molecules arising from hyper conjugative interaction have been demonstrated using natural bond orbital (NBO) analysis. Electron affinities clearly point that 1-methyl-5-nitropyrazole should be much more susceptible to reduction process than 1-methyl-3-nitropyrazole what has been experimentally confirmed by measurement of reduction potential. For 1-methyl-5-nitropyrazole, unambiguous assignment of values of proton and carbon chemical shifts to appropriate protons and carbons has been made thanks to full analysis of 1 H and 13 C NMR spectra and two dimensional (2D) 1 H 1 H and 1 H 13 C NMR COSY spectroscopy.

Both experimental and calculated spectral and electronic properties of 1-methyl-4-nitropyrazole have been demonstrated. Experimental values have been compared with theoretical computations and also new hybrid density functionals, APF (Austin–Petersson–Frisch) and APF(D), have been tested and compared to B3LYP hybrid functional. The theoretical wavenumbers of fully anharmonic infrared and Raman spectra with anharmonic intensities of 1-methyl-4-nitropyrazole are in very good agreement with the experimental observations. The detailed interpretation of the infrared and Raman spectra is reported based on potential energy distribution (PED). The ring N1 N2 bond distance of 1-methyl-4-nitropyrazole, calculated with both APF/6-311++G( df , pd ) and APF-D/6-311++G( df , pd ) models, is much underestimated in comparison with X-ray experimental value. Overall results point that B3LYP functional with 6-311++G( df , pd ) basis function better predicts the bond lengths and angles of titled compound than both APF and APF-D ones. As a key factor for biological activity of nitro compounds, the redox potential of 1-methyl-4-nitropyrazole in water solution was also measured and then was set against the calculated electronic properties. The analysis of the calculated components of HOMO and LUMO orbitals has shown that nitrogen and oxygen atoms of nitro group are the most probable site of acceptance of electron. Hence, nitro group should be the most sensitive fragment of 1-methyl-4-nitropyrazole molecule to the reduction process. Moreover, the stability of the 1-methyl-4-nitropyrazole arising from hyper conjugative interactions has been studied using natural bond orbital (NBO) analysis. Unambiguous assignment of values of proton chemical shifts to appropriate protons has been finally made thanks to two dimensional (2D) 1 H– 1 H NMR spectroscopy.

Both spectral and structural studies of 5-amino-3-methyl-4-isoxazolecarbohydrazide (HIX) were done and compared to calculated parameters using ab initio DFT methods. A detailed interpretation of the infrared and Raman spectra of title molecule is reported on the basis of the calculated potential energy distribution (PED). The conformational search for possible conformers and tautomers of title compound has been conducted and widely discussed. N-deuterated isotopologue of 5-amino-3-methyl-4-isoxazolecarbohydrazide (HIXD) was synthesized to eliminate disturbing frequencies in carbonyl region of IR and Raman. Besides, N-deutaration enabled the unambiguous assignment some bands to specific vibrations. Moreover, the stability of the 5-amino-3-methyl-4-isoxazolecarbohydrazide arising from hyper conjugative interactions has been studied using natural bond orbital (NBO) analysis.

The 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide (HIX) is a synthetic isoxazole derivative with a potential for development as an anti-inflammatory drug candidate. The goal of this study was to explore in vitro autoimmune and inflammatory gene modulation by HIX in human Caco-2 cultured cells. The effect of low dose of HIX was tested on the expression level of RNA in 24 h Caco-2 cultures using the QIAGEN Th17 for Autoimmunity & Inflammation RT2 Profiler PCR Array. We choose the PCR technology as the most reliable and sensitive gene expression profiling method for analyzing specific gene regulatory networks. In all experiments, Leflunomide (5-methyl-N-[4-(trifluoromethyl)phenyl]-4-isoxazolecarboxamide), an immuno-suppressive disease-modifying antirheumatic drug was used, as a reference to clinical utility of the isoxazole derivatives. Changes in RNA levels were analyzed and differentially expressed genes with at least 2-fold change were identified. For the majority of genes tested, the effe...

Reactions of 4-nitro-3(5)-pyrazolecarboxylic acid dipotassium salt with different methylating agents in various solvents have been investigated to improve the synthesis of isomeric 1-methyl-4-nitro-3- and -5-pyrazolecarboxylic acids.

The synthesis and in-vitro biological evaluation of the amide series 4 of 5-(4-chlorobenzoyl)aminoorotic acid 2 are presented. The biological properties of a few 5-(4-chlorobenzoyl)amino-2,6-dihydroxy-N-substituted-4-pyrimidinecarboxamide derivatives 4 tested here were compared with those of the isosteric isothiazole derivative MR-2/94 (5-(4-chlorobenzoyl)amino-N-(4-chlorophenyl)-3-methyl-4-isothiazolecarboxamide), which possesses a strong immunosuppressive and anti-inflammatory activity [1, 2], It must be suggested that replacement of the isothiazole by a pyrimidine core ring system resulted in considerable lowering of the anti-inflammatory and immunotropic actions of the obtained amides. Physicochemical properties of 2-(4-chlorophenyl)-6,8-dihydroxy-4H-pyrimido[5,4-d]-1,3-oxazin-4-on 3 are also briefly described.

Investigation of the reduction potential and calculation of the partition coefficient n-octanol/water allow the assessment of the potential suitability of nitropirydine N-oxide compounds in radiotherapy of cancer. Experiments were carried out using cyclic voltammetry with HMDE as working electrode. The electrode reduction of the investigated compounds is quite irreversible and strongly dependent on pH.

Three unknown olivacine derivatives (L-OCH3, L-OH, L-OAc) were synthesized according to a procedure that involves only a few steps, and used as ligands in the synthesis of neutral chelate platinum(II) complexes. The ligands, as well as their platinum complexes were spectroscopically characterized with IR, 1H/13C NMR and UV/Vis spectroscopic techniques. The solid state structures of two ligands (L-OCH3, L-OAc) and one complex {[(L-OCH3)PtCl2]} were determined by X-ray diffraction. Molecular structure analysis of the ligands and the complex indicated that complexation resulted in a change in the conformation of the bipyridine fragment of the compounds studied and caused other interesting effects. Two crystallographically independent molecules of the complex were revealed in the measured crystal, with short intramolecular H···H distances. The structural and energetic aspects of the conformational behavior of the ligand L-OCH3 and the complex [(L-OCH3)PtCl2] have been analyzed using semiempirical PM3 methods. In vitro antiproliferative activity was preliminarily estimated. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

The synthesis and biological investigation of the series of amide and ester derivatives 10-20 of 5-(4-chlorobenzoyl)amino-3-methyl-4-isothiazolecarboxylic acid 5 are presented. Because the amide series of 5-benzoylamino-3-methyl-4-isothiazolecarboxylic acid 2 has been studied extensively and from this series denotivir (vratizolin) 4 became the antiviral drug. The influence of exchanging the N-benzoyl for a N-(4-chlorobenzoyl) group at position 5 of the isothiazole ring on the pharmacological activity of 5-benzoylamino-3-methyl-4-isothiazolecarboxylic acid 2 derivatives is dealt with here. The effect of structure modifications in the carboxylic group of the 5-(4-chlorobenzoyl)amino-3-methyl-4-isothiazolecarboxylic acid 5 series of derivatives on their biological activity is discussed. Some of the tested 5-(4-chlorobenzoyl)amino-3-methyl-4-isothiazolecarboxylamides revealed significant anti-inflammatory activity in carrageenan induced edema and air-pouch inflammation tests. Physicochemical properties of 6-(4-chlorophenyl)-3-methylisothiazolo[5,4-d]-4H-1,3-oxazin-4-one 6 are described. Its use in the synthesis of isothiazole derivatives and its reactivity are also presented.

Several new amides 4 of 5-substituted 3-methyl-4-isothiazolecarboxylic acid were obtained. These compounds have acetylamino or benzoylamino groups in position 5 of the isothiazole ring. In position 4, the carboxylic group was transformed in the amides using amino-acid esters. Activities of the obtained derivatives were checked in the humoral immune response and delayed type hypersensitivity reaction to sheep red blood cells (SRBCs) in vivo.

Investigation of the reduction potential and calculation of the partition coefficient n-octanol/water allow the assessment of the potential suitability of nitropirydine N-oxide compounds in radiotherapy of cancer. Experiments were carried out using cyclic voltammetry with HMDE as working electrode. The electrode reduction of the investigated compounds is quite irreversible and strongly dependent on pH.