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•Hematological malignancies comprise 1.2 million new cases annually worldwide.•Current treatment options are limited by cancer cell resistance and relapse events.•The review ...summarizes 119 isoxazoles derivates against hematological malignancies.•Isoxazoles show cancer selectivity and ability to overcome cancer drug resistance.•Low toxicity is particularly promising characteristic of isoxazole derivates.
Compounds with a heterocyclic isoxazole ring are well known for their diverse biologic activities encompassing antimicrobial, antipsychotic, immunosuppressive, antidiabetic and anticancer effects. Recent studies on hematological malignancies have also shown that some of the isoxazole-derived compounds feature encouraging cancer selectivity, low toxicity to normal cells and ability to overcome cancer drug resistance of conventional treatments. These characteristics are particularly promising because patients with hematological malignancies face poor clinical outcomes caused by cancer drug resistance or relapse of the disease. This review summarizes the knowledge on isoxazole-derived compounds toward hematological malignancies and provides clues on their mechanism(s) of action (apoptosis, cell cycle arrest, ROS production) and putative pharmacological targets (c-Myc, BET, ATR, FLT3, HSP90, CARM1, tubulin, PD-1/PD-L1, HDACs) wherever known.
This study focuses on the synthesis and structural characterization of new compounds that integrate thiazolidine-2,4-dione, acridine moiety, and an acetamide linker, aiming to leverage the ...synergistic effects of these pharmacophores for enhanced therapeutic potential. The newly designed molecules were efficiently synthesized through a multi-step process and subsequently transformed into their hydrochloride salts. Comprehensive spectroscopic techniques, including nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), infrared (IR) spectroscopy, and elemental analysis, were employed to determine the molecular structures of the synthesized compounds. Biological evaluations were conducted to assess the therapeutic potential of the new compounds. The influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. An in-depth analysis of the structure–activity relationship (SAR) revealed intriguing insights into their cytotoxic profiles. Compounds with electron-withdrawing groups generally exhibited lower IC50 values, indicating higher potency. The presence of the methoxy group at the linking phenyl ring modulated both the potency and selectivity of the compounds. The variation in the acridine core at the nitrogen atom of the thiazolidine-2,4-dione core significantly affects the activity against cancer cell lines, with the acridin-9-yl substituent enhancing the compounds’ antiproliferative activity. Furthermore, compounds in their hydrochloride salt forms demonstrated better activity against cancer cell lines compared to their free base forms. Compounds 12c·2HCl (IC50 = 5.4 ± 2.4 μM), 13d (IC50 = 4.9 ± 2.9 μM), and 12f·2HCl (IC50 = 4.98 ± 2.9 μM) demonstrated excellent activity against the HCT116 cancer cell line, and compound 7d·2HCl (IC50 = 4.55 ± 0.35 μM) demonstrated excellent activity against the HeLa cancer cell line. Notably, only a few tested compounds, including 7e·2HCl (IC50 = 11.00 ± 2.2 μM), 7f (IC50 = 11.54 ± 2.06 μM), and 7f·2HCl (IC50 = 9.82 ± 1.92 μM), showed activity against pancreatic PATU cells. This type of cancer has a very high mortality due to asymptomatic early stages, the occurrence of metastases, and frequent resistance to chemotherapy. Four derivatives, namely, 7e·2HCl, 12d·2HCl, 13c·HCl, and 13d, were tested for their interaction properties with BSA using fluorescence spectroscopic studies. The values for the quenching constant (Ksv) ranged from 9.59 × 104 to 10.74 × 104 M−1, indicating a good affinity to the BSA protein.
The synthesis, anticancer, and antioxidant activities of a series of indole-derived hybrid chalcones are reported here. First, using the well-known Claisen–Schmidt condensation method, a set of 29 ...chalcones has been designed, synthesized, and consequently characterized. Subsequently, screening for the antiproliferative activity of the synthesized hybrid chalcones was performed on five cancer cell lines (HCT116, HeLa, Jurkat, MDA-MB-231, and MCF7) and two non-cancer cell lines (MCF-10A and Bj-5ta). Chalcone 18c, bearing 1-methoxyindole and catechol structural features, exhibited selective activity against cancer cell lines with IC50 values of 8.0 ± 1.4 µM (Jurkat) and 18.2 ± 2.9 µM (HCT116) and showed no toxicity to non-cancer cells. Furthermore, antioxidant activity was evaluated using three different methods. The in vitro studies of radical scavenging activity utilizing DPPH radicals as well as the FRAP method demonstrated the strong activity of catechol derivatives 18a–c. According to the ABTS radical scavenging assay, the 3-methoxy-4-hydroxy-substituted chalcones 19a–c were slightly more favorable. In general, a series of 3,4-dihydroxychalcone derivatives showed properties as a lead compound for both antioxidant and antiproliferative activity.
Performing solution-phase oximation reactions with hydroxylamine hydrochloride (NH
OH·HCl) carries significant risk, especially in aqueous solutions. In the present study, four
-substituted ...indole-3-carboxaldehyde oximes were prepared from the corresponding aldehydes by solvent-free reaction with NH
OH·HCl and a base (NaOH or Na
CO
) using a mechanochemical approach, thus minimizing the possible risk. In all cases, the conversion to oximes was almost complete. The focus of this work is on 1-methoxyindole-3-carboxaldehyde oxime, a key intermediate in the production of indole phytoalexins with useful antimicrobial properties. Under optimized conditions, it was possible to reach almost 95% yield after 20 min of milling. Moreover, for the products containing electron-donating substituents (-CH
, -OCH
), the isomerization from the oxime
to
isomer under acidic conditions was discovered. For the 1-methoxy analog, the acidic isomerization of pure isomers in solution resulted in the formation of
isomer, whereas the prevalence of
isomer was observed in solid state. From NMR data the
and
structures of produced oximes were elucidated. This work shows an interesting and possibly scalable alternative to classical synthesis and underlines environmentally friendly and sustainable character of mechanochemistry.
Derivatives combining acridine, pyrrole, and thiazolidine rings have emerged as promising candidates in the field of antitumor drug discovery. This paper aims to highlight the importance of these ...three structural motifs in developing potent and selective anticancer agents. The integration of these rings within a single molecule offers the potential for synergistic effects, targeting multiple pathways involved in tumor growth and progression. Spiro derivatives were efficiently synthesized in a two-step process starting from isothiocyanates and 2-cyanoacetohydrazide. The thiourea side chain in spiro derivatives was utilized as a key component for the construction of the thiazolidine-4-one ring through regioselective reactions with bifunctional reagents, namely methyl-bromoacetate, dietyl-acetylenedicarboxylate, ethyl-2-bromopropionate, and ethyl-2-bromovalerate. These reactions resulted in the formation of a single regioisomeric product for each derivative. Advanced spectroscopic techniques, including 1D and 2D NMR, FT-IR, HRMS, and single-crystal analysis, were employed to meticulously characterize the chemical structures of the synthesized derivatives. Furthermore, the influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. Notably, derivatives containing ester functional groups exhibited exceptional activity against all tested cancer cell lines, boasting IC50 values below 10 μM. Particularly striking were the spiro derivatives with methoxy groups at position 3 and nitro groups at position 4 of the phenyl ring. These compounds displayed remarkable selectivity and exhibited heightened activity against HCT-116 and Jurkat cell lines. Additionally, 4-oxo-1,3-thiazolidin-2-ylidene derivatives demonstrated a significant activity against MCF-7 and HCT-116 cancer cell lines.
Indole-based chalcones have been identified as interesting compounds with anticancer properties. In the present study, we report the synthesis and evaluation of new 1-methoxyindole and 2-alkoxyindole ...chalcone hybrids as antiproliferative agents active against colorectal carcinoma cell line. Among the 19 investigated molecules, four inhibit the proliferation of colorectal cancer cells HCT-116 with IC
50
values <8 µM and display low cytotoxicity to fibroblast cell line 3T3. The UV–visible, CD and fluorescence competitive displacement assays with ethidium bromide and Hoechst 33258 performed with two active chalcones demonstrated that investigated chalcones interact with calf thymus (CT) DNA through the groove binding mode. Likewise, the quenching interaction of chalcones with bovine serum albumin (BSA) was studied in vitro under optimal physiological condition (pH = 7.4). The Stern–Volmer constant for chalcone-BSA system was found in the range of 10
5
M
−1
.
Two series of novel chalcone derivatives containing acridin-9-yl or acridin-4-yl moiety have been synthesized, structure elucidated and further evaluated for their growth inhibitory activity against ...human cancer cell lines. Among the 12 investigated molecules, (2
E
)-3-(acridin-4-yl)-1-(3,4,5-trimethoxyphenyl)-prop-2-en-1-one (
4e
) exerted the best cytotoxic activity against aggressive and invasive, triple-negative breast cancer cell line MDA-MB-231 and estrogen responsive MCF-7 cells with the IC
50
values of 8.4 and 7.7 μM respectively and was selected for further studies. Furthermore, flow cytometry analysis showed
4e
-induced, cell cycle block in the G2/M phase with a concomitant increase in the number of cells with sub-G0/G1 content, which is considered as a marker of apoptosis. Thereafter, we evaluated that compound
4e
induced cell death by mitochondria-mediated apoptosis associated with loss of mitochondrial membrane potential (MMP), dysregulation of Bax and Bcl-xl protein expression, cytochrome
c
release, caspase 7 activation, and PARP cleavage. In addition, upregulation of p53 and p21 has also been observed. In vitro DNA interaction studies demonstrated that
4e
interacts with CT DNA by bimodal binding mode: intercalation and groove-binding. Chalcone
4e
showed an affinity to bovine serum albumin that indicates that can be efficiently transported by serum proteins in the bloodstream. This evidence fully confirmed that compound
4e
could be a potential candidate that deserves further development as an antitumor agent against breast cancer.
Graphical abstract
An efficient eco-friendly one-step mechanochemical synthesis of indole hybrid chalcones via the Claisen-Schmidt condensation of 1-methylindole-3-carboxaldehyde with various substituted acetophenones ...is described using liquid assisted grinding in a high-energy ball mill. The notable advantages of the present method are small organic solvent required (100 μL ethanol) and mainly shorter reaction time (15-60 min) as compared to the conventional method. Antiproliferative activity of synthesized chalcones was studied on several human cancer cell lines (MCF-7, HeLa, A549, MDA-MB-231, HCT116) and non-cancer lines (Cos-7 or BJ-5ta). 3,4,5-Trimethoxyphenyl 3g, 2,5-dimethoxyphenyl 3h, and 2,4,5-trimethylphenyl 3j chalcones showed considerable cytotoxicity, particularly, chalcones 3h and 3j were identified as the most potent and selective anticancer agents with IC
50
values 7.9 and 6.6 μM, respectively, against the colon cancer HCT116 cell line.
•Efficient direct LC separation of enantiomers of phytoalexins analogs.•Immobilized polysaccharide-based chiral stationary phases.•Comparison of recognition abilities of three polysaccharide ...columns.•Unusual temperature behavior, increase of retention with increasing temperature, was observed on Chiralpak IC.
Three immobilized polysaccharide chiral stationary phases, Chiralpak IA, Chiralpak IB and Chiralpak IC, were used for the study of enantioseparation of 36 derivatives of natural indole phytoalexins, in most cases bioactive, including racemic spirobrassinin, 1-methoxyspirobrassinin and 1-methoxyspirobrassinol methyl ether. Almost all analytes were baseline resolved at least on two different polysaccharide columns in normal phase mode. The effects of mobile phase composition, the analyte structure and the column temperature on the retention and enantioseparation were investigated. Evaluation of the corresponding thermodynamic parameters using van´t Hoff plots (ln k versus 1/T) in the temperature range -15 to 50 °C indicated that separations were enthalpy controlled in most cases, but some entropy controlled separations were also observed. Moreover, unusual phenomenon, an increase retention with increasing temperature accompanied with increased resolution was observed on the Chiralpak IC column. The elution order of enantiomers was determined in some cases and reversed elution order was also observed.
•Synthesis of new perillaldehyde and myrtenal based benzohydrazides.•The NMR experiments in solution confirmed the presence of two conformers as well as H-bond N–H···F.•The kinetics of the ...conformational interconversion were studied by 2D EXSY.•The FT–IR spectra confirmed the presence of the H-bonds N–H···O=C and N–H···N.•Hydrazones crystallized in the P1 and P41 space groups, the molecules are linked through N―H···O(N) H-bonds in the crystal.
N-Acylhydrazones have been an interesting scaffold due to their diverse biological activities toward different therapeutic targets. We synthesized seven new N'‐(E)‐(4S)‐4‐(prop‐1‐en‐2‐yl)cyclohex‐1‐en‐1‐ylmethylidenebenzohydrazides as well as seven new N'-(E)-{6,6-dimethylbicyclo3.1.1hept-2-en-2-yl}methylidenebenzohydrazides. The structure of synthesized hydrazides has been studied by using X-ray analysis, FT-IR, NMR, and HRMS spectra. Derivatives containing fluorine atoms in position 2 of the phenyl ring display versatile structures in solution and the solid state. The 1H NMR spectra of 3c and 5c measured in DMSO-d6 display at ambient temperature two unequally populated sets of signals. These facts confirm the existence of the two conformers of 3c and 5c of different stability which interconvert by rotation about their C―N bond slowly enough to lead to discrete sets of signals in 1H NMR spectra at room temperature. The kinetics of the conformational interconversion of derivatives 3c and 5c in DMSO-d6 were studied by two-dimensional exchange spectroscopy (2D EXSY). In 1H NMR spectra of 3c and 5c measured in CDCl3 and acetone-d6 was observed the strong splitting of the H-2 signal into a doublet because of H-bond formation between organic fluorine and NH donor. The FT–IR spectra of 3a–g and 5a–g confirmed the presence of the H-bonds N–H···O=C and N–H···N. Hydrazones 3f, 5a, and 5c crystallize in the P1 space group and the asymmetric units contain two pairs of pseudo-centrosymmetric molecules. Hydrazone 5b crystallizes in the P41 space group and the asymmetric units contain only one molecule. In the crystal, the molecules in 3f, 5a and 5b are linked through N―H···O hydrogen bonds, in 5c also N―H···N hydrogen bonds are present. In contrast to the NMR, the X-ray and IR spectra did not give unambiguous evidence of the F···H−N H-bond. The synthesized hydrazones 3c and 3g exhibited excellent antiproliferative effects in Jurkat cells with IC50 values of 3.8 and 4.2 μM, respectively. Our findings indicate that these compounds are promising antitumor agents.
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