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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.
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.
Ceramides and their roles in programmed cell death Pilátová, Martina Bago; Solárová, Zuzana; Mezencev, Roman ...
Advances in medical sciences,
September 2023, 2023-09-00, 20230901, Letnik:
68, Številka:
2
Journal Article
Recenzirano
Programmed cell death plays a crucial role in maintaining the homeostasis and integrity of multicellular organisms, and its dysregulation contributes to the pathogenesis of many diseases. Programmed ...cell death is regulated by a range of macromolecules and low-molecular messengers, including ceramides. Endogenous ceramides have different functions, that are influenced by their localization and the presence of their target molecules. This article provides an overview of the current understanding of ceramides and their impact on various types of programmed cell death, including apoptosis, anoikis, macroautophagy and mitophagy, and necroptosis. Moreover, it highlights the emergence of dihydroceramides as a new class of bioactive sphingolipids and their downstream targets as well as their future roles in cancer cell growth, drug resistance and tumor metastasis.
A short synthetic route towards novel cytotoxic FTY720 analogues bearing a variously substituted azobenzene unit was developed. The target compounds were constructed either via a Wittig olefination ...or Mills reaction as the key processes. Preliminary biological screening revealed the antiproliferative activity of several newly synthesised derivatives against Jurkat, HeLa and HCT-116 cells to be quite promising, comparable or higher than the potency of cisplatin (Brinkmann et al., 2010) 1. The structure-activity relationship showed that a loss of the alkyl side chain on the azobenzene core or its substitution with hydroxymethyl moiety seem to be detrimental for the resulting cytotoxic profile in this series of derivatives. To probe the photochromic properties of the final derivatives, the reversible E/Z isomerisation and thermal relaxation rate were determined.
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A divergent approach to a small library of long-chain 6-amino-1,4,5-triols as novel phytosphingosine-type entities, together with their preliminary cytotoxic evaluation, was achieved. Construction of ...the target compounds addressed two key aspects. First, the installation of a carbon-nitrogen bond via two prototypes of 3,3-sigmatropic rearrangements and second the introduction of an alkyl side chain unit by using a late stage olefin cross-metathesis process. As shown in cell viability experiments, the corresponding HCl salts proved to be the most cytotoxic derivatives among all the tested substances, with IC50 values in the lower micromolar range on the Jurkat, HeLa and HCT-116 cell lines.
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•Synthesis of a small library of phytosphingosine-type derivatives was achieved.•The developed approach relied on aza-Claisen rearrangements and a late stage OCM reaction.•The novel stereochemistry of the key substructures was assigned via NOESY experiments.•The target compounds were evaluated regarding their capacity to alter cancer cells viability.
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A short and flexible construction of novel dihydrosphingosine-type analogues has been accomplished. The pivotal step of this approach was a cascade 3,3-sigmatropic rearrangement of a ...tris(imidate) substrate, which provided the core motif of our final compounds with three carbon–nitrogen bonds, including two consecutive stereocentres, starting from an l-erythrofuranose chiron. The subsequent cross-metathesis scenario allowed for the instalment of an alkyl side chain unit. Antiproliferative/cytotoxic screening of the target derivative revealed its capacity to alter the viability of both leukaemia and solid tumour cell lines.
In this paper we describe the efficient synthesis of d-ribo-phytosphingosine and its analogues commencing from the easily available l-erythrose chiron, which already contained the future C-3 and C-4 ...stereocentres of our target compounds. Construction of the remaining C-2 stereochemistry relied on aza-Claisen rearrangements to establish the desired vicinal aminoalcohol motif. The aliphatic chain was introduced by means of an olefin cross metathesis process. Completion of this phytosphingolipid synthesis was then achieved through the suitable selection of functional group interconversions, accompanied by selective deprotection protocols. Preliminary in vitro experiments revealed higher antiproliferative activity of the unnatural d-arabino-phytosphingosine 3. HCl in comparison to cisplatin against three of the five cancer cell lines evaluated, with IC50 values ranging from 4.17 μM to 7.63 μM. Moreover, compound 3. HCl has better inhibitory effects on the proliferation of the aforementioned malignant cell lines than its natural stereochemical congener 2. HCl.
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•An approach to d-ribo-phytosphingosine and its analogues was achieved.•The strategy relied on sigmatropic rearrangements and OCM reaction.•The stereochemistry was assigned via X-ray analysis.•The target compounds were screened for anticancer activity.
Straightforward access to enantiomerically pure 3,4-diamino-3,4-dideoxyphytosphingosines, as novel analogues of natural d-ribo-phytosphingosine was accomplished, starting from two available chirons: ...dimethyl l-tartrate and d-isoascorbic acid. A sequential Overman rearrangement followed by late-stage introduction of the alkyl side chain moiety via olefin cross-metathesis is the cornerstone of this approach. The preliminary evaluation study of the synthesised sphingomimetics, based on their ability to inhibit a proliferation of human cancer cells, showed promising cytotoxicity against Jurkat and HeLa cells for (2R,3R,4S)-2,3,4-triaminooctadecan-1-ol trihydrochloride.
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•Construction of a small library of phytosphingomimetics was achieved.•Cascade rearrangement and metathesis were involved as pivotal steps.•The relative stereochemistry was determined via chemical correlations.•The target compounds were evaluated on a series of cancer cell lines (BLM/A2058, MCF-7, HCT-116, Jurkat, HeLa).
Substances containing a spirooxindole framework display important biological activities. Natural alkaloid capparine A (S)-(−)-1 has an anti-inflammatory effect. In the present study, attention has ...been paid to the first total synthesis of natural capparine A (S)-(−)-1. Racemic capparine A (±)-1 was synthesized by bromospirocyclization of 6-methoxy-1-Boc-brassinin with water, followed by oxidation of obtained spirobrassinol derivatives and removal of the Boc group. Synthesized racemic capparine A (±)-1 was enantioresolved by derivatization with (1R,2S,5R)-menthyl chloroformate, chromatographic separation of diastereoisomers and the cleavage of the chiral auxiliary using sodium methoxide. Screening of anti-proliferative activity against human cancer cells revealed no anti-proliferative activity of the capparine A (S)-(−)-1.
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•The first synthesis of alkaloid capparine A was accomplished.•The anti-proliferative activity of capparine A against cancer cell lines was also evaluated.
Straightforward access to a series of the cytotoxic sphingolipid-derived alkaloids possessing a pyrrolidine unit and a long hydrophobic side chain was accomplished. Two simple carbohydrate chirons, ...protected d- and l-erythrofuranose, were chosen as the starting material, and 3,3-sigmatropic rearrangements, a late stage cross metathesis and an intramolecular nucleophilic substitution were involved as the key transformations. The final analogues of natural broussonetines were evaluated for their capacity to alter the proliferation of cancer cells.
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•Synthesis of novel straight side chain broussonetine analogues was accomplished.•The used strategy relied on 3,3-sigmatropic rearrangements, the OCM reaction and SN2 cyclization.•The stereochemistry of a key substructure was determined via crystallographic analysis.•The target pyrrolidine-based alkaloids exhibit an ability to inhibit cancer cell proliferation.
