Acetylation of Oleanolic Acid Dimers as a Method of Synthesis of Powerful Cytotoxic Agents.

Oleanolic acid, a naturally occurring triterpenoid compound, has garnered significant attention in the scientific community due to its diverse pharmacological properties. Continuing our previous work on the synthesis of oleanolic acid dimers (OADs), a simple, economical, and safe acetylation reaction was performed. The newly obtained derivatives (AcOADs, -) were purified using two methods.

Oleanolic Acid Dimers with Potential Application in Medicine-Design, Synthesis, Physico-Chemical Characteristics, Cytotoxic and Antioxidant Activity.

The present work aimed to obtain a set of oleanolic acid derivatives with a high level of cytotoxic and antioxidant activities and a low level of toxicity by applying an economical method. Oleanolic acid was alkylated with α,ω-dihalogenoalkane/α,ω-dihalogenoalkene to obtain 14 derivatives of dimer structure. All of the newly obtained compounds were subjected to QSAR computational analysis to evaluate the probability of the occurrence of different types of pharmacological activities depending on the structure of the analysed compound.

Acylation of Oleanolic Acid Oximes Effectively Improves Cytotoxic Activity in In Vitro Studies.

(1) Background: The aim of the presented work was to obtain a set of oleanolic acid derivatives with a high level of anticancer activity and a low level of toxicity by applying an economic method. Three types of oleanolic acid derivatives were obtained: (i) derivatives of methyl oleanonate oxime, (ii) derivatives of methyl oleanonate oxime with an additional 11-oxo function, and (iii) derivatives of morpholide of oleanonic acid oxime. (2) Methods: The above oximes were acylated with aliphatic or aromatic carboxylic acid.

Cascade Transformation of the Ansamycin Benzoquinone Core into Benzoxazole Influencing Anticancer Activity and Selectivity.

The metal-free cascade transformation of geldanamycin benzoquinone core is proposed at relatively mild conditions. This approach yields new benzoxazole ansamycin antibiotics and enables their functionalization in an atom-economic manner, irrespective of the type of amine used. The analysis of the heterocyclization course reveals the dependence of its rate on the nature of the -substituent within the benzylamine moiety (EDG/EWG) and the strength of the base.

Modifications of geldanamycin via CuAAC altering affinity to chaperone protein Hsp90 and cytotoxicity.

Functionalization of alkyne (1) and azide (2) derivatives of geldanamycin (GDM) via dipolar cycloaddition CuAAC yielded 35 new congeners (3-37) with C(17)-triazole arms bearing caps of different nature (basic vs. acidic, hydrophilic vs. hydrophobic).

Highly Branched Betulin Based Polyanhydrides for Self-Assembled Micellar Nanoparticles Formulation.

Polyanhydrides based on betulin are promising materials for use in controlled drug delivery systems. Due to the broad biological activity of betulin derivatives and lack of toxicity in vitro and in vivo, these polymers can be used both as polymeric prodrug and as carriers of other biologically active compounds. In this study, we develop a novel amphiphilic branched polyanhydrides synthesized by the two-step melt polycondensation of betulin disuccinate (DBB) and a tricarboxylic derivative of poly(ethylene glycol) (PEG_COOH).

Biodegradable and Bioactive Carriers Based on Poly(betulin disuccinate--sebacic Acid) for Rifampicin Delivery.

This paper describes the preparation and characterization of polymer-drug systems based on polymeric microspheres obtained from poly(betulin disuccinate--sebacic acid). The active compound that was coupled to the betulin-based carriers was rifampicin (RIF), an ansamycin drug used in the treatment of tuberculosis. Poly(betulin disuccinate--sebacic acid) microspheres were prepared using a solvent evaporation technique from copolymers obtained by polycondensation of betulin disuccinate () and sebacic acid ().

EGDMA- and TRIM-Based Microparticles Imprinted with 5-Fluorouracil for Prolonged Drug Delivery.

Imprinted materials possess designed cavities capable of forming selective interactions with molecules used in the imprinting process. In this work, we report the synthesis of 5-fluorouracil (5-FU)-imprinted microparticles and their application in prolonged drug delivery. The materials were synthesized using either ethylene glycol dimethacrylate (EGDMA) or trimethylolpropane trimethacrylate (TRIM) cross-linkers.

Regioselective approach to colchiceine tropolone ring functionalization at C(9) and C(10) yielding new anticancer hybrid derivatives containing heterocyclic structural motifs.

The influence of base type, temperature, and solvent on regioselective C(9)/C(10) "" modifications within the tropolone ring of colchiceine () is investigated. New ether derivatives of , bearing alkyne, azide, vinyl, or halide aryl groups enable assembly of the alkaloid part with heterocycles or important biomolecules such as saccharides, geldanamycin or AZT into hybrid scaffolds by dipolar cycloaddition (CuAAC) or Heck reaction. Compared to colchicine () or colchiceine (), ether congeners, as e.

Anticancer activity and toxicity of new quaternary ammonium geldanamycin derivative salts and their mixtures with potentiators.

Geldanamycin () has been modified by different type neutral/acidic/basic substituents (-) and by quinuclidine motif (), transformed into ammonium salts (-) at C(17). These compounds have been characterised by spectroscopic and x-ray methods. Derivative shows better potency than in MCF-7, MDA-MB-231, A549 and HeLa (ICs = 0.

Bioactive Betulin and PEG Based Polyanhydrides for Use in Drug Delivery Systems.

In the course of this study, a series of novel, biodegradable polyanhydrides based on betulin disuccinate and dicarboxylic derivatives of poly(ethylene glycol) were prepared by two-step polycondensation. These copolymers can be used as carriers in drug delivery systems, in the form of microspheres. Betulin and its derivatives exhibit a broad spectrum of biological activity, including cytotoxic activity, which makes them promising substances for use as therapeutic agents.

Synthesis, structure and anticancer activity of new geldanamycin amine analogs containing C(17)- or C(20)- flexible and rigid arms as well as closed or open ansa-bridges.

The nucleophilic attack of amines at C(17) or C(17)/C(20) positions of geldanamycin's (GDM) benzoquinone, via initial 1,4-Michael conjugate addition mechanism, yield new analogs with closed or open ansa-bridges (1-31), respectively. X-ray structures of analogs 22 and 24 reveals an unexpected arrangement of the ansa-bridge in solid (conformer B), that is located between those of conformers A, prevailing in solution (trans-lactam), and C, crucial at binding to Hsp90 (cis-lactam). The structure of a new-type conformer B allows to better understand the molecular recognition mechanism between the GDM analogs and the target Hsp90.

Effects of combined statin and ACE inhibitor therapy on endothelial function and blood pressure in essential hypertension - a randomised double-blind, placebo controlled crossover study.

Background: The aim of this study was to compare the influence of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on endothelial function and blood pressure in patients with essential hypertension on long-term angiotensin-converting enzyme inhibitor therapy.

Method: The study was designed as a prospective, double-blind, randomised, placebo controlled, crossover clinical trial. Twenty patients with essential hypertension were treated with an angiotensin-converting enzyme inhibitor; the control group included 10 healthy subjects.

Synthesis and in vitro anticancer activity of new gemcitabine-nucleoside analogue dimers containing methyltriazole or ester-methyltriazole linker.

Two series of novel gemcitabine-nucleoside analogue dimers were synthesized using the 'click' chemistry approach. In the first series of dimers (21-30), the nucleoside units were connected with a stable methyltriazole 4N-3'(or 5')C linker whereas in the second series (31-40) with a cleavable ester-methyltriazole 4N-3'(or 5')C linker. Dimers 21-40 were evaluated for their cytotoxic activity in five human cancer cell lines such as cervical (HeLa), nasopharyngeal (KB), lung (A549), brain (U87), liver (HepG2) and normal dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay.

Nucleoside dimers analogs containing floxuridine and thymidine with unnatural linker groups: synthesis and cancer line studies. Part III.

Two series of novel fluorinated nucleosides dimers with an unnatural 1,2,3-triazole linkage were synthesized. The obtained molecules were prepared using "click" chemistry approach based on copper(I) catalyzed Huisgen azide-alkyne cycloaddition. It was performed between 3'- and 5'-azido-nucleosides as the azide components, and the 3'-- and 5'--propargyl-nucleosides as the alkyne components.

The influence of cross-linking agent onto adsorption properties, release behavior and cytotoxicity of doxorubicin-imprinted microparticles.

Molecularly imprinted polymers (MIPs) are synthetic polymers that possess cavities selective towards their molecular templates and have found many applications in separation science, drug delivery, and catalysis. Here, we report the synthesis of doxorubicin-imprinted microparticles cross-linked with two different compounds (ethylene glycol dimethacrylate or trimethylolpropane trimethacrylate) and examination of their physicochemical properties. During the synthesis methacrylic acid was used as functional monomer and 2-hydroxyethyl methacrylate was added into polymerization mixture to increase hydrophilicity of the obtained materials and therefore improve interactions with aqueous release medium.

Novel polymeric derivatives of betulin with anticancer activity.

In order to provide novel polymeric biomaterials for chemotherapeutic purposes, in this paper we described the synthesis and the characterization of the physicochemical properties of a betulin-based polyanhydride exhibiting anti-cancer effects. The polyanhydride was obtained by a melt polycondensation of a disuccinate betulin (3,28-di--succinyl betulin), and was thoroughly characterized through H NMR and C NMR spectroscopies, correlation spectroscopy, heteronuclear single quantum correlation, size exclusion chromatography, differential scanning calorimetry and FT-IR spectroscopy. It was confirmed, that the obtained polyanhydride undergoes hydrolytic degradation, releasing disuccinate betulin as a degradation product.

Nucleoside dimers analogues with a 1,2,3-triazole linkage: conjugation of floxuridine and thymidine provides novel tools for cancer treatment. Part II.

The fluorinated nucleoside dimers with a 1,2,3-triazole linkage are novel compounds within the field of bioorganic chemistry. We report on the synthesis and properties of two groups of nucleoside dimers analogs possessing a different arrangement of the 1,4-disubstituted 1,2,3-triazole linkage. Based on analysis of the , J, and J we estimated conformational preferences of sugar part and orientation around glycosidic bond.

Synthesis and anticancer activity of 3'-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine analogs and their phosphoramidates.

A series of novel 4-chlorophenyl -alkyl phosphoramidates of 3'-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidines (-) was synthesized by means of phosphorylation of 3'-[4-aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidines (-) with 4-chlorophenyl phosphoroditriazolide (), followed by a reaction with the appropriate amine. The synthesized compounds - and - were evaluated along with four known anticancer compounds for their cytotoxic activity in human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), osteosarcoma (143B) (only selected compounds , , , -, , , ) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Among 3'-[4-aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidines (-) the highest activity in all the investigated cancer cells was displayed by 3'-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3'-deoxythymidine () (IC in the range of 2.

Cytotoxic and trypanocidal activities of cinchona alkaloid derivatives.

A series of 27 cinchona alkaloid derivatives (1f-w, 2a-e and 3a-d) were investigated for their cytotoxic and trypanocidal activities using seven different cancer cell lines (KB, HeLa, MCF-7, A-549, Hep-G2, U-87 and HL-60), two normal cell lines (HDF and CHO) and bloodstream forms of Trypanosoma brucei brucei, respectively. Four compounds (1u, 1w, 2e and 3d) were identified with promising cytotoxic activity with 50% growth inhibition (GI ) values below 10 μM. Two (2e and 3d) of the four compounds also exhibited potent anti-trypanosomal activity with GI values of 0.

Enhancing anticancer activity through the combination of bioreducing agents and triterpenes.

Aim: Triterpenes are natural compounds, whose wide biological activity predestines them for application as promising new chemotherapeutics. In this paper, we report the results of our investigations into the substitution of oleanolic acid with aromatic and nitroaromatic moieties acting as bioreducing agents.

Results: The process of reduction of nitro groups was investigated through cyclic voltammetry, UV-Vis and electron paramagnetic resonance spectroelectrochemistry.

Synthesis and cytotoxic activity of novel acyclic nucleoside analogues with functionality in click chemistry.

We describe synthesis of novel acyclic nucleoside analogues which are building blocks for CuAAC reaction and their activity against two types of human cancer cell lines (HeLa, KB). Three of chosen compounds show promising cytotoxic activity. Synthesis pathway starting from simple and easily accessible substrates employing DMT or TBDPS protective groups is described.

Betulin-loaded PEDOT films for regional chemotherapy.

Chemotherapy is one of the most commonly used cancer treatments. Even so, it has significant adverse effects on healthy tissues. These effects can be avoided through the use of regional chemotherapy, an approach based on delivering the anti-cancer agents locally, to the site of cancer tissue accumulation.

Cytotoxic Activity of Some Lupeol Derivatives.

The synthesis of 3-0-acyl derivatives of lupeol is presented, as well as lupenone and the oxime of lupenone. The obtained derivatives were subjected to the MTT test in order to evaluate their cytotoxic activity toward HeLa, KB, MCF-7 and A-549 cell lines in comparison with lupeol (1). The IC₅₀ values for lupeol (1) and all of the tested derivatives (2-6) were from about 7-10 μM for lupenone (5) to about 81 μM for o-phthaloyl-lupeol (4).

Synthesis, Antibacterial, and Anticancer Evaluation of Novel Spiramycin-Like Conjugates Containing C(5) Triazole Arm.

Huisgen cycloaddition allowed obtaining of novel triazole-bridged antibiotics (6-16) with the reconstructed C(5) arm of spiramycin. (1)H-(1)H NOESY couplings indicated the structure of novel derivatives in solution and demonstrated that the rebuilt C(5) arm is slightly differently oriented relative to the aglycone part if compared to that of spiramycin (1). Combined analysis of biological data together with experimentally determined lipophilicity (clogP) and solubility show the importance of the chemical nature of the newly introduced triazole C(5) arm in the presence of attractive antibacterial and anticancer potency.