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1.
Pharmaceutics ; 16(1)2024 Jan 09.
Article in English | MEDLINE | ID: mdl-38258097

ABSTRACT

(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. The newly obtained compounds were subjected to ADMETox analysis and were also tested for cytotoxicity activity on the HeLa, KB, MCF-7, A-549, and HDF cell lines with the MTT assay. (3) Results: Among the tested acylated oximes of oleanolic acid, some derivatives, particularly those with two nitro groups attached to the aromatic ring, proved to be the most potent cytotoxic agents. These triterpene derivatives significantly inhibited the growth of the HeLa, KB, MCF-7, and A-549 cancer cell lines in micromolar concentrations. (4) Conclusions: The introduction of different moieties, particularly the 3,5-dinitro group, resulted in the synthesis of highly potent cytotoxic agents with favorable SI and ADMETox parameters.

2.
J Org Chem ; 88(13): 9469-9474, 2023 07 07.
Article in English | MEDLINE | ID: mdl-37276434

ABSTRACT

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 para-substituent within the benzylamine moiety (EDG/EWG) and the strength of the base. The reduction of the ansamycin core enables an increase in anticancer potency and selectivity.


Subject(s)
Benzoxazoles , Rifabutin , Lactams, Macrocyclic/pharmacology , Benzoxazoles/pharmacology , Benzoquinones
3.
Eur J Med Chem ; 256: 115450, 2023 Aug 05.
Article in English | MEDLINE | ID: mdl-37210951

ABSTRACT

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). Confrontation of biological data (anticancer activity vs. toxicity in normal cells) with lipophilicity (clogP), dissociation constants (Kd) of complexes with Hsp90 and binding modes to Hsp90 revealed SAR in specific subgroups of GDM derivatives. The most potent GDM congeners 14-16, bearing C(17)-triazole-benzyl-halogen arms exhibited the most optimal clogP values of 2.7-3.1 at favourable binding to Hsp90 (KdHsp90 at µM level). The anticancer activity of 14-16 (IC50 = 0.23-0.41 µM) is higher than those of GDM (IC50 = 0.58-0.64 µM) and actinomycin D (ActD, IC50 = 0.62-0.71 µM) in SKBR-3, SKOV-3 and PC-3 cell lines, with a comparable cytotoxicity in healthy cells. The relationship between structure and attractive anticancer potency (IC50 = 0.53-0.74 µM) is also observed for congeners with C(17)-triazole-saccharide or C(17)-triazole-unsaturated arms. In the former, the absolute configuration at C(4) (ᴅ-glucose vs. ᴅ-galactose) whereas in the latter the length of the unsaturated arm influences the cytotoxic effects due to different binding strength (Kd, ΔE) and modes with Hsp90. Among all triazole congeners of GDM that are biologically attractive and exhibit lower toxicity in normal cells than GDM and ActD, the derivative 22, bearing the C(17)-triazole-cinnamyl arm, shows the lowest Kd (Hsp90), optimal clogP = 2.82, the best pro-apoptotic properties in SKBR-3 and SKOV-3 and the best selectivity indices (SI). For the most potent GDM derivatives with C(17)-triazole arm, the docking studies have suggested the importance of the intermolecular stabilization between the arm and the D57 or Y61 of Hsp90.


Subject(s)
Antineoplastic Agents , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Benzoquinones/pharmacology , Benzoquinones/chemistry , HSP90 Heat-Shock Proteins/metabolism , Structure-Activity Relationship , Triazoles/pharmacology , Triazoles/chemistry , Azides/chemistry , Alkynes/chemistry
4.
Int J Mol Sci ; 23(19)2022 Sep 28.
Article in English | MEDLINE | ID: mdl-36232762

ABSTRACT

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). DBB and PEG_COOH were used as the hydrophobic and hydrophilic segments, respectively. The content of DBB in copolymers was from 10 to 95 wt%. Copolymers were assessed for their cytostatic activity against various cancer cell lines. Compared to linear DBB and PEG-based polyanhydrides, the branched polyanhydrides exhibited higher anticancer activity. The obtained polymers were able to self-assemble in water to form micelles with hydrodynamic diameters from 144.8 to 561.8 nm. and are stable over a concentration range from 12.5 µg/mL to 6.8 mg/mL. The formed micelles were found to be spherical in shape using a scanning electron microscope. It was found that the structure and composition of polyanhydrides affected the hydrodynamic diameter of the micelles. The branched betulin-based polyanhydrides have the potential to serve as biodegradable polymer prodrugs or carriers for other bioactive compounds.


Subject(s)
Cytostatic Agents , Nanoparticles , Polyanhydrides , Prodrugs , Drug Carriers/chemistry , Micelles , Nanoparticles/chemistry , Polyethylene Glycols/chemistry , Triterpenes , Water
5.
Polymers (Basel) ; 14(5)2022 Mar 04.
Article in English | MEDLINE | ID: mdl-35267850

ABSTRACT

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. For both types of polymers, methacrylic acid was used as a functional monomer, whereas 2-hydroxyethyl methacrylate was applied to increase the final materials' hydrophilicity. Adsorption isotherms and adsorption kinetics were investigated to characterize the interactions that occur between the materials and 5-FU. The microparticles synthesized using the TRIM cross-linker showed higher adsorption properties towards 5-FU than those with EGDMA. The release kinetics was highly dependent upon the cross-linker and pH of the release medium. The highest cumulative release was obtained for TRIM-based microparticles at pH 7.4. The IC50 values proved that 5-FU-loaded TRIM-based microparticles possess cytotoxic activity against HeLa cell lines similar to pure 5-FU, whereas their toxicity towards normal HDF cell lines was ca. three times lower than for 5-FU.

6.
Pharmaceutics ; 14(3)2022 Mar 06.
Article in English | MEDLINE | ID: mdl-35335954

ABSTRACT

This paper describes the preparation and characterization of polymer-drug systems based on polymeric microspheres obtained from poly(betulin disuccinate-co-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-co-sebacic acid) microspheres were prepared using a solvent evaporation technique from copolymers obtained by polycondensation of betulin disuccinate (DBB) and sebacic acid (SEB). The content of sebacic acid in the copolymers was 20, 40, 60 and 80 wt%, respectively. Small and large rifampicin-loaded microspheres were obtained for each of the copolymers. The initial amount of drug was 10, 30 or 50 wt%, based on the weight of the polymer. Particles obtained in this study were round in shape with diameter in the range of 2-21 µm and of orange to red colour originating from rifampicin. The RIF encapsulation efficacy varied from 7% to 33%. Drug loading varied from 2% to 13% and increased at a higher RIF ratio. The highest degree of drug loading was observed for large particles, in which the initial amount of drug (at the particle preparation stage) was 50 wt%. Microspheres prepared from betulin-based polyanhydrides may have significant applications in drug delivery systems. The concentration of loaded drug was enough to obtain bactericidal effects against reference S. Aureus ATCC 25923 bacteria.

7.
J Enzyme Inhib Med Chem ; 37(1): 597-605, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35067138

ABSTRACT

The influence of base type, temperature, and solvent on regioselective C(9)/C(10) "click" modifications within the tropolone ring of colchiceine (2) is investigated. New ether derivatives of 2, 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 (1) or colchiceine (2), ether congeners, as e.g. 3e [IC50s(3e) ∼ 0.9 nM], show improved or similar anticancer effects, whereby the bulkiness of the substituents and the substitution pattern of the tropolone proved to be essential. Biological studies reveal that expanding the ether arms by terminal basic heterocycles as quinoline or pyridine, decreases the toxicity in HDF cells at high anticancer potency (IC50s ∼ 1-2 nM). Docking of ether and hybrid derivatives into the colchicine pocket of αGTP/ß tubulin dimers reveals a relationship between the favourable binding mode and the attractive anticancer potency.


Subject(s)
Antineoplastic Agents/pharmacology , Colchicine/pharmacology , Heterocyclic Compounds/pharmacology , Tropolone/pharmacology , Tubulin Modulators/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Colchicine/chemical synthesis , Colchicine/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Humans , Molecular Docking Simulation , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Tropolone/chemical synthesis , Tropolone/chemistry , Tubulin/metabolism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry
8.
J Enzyme Inhib Med Chem ; 36(1): 1898-1904, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34344239

ABSTRACT

Geldanamycin (GDM) has been modified by different type neutral/acidic/basic substituents (1-7) and by quinuclidine motif (8), transformed into ammonium salts (9-13) at C(17). These compounds have been characterised by spectroscopic and x-ray methods. Derivative 8 shows better potency than GDM in MCF-7, MDA-MB-231, A549 and HeLa (IC50s = 0.09-1.06 µM). Transformation of 8 into salts 9-13 reduces toxicity (by 11-fold) at attractive potency, e.g. MCF-7 cell line (IC50∼2 µM). Our studies show that higher water solubility contributes to lower toxicity of salts than GDM in healthy CCD39Lu and HDF cells. The use of 13 mixtures with potentiators PEI and DOX enhanced anticancer effects from IC50∼2 µM to IC50∼0.5 µM in SKBR-3, SKOV-3, and PC-3 cancer cells, relative to 13. Docking studies showed that complexes between quinuclidine-bearing 8-13 and Hsp90 are stabilised by extra hydrophobic interactions between the C(17)-arms and K58 or Y61 of Hsp90.


Subject(s)
Antineoplastic Agents/pharmacology , Benzoquinones/pharmacology , Lactams, Macrocyclic/pharmacology , Quaternary Ammonium Compounds/chemistry , Antineoplastic Agents/chemistry , Benzoquinones/chemistry , Cell Line , Cell Line, Tumor , Drug Screening Assays, Antitumor , Drug Synergism , Humans , Lactams, Macrocyclic/chemistry , Molecular Structure , Salts/chemistry , Spectrum Analysis/methods
9.
Int J Mol Sci ; 22(3)2021 Jan 22.
Article in English | MEDLINE | ID: mdl-33499242

ABSTRACT

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. Microspheres that were prepared from betulin based polyanhydrides show promising properties for use in application in drug delivery systems, including inhalation systems. The obtained copolymers release the active substance-betulin disuccinate-as a result of hydrolysis under physiological conditions. The use of a poly(ethylene glycol) derivative as a co-monomer increases the solubility and bioavailability of the obtained compounds. Microspheres with diameters in the range of 0.5-25 µm were prepared by emulsion solvent evaporation method and their physicochemical and aerodynamic properties were analyzed. The morphological characteristics of the microspheres depended on the presence of poly(ethylene glycol) (PEG) segment within the structure of polyanhydrides. The porosity of the particles depended on the amount and molecular weight of the PEG used and also on the speed of homogenization. The most porous particles were obtained from polyanhydrides containing 20% wt. of PEG 600 by using a homogenization speed of 18,000 rpm.


Subject(s)
Drug Delivery Systems , Phytochemicals/chemistry , Polyanhydrides/chemistry , Polyethylene Glycols/chemistry , Triterpenes/chemistry , A549 Cells , Aerosols , Cell Line, Tumor , Drug Carriers/chemistry , HeLa Cells , Hep G2 Cells , Humans , Hydrogen-Ion Concentration , Hydrolysis , MCF-7 Cells , Magnetic Resonance Spectroscopy , Microspheres , Molecular Weight , Particle Size , Polymers/chemistry , Porosity , Solvents
10.
Eur J Med Chem ; 202: 112624, 2020 Sep 15.
Article in English | MEDLINE | ID: mdl-32663707

ABSTRACT

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. Combined analysis of: anticancer test results (SKBR-3, SKOV-3, PC-3, U-87, A-549) and those performed in normal cells (HDF), KD values and docking modes at Hsp90 as well as clogP parameters, reveals that the rigid C(17)-arm (piperidyl, cyclohexyl) with a H-bond acceptor as carbonyl group together with a lipophilicity clogP∼3 favor high potency of analogs, even up to IC50 ∼0.08 µM, at improved selectivity (SIHDF > 30), when compared to GDM. The most active 25 show higher anticancer potency than 17-AAG (in SKOV-3 and A-549) as well as reblastatin (in SKBR-3 and SKOV-3). Opening of the ansa-bridge within GDM analogs, at the best case, decreases activity (IC50∼2 µM) and toxicity in HDF cells (SIHDF∼2-3), relative to GDM.


Subject(s)
Amines/pharmacology , Antineoplastic Agents/pharmacology , Benzoquinones/pharmacology , Lactams, Macrocyclic/pharmacology , Amines/chemical synthesis , Amines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzoquinones/chemical synthesis , Benzoquinones/chemistry , Cell Proliferation/drug effects , Cells, Cultured , Density Functional Theory , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Lactams, Macrocyclic/chemical synthesis , Lactams, Macrocyclic/chemistry , Molecular Structure , Structure-Activity Relationship
11.
J Renin Angiotensin Aldosterone Syst ; 20(3): 1470320319868890, 2019.
Article in English | MEDLINE | ID: mdl-31486700

ABSTRACT

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. Hypertensive patients received in random order 80 mg of fluvastatin daily or placebo for 6 weeks. The following parameters were assessed at baseline and after each treatment period: serum lipids, flow-mediated vasodilation, activity of von Willebrand factor, concentration of vascular endothelial growth factor, C-reactive protein and 24-hour blood pressure profile. RESULTS: Hypertensive patients did not differ from healthy subjects with respect to age, body mass and biochemical parameters, with the exception of C-reactive protein, which was higher in hypertensive patients (P=0.02). After statin therapy, low-density lipoprotein cholesterol (P<0.0001), C-reactive protein (P=0.03), von Willebrand factor (P=0.03) and vascular endothelial growth factor (P<0.01) decreased and flow-mediated vasodilation improved (P<0.001). Statins had no significant effect on blood pressure. CONCLUSIONS: Statins added to angiotensin-converting enzyme inhibitors may improve endothelial function and ameliorate inflammation independently of blood pressure.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Blood Pressure/drug effects , Endothelium, Vascular/physiopathology , Essential Hypertension/drug therapy , Essential Hypertension/physiopathology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Biomarkers/blood , Drug Therapy, Combination , Endothelium, Vascular/drug effects , Essential Hypertension/blood , Female , Fluvastatin/pharmacology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Male , Middle Aged , Placebos
12.
Nucleosides Nucleotides Nucleic Acids ; 38(12): 980-1005, 2019.
Article in English | MEDLINE | ID: mdl-31380708

ABSTRACT

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'-O- and 5'-O-propargyl-nucleosides as the alkyne components. Based on analysis of the 3 JHH, 3 JH1'C2 and 3 JH1'C6 we estimated conformational preferences of sugar part and orientation around glycosidic bond. All described nucleosides dimers analogs were characterized by spectroscopic methods and evaluated for their in vitro cytotoxicity in three human cancer cell lines: cervical (HeLa), oral (KB) and breast (MCF-7).


Subject(s)
Antineoplastic Agents/chemical synthesis , Floxuridine/chemistry , Nucleosides/chemical synthesis , Thymidine/chemistry , Triazoles/chemistry , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Click Chemistry/methods , Cycloaddition Reaction/methods , Dimerization , HeLa Cells , Humans , KB Cells , MCF-7 Cells , Neoplasms/drug therapy , Neoplasms/pathology , Nucleosides/pharmacology
13.
Bioorg Med Chem Lett ; 29(18): 2587-2594, 2019 09 15.
Article in English | MEDLINE | ID: mdl-31400940

ABSTRACT

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. Compound 29 comprising two gemcitabine (dFdC) units exhibited the highest activity among dimers 21-30. The activity of compound 29 was higher than that of dFdC in all the studied cancer cell lines. A similar order of activity was observed for compounds 25, 28, and 30. The best activity among all the dimers synthesized was displayed by compound 39, comprising two gemcitabine units with a cleavable linker. The activity of compound 39 was 5 to 9 times higher than that of dFdC, depending on the cell line. In addition, marked cytotoxic activity was shown by compounds 31, 36, 38, and 40.


Subject(s)
Antineoplastic Agents/pharmacology , Deoxycytidine/analogs & derivatives , Esters/pharmacology , Nucleosides/pharmacology , Triazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Click Chemistry , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Dimerization , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Esters/chemistry , Humans , Molecular Structure , Nucleosides/chemistry , Structure-Activity Relationship , Triazoles/chemistry , Gemcitabine
14.
Colloids Surf B Biointerfaces ; 182: 110379, 2019 Oct 01.
Article in English | MEDLINE | ID: mdl-31351269

ABSTRACT

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. The influence of initial concentration and contact time onto doxorubicin adsorption by obtained MIPs microparticles have been investigated. The microparticles obtained using ethylene glycol dimethacrylate as a cross-linker showed 3 times higher adsorption properties towards doxorubicin, than the ones obtained using trimethylolpropane trimethacrylate cross-linker. The release kinetics of doxorubicin from drug-loaded MIPs microparticles has been proven to be dependent upon cross-linker used and pH of the release medium. For drug-loaded MIPs microparticles obtained using both cross-linkers the IC50 values measured for cancer cell were comparable to the ones measured for pure doxorubicin, whereas the cytotoxicity towards normal HDF cell lines was lower.


Subject(s)
Cross-Linking Reagents/chemistry , Doxorubicin/administration & dosage , Drug Delivery Systems/methods , Molecular Imprinting , Polymers/chemistry , A549 Cells , Adsorption , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/chemistry , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Doxorubicin/chemistry , Doxorubicin/pharmacokinetics , HeLa Cells , Humans , MCF-7 Cells , Methacrylates/chemistry
15.
Article in English | MEDLINE | ID: mdl-31177919

ABSTRACT

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 3JHH, 3JH1'C2, and 3JH1'C6 we estimated conformational preferences of sugar part and orientation around glycosidic bond. These compounds show moderate anticancer activity, with cytostatic studies in three different cancer cell lines.


Subject(s)
Antineoplastic Agents/pharmacology , Nucleosides/pharmacology , Triazoles/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Click Chemistry , Cycloaddition Reaction , Dimerization , Floxuridine/analogs & derivatives , Floxuridine/pharmacology , Humans , Molecular Conformation , Nucleosides/chemistry , Thymidine/analogs & derivatives , Thymidine/pharmacology , Triazoles/chemistry
16.
Article in English | MEDLINE | ID: mdl-30968733

ABSTRACT

A series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3'-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidines (20-49) was synthesized by means of phosphorylation of 3'-[4-aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidines (7-11) with 4-chlorophenyl phosphoroditriazolide (14), followed by a reaction with the appropriate amine. The synthesized compounds 7-11 and 20-49 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 20, 24, 28, 32-36, 38, 40, 46) 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 (7-11) the highest activity in all the investigated cancer cells was displayed by 3'-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3'-deoxythymidine (9) (IC50 in the range of 2.58-3.61 µM) and its activity was higher than that of cytarabine. Among phosphoramidates 20-49 the highest activity was demonstrated by N-n-propyl phosphoramidate of 3'-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3'-deoxythymidine (35) in all the cancer cells (IC50 in the range of 0.97-1.94 µM). Also N-ethyl phosphoramidate of 3'-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3'-deoxythymidine (33) exhibited good activity in all the used cell lines (IC50 in the range of 4.79-4.96 µM).


Subject(s)
Amides/chemistry , Antineoplastic Agents/chemical synthesis , Phosphoric Acids/chemistry , Thymidine/analogs & derivatives , Thymidine/chemical synthesis , Triazoles/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Drug Design , Humans , Molecular Structure , Structure-Activity Relationship , Thymidine/pharmacology , Triazoles/pharmacology
17.
RSC Adv ; 9(36): 20892-20900, 2019 Jul 01.
Article in English | MEDLINE | ID: mdl-35515533

ABSTRACT

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-O-succinyl betulin), and was thoroughly characterized through 1H NMR and 13C 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. Polyanhydride of a disuccinate betulin was tested for cytostatic activity against a wide range of cancer cell lines (HeLa, MCF-7, A-549, U-87MG, KB and HepG2), proving its efficiency in inhibiting the growth of selected cancer cells. To realize the concept of an easily administrated drug release system, polyanhydride was fabricated in a form of micro- (1-30 µm) and nanospheres (∼400 nm) by using an emulsion solvent evaporation method. The micro- and nanospheres were characterized by SEM.

18.
Chem Biol Drug Des ; 92(4): 1778-1787, 2018 10.
Article in English | MEDLINE | ID: mdl-29877033

ABSTRACT

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 (GI50 ) values below 10 µM. Two (2e and 3d) of the four compounds also exhibited potent anti-trypanosomal activity with GI50 values of 0.3-0.4 µM. All four active compounds represented derivatives modified at their C-9 hydroxy group. With respect to anti-proliferative activity and selectivity, 2e (epi-N-quinidyl-N'-bis(3,5-trifluoromethyl)phenylthiourea) proved to be the most promising derivative for both cancer cells and bloodstream forms of T. b. brucei. The cytotoxic activity of compounds 1u, 1w, 2e and 3d was attributed to their ability to induce apoptosis in cancer cells. The results demonstrate the potential of cinchona alkaloid derivatives as novel anti-cancer and anti-trypanosome drug candidates.


Subject(s)
Cinchona Alkaloids/chemistry , Trypanocidal Agents/chemistry , Animals , Apoptosis/drug effects , CHO Cells , Cell Line, Tumor , Cinchona Alkaloids/pharmacology , Cricetinae , Cricetulus , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Phenylthiourea/chemistry , Phenylthiourea/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects
19.
Future Med Chem ; 10(5): 511-525, 2018 03 01.
Article in English | MEDLINE | ID: mdl-29424550

ABSTRACT

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. The cytotoxic activity against selected cancer cell lines was determined, showing a significant increase in cytotoxicity when the triterpene is equipped with a nitroaromatic moiety. CONCLUSION: We believe this approach to the functionalization is promising in terms of enhancing anticancer activity. We also indicate electrochemical techniques as advantageous preclinical screening methods for the identification of cytotoxic agents.


Subject(s)
Antineoplastic Agents/pharmacology , Oleanolic Acid/pharmacology , Triterpenes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , Oleanolic Acid/chemistry , Structure-Activity Relationship , Triterpenes/chemistry
20.
Nucleosides Nucleotides Nucleic Acids ; 37(1): 53-66, 2018 Jan 02.
Article in English | MEDLINE | ID: mdl-29336675

ABSTRACT

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. Adenosine and thymidine analogues containing alkyne moiety and adenosine analogue containing azido group were synthesized. The obtained units showed ability of forming triazole motif under the CuAAC reaction conditions.


Subject(s)
Adenosine/chemical synthesis , Antineoplastic Agents/chemical synthesis , Thymidine/chemical synthesis , Acids, Acyclic/chemistry , Adenosine/pharmacology , Alkynes/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival , Click Chemistry , Humans , Magnetic Resonance Spectroscopy/methods , Molecular Structure , Spectrometry, Mass, Electrospray Ionization/methods , Thymidine/pharmacology , Triazoles/chemistry
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