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1.
Anticancer Agents Med Chem ; 20(3): 359-368, 2020.
Article in English | MEDLINE | ID: mdl-31823706

ABSTRACT

BACKGROUND: Hybrid molecules combining uracil skeleton with methylidene exo-cyclic group were designed in the search for novel anticancer drug candidates. OBJECTIVE: Two series of racemic 5-methylidenedihydrouracils, either 1,3-disubstituted or 1,3,6-trisubstituted were synthesized and tested for their possible cytotoxic activity against two cancer cell lines (HL-60 and MCF-7) and two healthy cell lines (HUVEC and MCF-10A). The most cytotoxic analogs were re-synthesized as pure enantiomers. The analog designated as U-332 [(R)-3-(4-bromophenyl)-1-ethyl-5-methylidene-6-phenyldihydrouracil], which had a very low IC50 value in HL-60 cell line (0.77µM) and was the most selective towards cancer cells was chosen for further experiments on HL-60 cell line, in order to determine the possible mechanism involved in its antineoplastic action. METHODS: Cytotoxic activities of compound was assessed by the MTT assay. In order to explore the mechanism of U-332 activity, we performed quantitative real-time PCR analysis of p53 and p21 genes. Apoptosis, cell proliferation and DNA damage in HL-60 cells were determined using the flow cytometry. The ability of U-332 to determine GADD45ɑ protein level in HL-60 cells incubated with U-332 was analyzed by ELISA test. RESULTS: U-332 was shown to generate excessive DNA damage (70% of the cell population), leading to p53 activation, resulting in p21 down-regulation and a significant increase of GADD45α protein, responsible for the cell cycle arrest in G2/M phase. CONCLUSION: U-332 can be used as a potential lead compound in the further development of novel uracil analogs as anticancer agents.


Subject(s)
Alkenes/chemistry , Antineoplastic Agents/chemical synthesis , Uracil/analogs & derivatives , Uracil/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , DNA Damage/drug effects , Drug Screening Assays, Antitumor , Gene Expression Regulation/drug effects , HL-60 Cells , Humans , MCF-7 Cells , Molecular Structure , Structure-Activity Relationship , Tumor Suppressor Protein p53/metabolism , Uracil/pharmacology
2.
Molecules ; 24(10)2019 May 15.
Article in English | MEDLINE | ID: mdl-31096601

ABSTRACT

In the search for new anticancer agents, a library of variously substituted 3-methylidenechroman-4-ones was synthesized using Horner-Wadsworth-Emmons methodology. Acylation of diethyl methylphosphonate with selected ethyl salicylates furnished 3-diethoxyphosphorylchromen-4-ones which were next used as Michael acceptors in the reaction with various Grignard reagents. The adducts were obtained as the mixtures of trans and cis diastereoisomers along with a small amount of enol forms. Their relative configuration and preferred conformation were established by NMR analysis. The adducts turned up to be effective Horner-Wadsworth-Emmons reagents giving 2-substituted 3-methylidenechroman-4-ones, which were then tested for their possible cytotoxic activity against two leukemia cell lines, HL-60 and NALM-6, and against MCF-7 breast cancer cell line. All new compounds (14a-o) were highly cytotoxic for the leukemic cells and showed a moderate or weak effect on MCF-7 cells. Analog 14d exhibited the highest growth inhibitory activity and was more potent than carboplatin against HL-60 (IC50 = 1.46 ± 0.16 µM) and NALM-6 (IC50 = 0.50 ± 0.05 µM) cells. Further tests showed that 14d induced apoptosis in NALM-6 cells, which was mediated mostly through the extrinsic pathway.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Models, Chemical , Molecular Structure , Structure-Activity Relationship
3.
Curr Drug Targets ; 20(4): 444-452, 2019.
Article in English | MEDLINE | ID: mdl-30317996

ABSTRACT

Sesquiterpene lactones, secondary metabolites of plants, present in a large number of species mostly from the Asteracea family, are used in the traditional medicine of many countries for the treatment of various pathological conditions. They exert a broad range of activities, including antiinflammatory, anti-bacterial and anti-cancer properties. The best-known sesquiterpene lactones which are already used as drugs or are used in clinical trials are artemisinin, thapsigargin and parthenolide. Yet another sesquiterpene lactone, helenalin, an active component of Arnica montana, known for its strong anti-inflammatory activity, has been used for centuries in folk medicine to treat minor injuries. Unfortunately, helenalin's ability to cause allergic reactions and its toxicity to healthy tissues prevented so far the development of this sesquiterpene lactone as an anticancer or anti-inflammatory drug. Recently, the new interest in the biological properties, as well as in the synthesis of helenalin analogs has been observed. This review describes helenalin's major biological activities, molecular mechanisms of action, its toxicity and potential for further research.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Plants/chemistry , Sesquiterpenes, Guaiane/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Humans , Medicine, Traditional , Molecular Structure , Plant Extracts/chemistry , Secondary Metabolism , Sesquiterpenes, Guaiane/adverse effects , Sesquiterpenes, Guaiane/chemistry
4.
Mol Biol Rep ; 45(5): 1187-1195, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30088201

ABSTRACT

Coumarin is a plant-derived compound but as such has no medical uses. Several synthetic coumarin analogs have been shown to possess anti-proliferative activity and to induce apoptosis in cancer cells. Here, we explored DNA damage responses in MCF-7 cells treated with our novel synthetic hybrid compound AD-013, which integrates a coumarin moiety and an α-methylene-δ-lactone motif. The mRNA expression of several genes engaged in DNA-damage-induced responses was assessed by quantitative real-time PCR. The protein levels of a few members of phosphoinositide-3-kinases family (ATM, ATR and DNA-PK) and BRCA1 were assessed by ELISA, while p53 was evaluated by western blot method. AD-013 down-regulated DNA-PK gene expression but increased the level of ATM/ATR and p53. The new analog completely inhibited BRCA1 and greatly decreased the activity of BRCA1 protein, engaged in DNA damage repair. Exposure of MCF-7 cells to a coumarin analog AD-013 led to DNA damage and decreased expression of several repair-associated genes.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/genetics , Coumarins/pharmacology , DNA Damage , Antineoplastic Agents/chemistry , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , BRCA1 Protein/genetics , BRCA1 Protein/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Coumarins/chemistry , DNA-Activated Protein Kinase/genetics , DNA-Activated Protein Kinase/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
5.
Chem Biodivers ; 15(9): e1800242, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29935105

ABSTRACT

An efficient synthetic strategy to 3-methylidene-2,3-dihydroquinolin-4(1H)-ones variously substituted in position 2 has been developed. The title compounds were synthesized in the reaction sequence involving reaction of diethyl methylphosphonate with methyl 2-(tosylamino)benzoate, condensation of thus formed diethyl 2-oxo-2-(2-N-tosylphenyl)ethylphosphonate with various aldehydes followed by successful application of the obtained 3-(diethoxyphosphoryl)-1,2-dihydroquinolin-4-ols as Horner-Wadsworth-Emmons reagents for the olefination of formaldehyde. Also, enantioselective approach to the target compounds has been evaluated using 3-dimenthoxyphosphoryl group as a chiral auxiliary. Single X-ray crystal analysis of (2S)-3-(dimenthoxyphosphoryl)-2-phenyl-1-tosyldihydroquinolin-4-ol revealed the presence of strong resonance-assisted hydrogen bond (RAHB). The obtained 3-methylidene-2,3-dihydroquinolin-4(1H)-ones were then tested for their cytotoxic activity against two leukemia cell lines NALM-6 and HL-60 and a breast cancer MCF-7 cell line. All compounds showed very high cytotoxic activity with the IC50 values mostly below 1 µm in all three cancer cell lines. The selected analogs were also tested on human umbilical vein endothelial cells (HUVEC) and on human mammary gland/breast cells (MCF-10A) to evaluate their influence on normal cells. Since one of the most serious problems in cancer chemotherapy is the development of drug resistance, the mRNA levels and activity of ABCB1 transporter considered to be the most important factor engaged in drug resistance, were evaluated in MCF-7 cells treated with two selected analogs. Both compounds were strong ABCB1 transporter inhibitors that could prevent efflux of anticancer drugs from cancer cells.


Subject(s)
Antineoplastic Agents/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Tosyl Compounds/chemical synthesis , Tosyl Compounds/pharmacology , ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Models, Molecular , Molecular Structure , Quinolines/chemistry , Structure-Activity Relationship , Tosyl Compounds/chemistry
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