12 results on '"Adrián Puerta"'
Search Results
2. One-pot multicomponent green Hantzsch synthesis of 1,2-dihydropyridine derivatives with antiproliferative activity
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Giovanna Bosica, Adrián Puerta, Kaylie Demanuele, and José M. Padrón
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antiproliferative activity ,Organic chemistry ,Heterogeneous catalysis ,Biochemistry ,Full Research Paper ,Catalysis ,lcsh:QD241-441 ,chemistry.chemical_compound ,Chemical engineering ,lcsh:Organic chemistry ,Structural isomer ,Phosphotungstic acid ,lcsh:Science ,Solid tumor ,Reaction conditions ,green hantzsch synthesis ,Organic Chemistry ,Combinatorial chemistry ,Chemistry ,heterogeneous catalysis ,chemistry ,1,2-dihydropyridines ,lcsh:Q ,Dihydropyridine derivatives ,Peptides ,one-pot multicomponent reaction - Abstract
A rapid route for obtaining unsymmetrical 1,2-dihydropyridines (1,2-DHPs) as opposed to 1,4-dihydropyridines (1,4-DHPs) has been achieved via a one-pot multicomponent Hantzsch reaction. A benign protocol has been developed for the preparation of various 1,2-dihydropyridine derivatives using heterogenized phosphotungstic acid on alumina support (40 wt %). High yields of over 75% have been accomplished in just 2–3.5 h after screening several heterogeneous catalysts and investigating the optimal reaction conditions. The catalyst chosen has passed the heterogeneity test and was shown to have the potential of being reused for up to 8 consecutive cycles before having a significant loss in activity. In addition, aromatic aldehydes gave the aforementioned regioisomer while the classical 1,4-DHPs were obtained when carrying out the reaction using aliphatic aldehydes. The preliminary study of the antiproliferative activity against human solid tumor cells demonstrated that 1,2-DHPs could inhibit cancer cell growth in the low micromolar range., peer-reviewed
- Published
- 2020
3. Synthesis of Novel 1,2,3-Triazole-Dihydropyrimidinone Hybrids Using Multicomponent 1,3-Dipolar Cycloaddition (Click)–Biginelli Reactions: Anticancer Activity
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Adrián Puerta, Elisabete P. Carreiro, Ana M. Sena, Anthony J. Burke, and José M. Padrón
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chemistry.chemical_classification ,1,2,3-Triazole ,biology ,010405 organic chemistry ,Organic Chemistry ,Biginelli reaction ,Alkyne ,010402 general chemistry ,biology.organism_classification ,01 natural sciences ,Combinatorial chemistry ,Cycloaddition ,0104 chemical sciences ,HeLa ,chemistry.chemical_compound ,chemistry ,1,3-Dipolar cycloaddition ,Click chemistry ,Azide - Abstract
In this work, 21 novel (1,4-disubstituted 1,2,3-triazole)-dihydropyrimidinone (1,2,3-trzl-DHPM) type hybrids were synthesized and characterized. These were divided into two types: hybrids A (5 in total) containing the dihydropyrimidinone heterocyclic ring decorated with a 1,4-disubstituted 1,2,3-triazole in the C-5 position [these compounds were accessed by a multicomponent copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) (or click)–Biginelli reactions with satisfactory yields (39–57%)] and hybrids B (16 in total) containing two 1,2,3-triazole units in the C-5 and C-6 methyl position of the DHPM. Hybrids B were synthesized via functionalization of the C-6 methyl group of hybrids A, a multistep sequence of reactions was used that included bromination, azidation, and a CuAAC. Hybrids B were obtained in very good to excellent yields (up to 99%). Some hybrids A and B were evaluated for their antiproliferative activity against different cancer cell lines that included A549 and SW1573 (non-small-cell lung), HBL-100 and T-47D (breast), HeLa (cervix) and WiDr (colon). Three of these hybrids were potent cell proliferation inhibitors of non-small-cell lung cancer, cervix cancer, breast cancer, and colon cancer.
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- 2020
4. Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents
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Jelena Dinić, José M. Padrón, José G. Fernández-Bolaños, Milica Pešić, Óscar López, Adrián Puerta, and Francisco J. Hicke
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Phosphonium salts ,Tariquidar ,Chemosensitizer ,Antineoplastic Agents ,Mitochondriotropics ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,Cell Line, Tumor ,Multidrug resistant cells ,Drug Discovery ,medicine ,Humans ,Cytotoxicity ,030304 developmental biology ,Cell Proliferation ,Pharmacology ,Membrane Potential, Mitochondrial ,0303 health sciences ,Cell Death ,Dose-Response Relationship, Drug ,Ethanol ,Molecular Structure ,Chemistry ,Organic Chemistry ,Antiproliferative agents ,General Medicine ,3. Good health ,Tyrosol ,Biochemistry ,Cell culture ,030220 oncology & carcinogenesis ,Mitocans ,Hydroxytyrosol ,Phenethyl alcohol ,Efflux ,Drug Screening Assays, Antitumor ,medicine.drug - Abstract
[EN] The necessity for developing novel cytostatic agents with improved activities and reduced side-effects to tackle cancer prompted us to investigate mitochondria-targeted compounds, an approach that is gaining attention for the selective transportation of cytotoxic agents. We envisioned the possibility of conjugating a phenethyl alcohol motif, decorated with a series of phenol-based substituents on the aryl moiety, with a triphenyl phosphonium scaffold (a mitochondriadirected vector), through a hydrocarbon chain of different lengths. Thus, such compounds that incorporate the phenethyl skeleton can be considered as masked phenolic compounds derived from relevant natural counterparts found in olive tree (e.g. tyrosol, hydroxytyrosol). Title compounds exhibited very strong in vitro antiproliferative activities against the panel of six human tumor cell lines tested, with GI50 values ranging from the nanomolar (0.026 ± 0.010 mM for 36) to the submicromolar range in most of the cases; this represents an improvement of up to 350-fold compared to classical chemotherapeutic agents, like 5-fluorouracil or cisplatin. Interestingly, decrease in the linker length led to an increase of GI50 values against non-tumor cells, thus allowing a remarkable improvement of selectivity (SI up to 269). The very promising antiproliferative activities prompted us to further investigate their behaviour against multidrug resistant cell lines (MDR). The results indicated a reduced sensitivity of the multidrug resistant cells to compounds, probably due to P-gp-mediated efflux of these antiproliferative agents. Interestingly, activities were completely restored to the same levels by co-administration of tariquidar, a well-known inhibitor of P-gp. Flow cytometry analysis on sensitive cell lines revealed a decrease in the percentage of cells in G1 phase accompanied by increase in S and G2/M phases. In addition, a significant increase in subG1 area, was observed. These results are compatible with the necrotic and apoptotic cell death detected in the Annexin V assay, and with the depolarization of the mitochondria membrane. Thus, the new mitochondriotropic agents reported herein can be considered as promising antiproliferative agents, endowed with remarkable potency and selectivity, including MDR cells, upon coadministration with a pump-efflux inhibitor., We thank Grant PID2020-116460RB-I00 funded by MCIN/AEI/10.13039/501100011033, and Junta de Andalucia (FQM134) for financial support. A.P. and J.M.P. thank the Spanish Government (PGC2018-094503-B-C22, MCIU/AEI/FEDER, UE) and the Canary Islands Government (ProID2020010101, ACIISI/FEDER, UE) for financial support. A.P. thanks the EU Social Fund (FSE) and the Canary Islands ACIISI for a predoctoral grant TESIS2020010055. J.D. and M.P thank the Ministry of Education, Science and Technological Development of the Republic of Serbia for financial support (451-03-9/2021e14/200007). This work was performed within the framework of COST Action CA17104 STRATAGEM -"New diagnostic and therapeutic tools against multidrug resistant tumors". We would also like to thank the Servicio de Resonancia Magn~etica Nuclear, CITIUS (University of Seville) for the performance of NMR experiments.
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- 2022
5. Synthesis and in vitro study of antiproliferative benzyloxy dihydropyrimidinones
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Venkatachalam Ramkumar, Hitendra M. Patel, José M. Padrón, Ruturajsinh M. Vala, Divyang M. Patel, Ramesh L. Gardas, Mayank Sharma, and Adrián Puerta
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Biginelli reaction ,Pharmaceutical Science ,Antineoplastic Agents ,Pyrimidinones ,01 natural sciences ,Benzaldehyde ,chemistry.chemical_compound ,Structure-Activity Relationship ,Lanthanum ,Cell Line, Tumor ,Drug Discovery ,Humans ,Urea ,Cell Proliferation ,Molecular Structure ,010405 organic chemistry ,Druglikeness ,Combinatorial chemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,Yield (chemistry) ,Lipinski's rule of five ,Drug Screening Assays, Antitumor ,Trifluoromethanesulfonate ,Derivative (chemistry) - Abstract
In this study, we report on antiproliferative benzyloxy dihydropyrimidinones (DHPMs) produced by the Biginelli reaction of benzyloxy benzaldehyde, urea, and diverse 1,3-diones. The reaction was catalyzed by lanthanum triflate and completed within 1-1.5 h, with 74-97% yield. The antiproliferative assay was carried out for all synthesized dihydropyrimidinones against six human solid tumor cell lines. Six compounds showed good antiproliferative activity with GI50 values below 5 μM. Among all the synthesized compounds, the most potent derivative showed good antiproliferative activity against all cell lines with GI50 values in the range of 1.1-3.1 μM. These DHPMs comply with druglikeness. Furthermore, ADMET prediction and the effect of P-glycoprotein on the antiproliferative activity were also studied. Overall, our method allows eco-friendly access to benzyloxy DHPMs as potential anticancer drugs.
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- 2021
6. Novel 1,2,3-triazole epicinchonas: Transitioning from organocatalysis to biological activities
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Elisabete P. Carreiro, Anthony J. Burke, Philip J. Rosenthal, Adrián Puerta, Óscar López, Ana C. Amorim, José G. Fernández-Bolaños, Giri Gut, José M. Padrón, Pedro Barrulas, and Luis F. Veiros
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chemistry.chemical_compound ,1,2,3-Triazole ,Chemistry ,Yield (chemistry) ,Organocatalysis ,Organic Chemistry ,Click chemistry ,Organic chemistry ,Cinchona Alkaloids ,Cinchonidine - Abstract
A small family of novel modular monofunctional epicinchonidine-1,2,3-triazole compounds was prepared in very good overall yield (3 steps from cinchonidine, 49���87% yield) using simple Cu(I) catalyzed click-chemistry. The objective of this study was to access their hitherto unknown catalytic role in some key organic reactions like: ketimine hydrosilylation, Michael-addition and the Biginelli reaction. This is the first report on the application of cinchonidine derived 1,2,3-triazoles in organocatalysis, and includes catalytic screening and preliminary Density Functional Theory (DFT) mechanistic studies. The new compounds were screened for antimalarial activity against Plasmodium falciparum (W2 strain), exhibiting IC50 values in the range 2.0���6.8 ��M; and cholinesterase inhibition, showing activity against eqBuChE, but their main potential is for tumor anti-proliferation (showing a lowest GI50 of 8.1 ��M). Gratifyingly, all our compounds were non-cytotoxic against the non-tumor healthy cell line, BJ-hTERT and they presented excellent simulated pharmacological properties.
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- 2021
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7. Masked Phenolic-Selenium Conjugates: Potent and Selective Antiproliferative Agents Overcoming P-gp Resistance
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José G. Fernández-Bolaños, Óscar López, Inés Maya, Samuel Bayort, Rebecca Puckett, Adrián Puerta, Paloma Begines, José M. Padrón, Lucía Sevilla-Horrillo, Irene Lagunes, and Universidad de Sevilla. Departamento de Química orgánica
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0301 basic medicine ,Antioxidant ,antioxidant ,medicine.medical_treatment ,phenolics ,Organoselenium ,Pharmaceutical Science ,lcsh:Medicine ,lcsh:RS1-441 ,01 natural sciences ,Article ,Diselenide ,lcsh:Pharmacy and materia medica ,03 medical and health sciences ,chemistry.chemical_compound ,antiproliferative ,Drug Discovery ,medicine ,Moiety ,organoselenium ,Cytotoxicity ,010405 organic chemistry ,lcsh:R ,0104 chemical sciences ,030104 developmental biology ,chemistry ,Biochemistry ,Cell culture ,Molecular Medicine ,P-gp ,Efflux ,Phenolics ,Antiproliferative ,Lead compound ,Conjugate - Abstract
Cancer accounts for one of the most complex diseases nowadays due to its multifactorial nature. Despite the vast number of cytotoxic agents developed so far, good therapeutic approaches are not always reached. In recent years, multitarget drugs are gaining great attention against multifactorial diseases in contraposition to polypharmacy. Herein we have accomplished the conjugation of phenolic derivatives with an ample number of organochalcogen motifs with the aim of developing novel antiproliferative agents. Their antioxidant, and antiproliferative properties (against six tumour and one non-tumour cell lines) were analysed. Moreover, in order to predict P-gp-mediated chemoresistance, the P-glycoprotein assay was also conducted in order to determine whether compounds prepared herein could behave as substrates of that glycoprotein. Selenium derivatives were found to be significantly stronger antiproliferative agents than their sulfur isosters. Moreover, the length and the nature of the tether, together with the nature of the organoselenium scaffold were also found to be crucial features in the observed bioactivities. The lead compound, bearing a methylenedioxyphenyl moiety, and a diselenide functionality, showed a good activity (GI50 = 0.88‒2.0 µ, M) and selectivity towards tumour cell lines (selectivity index: 14‒32), moreover, compounds considered herein were not substrates for the P-gp efflux pump, thus avoiding the development of chemoresistance coming from such mechanism, commonly found for widely-used chemotherapeutic agents.
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- 2020
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8. UHPLC-MS Chemical Fingerprinting and Antioxidant, Antiproliferative, and Enzyme Inhibition Potential of Gaultheria pumila Berries
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Javier Romero-Parra, Carlos Fernández-Galleguillos, Adrián Puerta, Luisa Quesada-Romero, Ernane Souza, Mario J. Simirgiotis, and José M. Padrón
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chemistry.chemical_classification ,gaultheria ,phenolics ,enzyme inhibition ,native berries ,antioxidant ,DPPH ,Endocrinology, Diabetes and Metabolism ,Flavonoid ,Berry ,Microbiology ,Biochemistry ,Article ,QR1-502 ,chemistry.chemical_compound ,chemistry ,Anthocyanin ,Gallic acid ,Food science ,Trolox ,Quercetin ,Molecular Biology ,Chemical fingerprinting - Abstract
Gaultheria pumila (Ericaceae) (known as Chaura or Mutilla) is a Chilean native small shrub that produces berry fruits consumed by local Mapuche people. In this study, the chemical fingerprinting and antioxidant, enzyme inhibition, and antiproliferative activities of the berries were investigated for the first time. Thirty-six metabolites were identified in the fruits by ultra-high performance liquid chromatography-photodiode array detection, hyphenated with Orbitrap mass spectrometry analysis (UHPLC-DAD-Orbitrap-MS). Metabolites, included anthocyanins, phenolic acids, flavonoids, iridoids, diterpenes, and fatty acids. Moderate inhibitory activities against acetylcholinesterase (7.7 ± 0.3 µg/mL), butyrylcholinesterase (34.5 ± 0.5 µg/mL), and tyrosinase (3.3 ± 0.2 µg/mL) enzymes were found. Moreover, selected major compounds were subjected to docking assays in light of their experimental inhibition. Results indicated that hydrogen bonding, π–π interaction, and a salt bridge interaction contributed significantly. Gaultheria pumila berries showed a total phenolic content of 189.2 ± 0.2 mg of gallic acid equivalents/g, total flavonoid content of 51.8 ± 0.1 mg quercetin equivalents/g, and total anthocyanin content of 47.3 ± 0.2 mg of cianydin-3-glucoside equivalents/g. Antioxidant activity was assessed using DPPH (92.8 ± 0.1 µg/mL), FRAP (134.1 ± 0.1 μmol Trolox equivalents/g), and ORAC (4251.6 ± 16.9 μmol Trolox equivalents/g) assays. Conversely, Gaultheria pumila showed a scarce antiproliferative potential against several solid human cancer cells. Our findings suggest that Gaultheria pumila berries have several bioactive metabolites with inhibitory effects against acetylcholinesterase, butyrylcholinesterase, and tyrosinase, and have the potential for use in food supplements.
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- 2021
9. Silver-based monomer and coordination polymer with organic thiocyanate ligand: Structural, computational and antiproliferative activity study
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Morgan Donnard, José M. Padrón, Goran V. Janjić, Nenad Filipovic, Mihaela Gulea, Olivera R. Klisurić, Adrián Puerta, Predrag Ristić, Tamara R. Todorović, University of Belgrade [Belgrade], Laboratoire d'innovation moléculaire et applications (LIMA), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Innovation Thérapeutique (LIT), and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)
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binding ,Silver ,Coordination polymer ,Intercalation (chemistry) ,Antiproliferative activity ,dna ,010402 general chemistry ,01 natural sciences ,Docking ,Inorganic Chemistry ,chemistry.chemical_compound ,Perchlorate ,Silver Organic thiocyanates ,Pyridine ,Materials Chemistry ,Molecule ,Physical and Theoretical Chemistry ,database ,ComputingMilieux_MISCELLANEOUS ,complexes ,Thiocyanate ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,010405 organic chemistry ,drug ,[CHIM.CATA]Chemical Sciences/Catalysis ,sequence ,0104 chemical sciences ,Coordination polymers ,Silver nitrate ,Crystallography ,Monomer ,chemistry ,Organic thiocyanates ,program ,recognition ,crystal-structures - Abstract
© 2019 Elsevier Ltd The first complexes of 2-pyridylthiocyanate (L) and silver nitrate (1) and perchlorate (2) were prepared and characterized by a single crystal X-ray analysis. The common structural motif of both 1 and 2 is coordination of two L molecules via pyridine nitrogen atom to Ag(I). In order to properly describe the nature of coordinative bonds in 1 and 2, as well as crystal packings in respective structures, a Quantum Theory of Atoms in Molecule topological analysis was performed. Coordinated nitrate ion provides more electron density to Ag(I) in comparison to perchlorate ion. Additional electron density in the case of 2 was provided by the coordination of third L molecule via thiocyanate nitrogen atom resulting in a 1D polymeric structure. Detailed computational analysis of intermolecular interactions, as well analysis of interactions between pyridine ring and –SCN group was performed. Antiproliferative activity of monomeric compound 1 was found to be better than of cisplatin on three out of four studied human cancer cell lines. Docking studies indicate intercalation as a major binding mode of 1 to DNA, while human serum albumin was revealed as possible carrier for distribution of 1 in the blood stream.
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- 2019
10. Selenocoumarins as new multitarget antiproliferative agents: Synthesis, biological evaluation and in silico calculations
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Adrián Puerta, Inés Maya, Miguel X. Fernandes, Alexis R. Galán, José M. Padrón, Irene Lagunes, Paloma Begines, Óscar López, Adrián Silva, and José G. Fernández-Bolaños
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Models, Molecular ,Selenourea ,In silico ,Antineoplastic Agents ,01 natural sciences ,Histone Deacetylases ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Cell Line, Tumor ,Organoselenium Compounds ,Drug Discovery ,Humans ,Mode of action ,030304 developmental biology ,Cell Proliferation ,Pharmacology ,0303 health sciences ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Active site ,HDAC8 ,General Medicine ,Fibroblasts ,Coumarin ,Combinatorial chemistry ,0104 chemical sciences ,Histone Deacetylase Inhibitors ,Repressor Proteins ,Cancer cell ,biology.protein ,Histone deacetylase ,Drug Screening Assays, Antitumor ,Reactive Oxygen Species - Abstract
Herein we report a straightforward preparation of new antiproliferative agents based on the hybridization of a coumarin skeleton and an organoselenium motif. Three families were obtained: isoselenocyanate, selenocarbamates and selenoureas. The main purpose of these hybrid structures is the development of new antiproliferative agents with a multitarget mode of action. A strong correlation between the nature of the organosenium scaffold and the antiproliferative activity was observed. Thus, whereas selenocarbamates proved to be inactive, or moderate antiproliferative agents, isoselenocyanate and most of the selenoureas behaved as strong antiproliferative agents, with GI50 values within the low micromolar range. Interestingly, a good selectivity toward tumor cell lines was found for some of the compounds. Moreover, an increase in the ROS level was observed for tumor cells, and accordingly, these pro-oxidant species might be involved in their mode of action. Overall, title compounds were found not to be substrates for P-glycoprotein, which is overexpressed in many cancer cells as a way of detoxification, and thus, to develop drug resistance. In silico calculations revealed that the selenoderivatives prepared herein might undergo a strong interaction with the active site of HDAC8, and therefore, be potential inhibitors of histone deacetylase 8. In vitro assessment against HDAC8 revealed a strong inhibition of such enzyme exerted by selenoureas, particularly by symmetrical coumarin-containing selenourea. Two compounds showed good antiproliferative data and appear as plausible leads for further testings. The symmetrical coumarin 6 displays the best in vitro inhibition of HDAC8, but is affected by P-gp. In contrast, the N-butyl selenourea coumarin derivative 5a escapes P-gp resistance but has lower HDAC8 inhibition activity.
- Published
- 2018
11. Hydroxyl alkyl ammonium ionic liquid assisted green and one-pot regioselective access to functionalized pyrazolodihydropyridine core and their pharmacological evaluation
- Author
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Mayank Sharma, Hitendra M. Patel, Irene Lagunes, Adrián Puerta, Dhanji P. Rajani, Ruturajsinh M. Vala, Divyang M. Patel, and José M. Padrón
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Dihydropyridines ,Staphylococcus aureus ,Antifungal Agents ,Ionic Liquids ,Antineoplastic Agents ,Microbial Sensitivity Tests ,Biochemistry ,Cell Line ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Ammonium Compounds ,Candida albicans ,Escherichia coli ,Potency ,Humans ,Ammonium ,Molecular Biology ,Alkyl ,Cell Proliferation ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,Hydroxyl Radical ,Organic Chemistry ,Regioselectivity ,Stereoisomerism ,Griseofulvin ,Combinatorial chemistry ,In vitro ,Anti-Bacterial Agents ,chemistry ,Ionic liquid ,Michael reaction ,Pyrazoles ,Drug Screening Assays, Antitumor - Abstract
Herein our team explored a promising synthetic trail to Functionalized pyrazolodihydropyridine core using hydroxyl alkyl ammonium ionic liquid via one-pot fusion of 3-methyl-1-phenyl-1H-pyrazole-5-amine, different heterocyclic aldehydes and 1, 3-Cyclic diones. The aimed compounds were obtained by Domino-Knoevenagel condensation and Michael addition followed by cyclization. The reaction transformation involves the formation of two CC and one CN bond formation. The perspective of the present work is selectively approached to Functionalized pyrazolodihydropyridine core excluding other potential parallel reactions under environmentally benign reaction condition. The present protocol show features such as the low E-factor, ambiphilic behavior of ionic liquid during reaction transformation, scale-up to a multigram scale, reusability of the ionic liquid, mild reaction condition, and produce water as a byproduct. All newly derived compounds were evaluated for their in vitro biological activities. In preliminary biological studies compound, 4c showed better potency than the standard drug ampicillin against Gram-negative bacteria (E. coli); the compound 4i exhibited outstanding activity against S. aeruginosa which is far better than ampicillin, chloramphenicol, and ciprofloxacin. The compound 4m was found more potent against C. albicans, than that of griseofulvin and show equipotency to nystatin whereas, in preliminary antitubercular screening, compound 4o was exhibited more potency than rifampicin. Noteworthy compounds 4f and 4i were found most active in antiproliferative screening.
- Published
- 2018
12. Synthesis and Evaluation of Pyrimidine Steroids as Antiproliferative Agents
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José M. Padrón, Adrián Puerta, Sara Montiel-Smith, Alejandra Cortés-Percino, José Luis Vega-Baez, Socorro Meza-Reyes, Anabel Romero-López, and Penélope Merino-Montiel
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antiproliferative activity ,pyrimidine ,Ketone ,Pyrimidine ,Nitrogen ,Pharmaceutical Science ,Acetates ,01 natural sciences ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,lcsh:Organic chemistry ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Humans ,Physical and Theoretical Chemistry ,Guanidine ,Cell Proliferation ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,010405 organic chemistry ,Organic Chemistry ,Diosgenin ,Combinatorial chemistry ,Cycloaddition ,0104 chemical sciences ,Pyrimidines ,Pregnenolone Acetate ,chemistry ,Thiourea ,Chemistry (miscellaneous) ,Pregnenolone ,cycloaddition reactions ,Urea ,Molecular Medicine ,Drug Screening Assays, Antitumor ,steroids ,heterocycle - Abstract
A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the cycloaddition reaction of nitrogen-containing 1,3-binucleophiles with the steroidal &alpha, &beta, unsaturated ketone. Urea, thiourea and guanidine reacted in a similar manner and afforded the steroidal pyrimidines in good yields. The antiproliferative tests against human tumor cell lines gave GI50 values in the micromolar range and had no effect on healthy fibroblasts. Additional experiments indicated that the compounds did not act as P-glycoprotein substrates, thus avoiding the rise of drug resistance. The fused steroidal pyrimidinethione was selected as drug lead for further testing due to its strong antiproliferative activities within the low micromolar range.
- Published
- 2019
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