QUIMORG - Artículos
http://hdl.handle.net/10017/272
QUIMORG - Artículos2024-03-29T22:15:19ZMolecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamics
http://hdl.handle.net/10017/60671
Molecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamics
Gómez Rubio, Elena; García Marin, Javier
NUDT15, also known as MTH2, is a member of the NUDIX protein family that catalyzes the hydrolysis of nucleotides and deoxynucleotides, as well as thioguanine analogues. NUDT15 has been reported as a DNA sanitizer in humans, and more recent studies have shown that some genetic variants are related to a poor prognosis in neoplastic and immunologic diseases treated with thioguanine drugs. Despite this, the role of NUDT15 in physiology and molecular biology is quite unclear, as is the mechanism of action of this enzyme. The existence of clinically relevant variants has prompted the study of these enzymes, whose capacity to bind and hydrolyze thioguanine nucleotides is still poorly understood. By using a combination of biomolecular modeling techniques and molecular dynamics, we have studied the monomeric wild type NUDT15 as well as two important variants, R139C and R139H. Our findings reveal not only how nucleotide binding stabilizes the enzyme but also how two loops are responsible for keeping the enzyme in a packed, close conformation. Mutations in ?2 helix affect a network of hydrophobic and ?-interactions that enclose the active site. This knowledge contributes to the understanding of NUDT15 structural dynamics and will be valuable for the design of new chemical probes and drugs targeting this protein.
2023-03-12T00:00:00ZDNA Interactions and Biological Activity of 2,9-Disubstituted 1,10-Phenanthroline Thiosemicarbazone-Based Ligands and a 4-Phenylthiazole Derivative
http://hdl.handle.net/10017/59880
DNA Interactions and Biological Activity of 2,9-Disubstituted 1,10-Phenanthroline Thiosemicarbazone-Based Ligands and a 4-Phenylthiazole Derivative
Nicolás Prieto, Álvaro; González Quero, Julia; Barroso, Marta; Gándara Barreiro, Zoila; Gude Rodríguez, Lourdes
Four 1,10-phenanthroline derivatives (1–4) were synthesized as potential telomeric DNA
binders, three substituted in their chains with thiosemicarbazones (TSCs) and one 4-phenylthiazole
derivative. The compounds were characterized using NMR, HRMS, FTIR-spectroscopy and combustion elemental analysis. Quadruplex and dsDNA interactions were preliminarily studied, especially
for neutral derivative 1, using FRET-based DNA melting assays, equilibrium dialysis (both competitive and non-competitive), circular dichroism and viscosity titrations. The TSC derivatives bind and
stabilize the telomeric Tel22 quadruplex more efficiently than dsDNA, with an estimated 24-fold
selectivity determined through equilibrium dialysis for compound 1. In addition, cytotoxic activity
against various tumor cells (PC-3, DU145, HeLa, MCF-7 and HT29) and two normal cell lines (HFF-1
and RWPE-1) was evaluated. Except for the 4-phenylthiazole derivative, which was inactive, the
compounds showed moderate cytotoxic properties, with the salts displaying lower IC50 values
(30–80 µM), compared to the neutral TSC, except in PC-3 cells (IC50 (1) = 18 µM). However, the
neutral derivative was the only compound that exhibited a modest selectivity in the case of prostate
cells (tumor PC-3 versus healthy RWPE-1). Cell cycle analysis and Annexin V/PI assays revealed that
the compounds can produce cell death by apoptosis, an effect that has proven to be similar to that
demonstrated by other known 1,10-phenanthroline G4 ligands endowed with antitumor properties,
such as PhenDC3 and PhenQE8.
2024-01-20T00:00:00ZSynthesis, structural study and antitumor activity of novel alditol-based imidazophenanthrolines (aldo-IPs)
http://hdl.handle.net/10017/59407
Synthesis, structural study and antitumor activity of novel alditol-based imidazophenanthrolines (aldo-IPs)
Gómez Bra, Ana; Gude Rodríguez, Lourdes; Arias Pérez, María Selma
A series of 1H-imidazo [4,5-f][1,10] phenanthroline derivatives functionalized at 2-position with chiral, and conformationally flexible polyhydroxy alkyl chains derived from carbohydrates (alditol-based imidazophenanthrolines, aldo-IPs) is presented herein. These novel glycomimetics showed relevant and differential cytotoxic activity against several cultured tumor cell lines (PC3, HeLa and HT-29), dependent on the nature and stereochemistry of the polyhydroxy alkyl chain. The mannose-based aldo-IP demonstrated the higher cytotoxicity in the series, substantially better than cisplatin metallo-drug in all cell lines tested, and better than G-quadruplex ligand 360A in HeLa and HT29 cells. Cell cycle experiments and Annexin V-PI assays revealed that aldo-IPs induce apoptosis in HeLa cells. Initial study of DNA interactions by DNA FRET melting assays proved that the aldo-IPs produce only a slight thermal stabilization of DNA secondary structures, more pronounced in the case of quadruplex DNA. Viscosity titrations with CT dsDNA suggest that the compounds behave as DNA groove binders, whereas equilibrium dialysis assays showed that the compounds bind CT with Ka values in the range 104–105 M−1. The aldo-IP derivatives were obtained with synthetically useful yields through a feasible one-pot multistep process, by aerobic oxidative cyclization of 1,10‐phenanthroline‐5,6‐diamine with a selection of unprotected aldoses using (NH4)2SO4 as promoter.
2024-02-01T00:00:00ZGold-catalyzed endo-selective cyclization of alkynylcyclobutanecarboxamides: synthesis of cyclobutane-fused dihydropyridones
http://hdl.handle.net/10017/59222
Gold-catalyzed endo-selective cyclization of alkynylcyclobutanecarboxamides: synthesis of cyclobutane-fused dihydropyridones
Garre, M. Soledad; Otárola, Guillermo G.; Merino Marcos, Estíbaliz; Sucunza Sáenz, David; Aguilar, Enrique; Quirós López, María Teresa; Vaquero López, Juan José; García García, Patricia
Cyclobutane-fused dihydropyridones can be efficiently synthesized by a completely endo-selective gold-catalyzed cyclization of alkynylcyclobutanes bearing an appended amide, which proceeds under mild conditions. The observed selectivity, which is reversed from that previously observed for the cyclization of related alcohols and acids, is supported by DFT calculations.
2023-03-01T00:00:00Z