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1.
Appl Radiat Isot ; 96: 91-101, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25479439

ABSTRACT

We evaluated and compared a new bombesin analog [Tyr-Gly5, Nle(14)]-BBN(6-14) conjugated to DOTA or DTPA and radiolabeled with In-111 in low and high GRPR expressing tumor models. Both peptides were radiolabeled with high radiochemical purity and specific activity. In vitro assays on T-47D, LNCaP and PC-3 cells showed that the affinity of peptides is similar and a higher binding and internalization of DOTA-peptide to PC-3 cells was observed. Both peptides could target PC-3 and LNCaP tumors in vivo and both tumor types could be visualized by microSPECT/CT.


Subject(s)
Bombesin/analogs & derivatives , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/metabolism , Heterocyclic Compounds, 1-Ring , Pentetic Acid/analogs & derivatives , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/metabolism , Radiopharmaceuticals , Receptors, Bombesin/metabolism , Animals , Bombesin/chemistry , Cell Line, Tumor , Drug Stability , Female , Heterografts , Humans , In Vitro Techniques , Indium Radioisotopes , Male , Mice, SCID , Neoplasm Transplantation , Radionuclide Imaging , Radiopharmaceuticals/chemistry , Tissue Distribution
2.
Peptides ; 68: 113-9, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25305549

ABSTRACT

Mastoparan is an α-helical and amphipathic tetradecapeptide obtained from the venom of the wasp Vespula lewisii. This peptide exhibits a wide variety of biological effects, including antimicrobial activity, increased histamine release from mast cells, induction of a potent mitochondrial permeability transition and tumor cell cytotoxicity. Here, the effects of mastoparan in malignant melanoma were studied using the murine model of B16F10-Nex2 cells. In vitro, mastoparan caused melanoma cell death by the mitochondrial apoptosis pathway, as evidenced by the Annexin V-FITC/PI assay, loss of mitochondrial membrane potential (ΔΨm), generation of reactive oxygen species, DNA degradation and cell death signaling. Most importantly, mastoparan reduced the growth of subcutaneous melanoma in syngeneic mice and increased their survival. The present results show that mastoparan induced caspase-dependent apoptosis in melanoma cells through the intrinsic mitochondrial pathway protecting the mice against tumor development.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Melanoma, Experimental/drug therapy , Peptides/pharmacology , Wasp Venoms/pharmacology , Animals , Cell Line, Tumor , Cell Shape/drug effects , Drug Screening Assays, Antitumor , Intercellular Signaling Peptides and Proteins , Male , Melanoma, Experimental/pathology , Membrane Potential, Mitochondrial/drug effects , Mice, Inbred C57BL , Mitochondria/drug effects , Neoplasm Transplantation , Oxidative Stress , Tumor Burden/drug effects
3.
Arch Pharm (Weinheim) ; 347(12): 885-95, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25283529

ABSTRACT

A novel class of benzo[d][1,3]dioxol-5-ylmethyl alkyl/aryl amide and ester analogues of capsaicin were designed, synthesized, and evaluated for their cytotoxic activity against human and murine cancer cell lines (B16F10, SK-MEL-28, NCI-H1299, NCI-H460, SK-BR-3, and MDA-MB-231) and human lung fibroblasts (MRC-5). Three compounds (5f, 6c, and 6e) selectively inhibited the growth of aggressive cancer cells in the micromolar (µM) range. Furthermore, an exploratory data analysis pointed at the topological and electronic molecular properties as responsible for the discrimination process regarding the set of investigated compounds. The findings suggest that the applied designing strategy, besides providing more potent analogues, indicates the aryl amides and esters as well as the alkyl esters as interesting scaffolds to design and develop novel anticancer agents.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Capsaicin/chemical synthesis , Capsaicin/pharmacology , Computer-Aided Design , Drug Design , Molecular Dynamics Simulation , Animals , Capsaicin/analogs & derivatives , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cluster Analysis , Humans , Inhibitory Concentration 50 , Mice , Molecular Structure , Principal Component Analysis , Structure-Activity Relationship
4.
J Mol Model ; 18(5): 2257-69, 2012 May.
Article in English | MEDLINE | ID: mdl-21965079

ABSTRACT

A molecular modeling study was carried out to investigate the most likely enzymatic disassembly mechanism of dendrimers that were designed as potential antichagasic and antileishmanial prodrugs. The models contained myo-inositol (core), L-malic acid (spacer), and active agents such as 3-hydroxyflavone, quercetin, and hydroxymethylnitrofurazone (NFOH). A theoretical approach that considered one, two, or three branches has already been performed and reported by our research group; the work described herein focused on four (models A and B), five, or six branches, and considered their physicochemical properties, such as spatial hindrance, electrostatic potential mapping, and the lowest unoccupied molecular orbital energy (E(LUMO)). The findings suggest that the carbonyl group next to the myo-inositol is the most promising ester breaking point.


Subject(s)
Dendrimers/chemistry , Molecular Dynamics Simulation , Prodrugs/chemistry , Trypanocidal Agents/chemistry , Flavonoids/chemistry , Inositol/chemistry , Malates/chemistry , Nitrofurazone/analogs & derivatives , Nitrofurazone/chemistry , Quercetin/chemistry , Static Electricity , Thermodynamics
5.
Rev. bras. farmacogn ; 21(1): 170-180, jan.-fev. 2011. ilus, graf, tab
Article in English | LILACS | ID: lil-580355

ABSTRACT

Aldose Reductase (AR) is the polyol pathway key enzyme which converts glucose to sorbitol. High glucose availability in insulin resistant tissues in diabetes leads into an accumulation of sorbitol, which has been associated with typical chronic complications of this disease, such as neuropathy, nephropathy and retinopathy. In this study, 71 flavonoids AR inhibitors were subjected to two methods of SAR to verify crucial substituents. The first method used the PCA (Principal Component Analysis) to elucidate physical and chemical characteristics in the molecules that would be essential for the activity, employing VolSurf descriptors. The rate obtained explained 53 percent of the system total variance and revealed that a hydrophobic-hydrophilic balance in the molecules is required, since very polar or nonpolar substituents decrease the activity. Artificial Neural Networks (ANNs) was also employed to determine key substituents by evaluating substitution patterns, using NMR data. This study had a high success rate (85 percent accuracy in the training set and 88 percent accuracy in the test set) and showed polihydroxilations are essential for high activity and methoxylations and glicosilations primarily at positions C7, C3' and C4' decrease the activity.

6.
Molecules ; 15(5): 3281-94, 2010 May 04.
Article in English | MEDLINE | ID: mdl-20657478

ABSTRACT

Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. The quantitative structure-activity relationship (QSAR) formalisms are among the most important strategies that can be applied for the successful design new molecules. This review provides a comprehensive review on the evolution and current status of 4D-QSAR, highlighting present challenges and new opportunities in drug design.


Subject(s)
Drug Design , Quantitative Structure-Activity Relationship
7.
J Comput Aided Mol Des ; 24(2): 157-72, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20217185

ABSTRACT

Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis monophosphate kinase (TMPKmt) is essential to DNA replication. Thus, this enzyme represents a promising target for developing new drugs against TB. In the present study, the receptor-independent, RI, 4D-QSAR method has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 81 thymidine analogues, and two corresponding subsets, reported as inhibitors of TMPKmt. The resulting optimized models are not only statistically significant with r(2) ranging from 0.83 to 0.92 and q(2) from 0.78 to 0.88, but also are robustly predictive based on test set predictions. The most and the least potent inhibitors in their respective postulated active conformations, derived from each of the models, were docked in the active site of the TMPKmt crystal structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. Moreover, the QSAR models provide insights regarding a probable mechanism of action of the analogues.


Subject(s)
Antitubercular Agents/chemistry , Enzyme Inhibitors/chemistry , Mycobacterium tuberculosis/enzymology , Nucleoside-Phosphate Kinase/antagonists & inhibitors , Thymidine/analogs & derivatives , Algorithms , Binding Sites/drug effects , Computer Simulation , Molecular Conformation , Mycobacterium tuberculosis/drug effects , Protein Conformation , Quantitative Structure-Activity Relationship , Tuberculosis/drug therapy
8.
Arch Pharm (Weinheim) ; 343(2): 91-7, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20099263

ABSTRACT

Tuberculosis is an infection caused mainly by Mycobacterium tuberculosis. A first-line antimycobacterial drug is pyrazinamide (PZA), which acts partially as a prodrug activated by a pyrazinamidase releasing the active agent, pyrazinoic acid (POA). As pyrazinoic acid presents some difficulty to cross the mycobacterial cell wall, and also the pyrazinamide-resistant strains do not express the pyrazinamidase, a set of pyrazinoic acid esters have been evaluated as antimycobacterial agents. In this work, a QSAR approach was applied to a set of forty-three pyrazinoates against M. tuberculosis ATCC 27294, using genetic algorithm function and partial least squares regression (WOLF 5.5 program). The independent variables selected were the Balaban index (J), calculated n-octanol/water partition coefficient (ClogP), van-der-Waals surface area, dipole moment, and stretching-energy contribution. The final QSAR model (N = 32, r(2) = 0.68, q(2) = 0.59, LOF = 0.25, and LSE = 0.19) was fully validated employing leave-N-out cross-validation and y-scrambling techniques. The test set (N = 11) presented an external prediction power of 73%. In conclusion, the QSAR model generated can be used as a valuable tool to optimize the activity of future pyrazinoic acid esters in the designing of new antituberculosis agents.


Subject(s)
Antitubercular Agents/pharmacology , Models, Molecular , Mycobacterium tuberculosis/drug effects , Pyrazinamide/analogs & derivatives , Algorithms , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Drug Design , Esters , Least-Squares Analysis , Microbial Sensitivity Tests , Prodrugs , Pyrazinamide/chemical synthesis , Pyrazinamide/chemistry , Pyrazinamide/pharmacology , Quantitative Structure-Activity Relationship
9.
Arch. pharm ; 343(2): 91-97, Jan 22, 2010.
Article in English | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP, SESSP-IBACERVO | ID: biblio-1059804

ABSTRACT

Tuberculosis is an infection caused mainly by Mycobacterium tuberculosis. A first-line antimycobacterial drug is pyrazinamide (PZA), which acts partially as a prodrug activated by a pyrazinamidase releasing the active agent, pyrazinoic acid (POA). As pyrazinoic acid presents some difficulty to cross the mycobacterial cell wall, and also the pyrazinamide-resistant strains do not express the pyrazinamidase, a set of pyrazinoic acid esters have been evaluated as antimycobacterial agents. In this work, a QSAR approach was applied to a set of forty-three pyrazinoates against M. tuberculosis ATCC 27294, using genetic algorithm function and partial least squares regression (WOLF 5.5 program). The independent variables selected were the Balaban index (J), calculated n-octanol/water partition coefficient (ClogP), van-der-Waals surface area, dipole moment, and stretching-energy contribution. The final QSAR model (N = 32, r2 = 0.68, q2 = 0.59, LOF = 0.25, and LSE = 0.19) was fully validated employing leave-N-out cross-validation and y-scrambling techniques. The test set (N = 11) presented an external prediction power of 73%. In conclusion, the QSAR model generated can be used as a valuable tool to optimize the activity of future pyrazinoic acid esters in the designing of new antituberculosis agents.


Subject(s)
Antitubercular Agents/pharmacokinetics , Antitubercular Agents/chemical synthesis , Models, Molecular , Mycobacterium tuberculosis , Pyrazinamide/analogs & derivatives , Algorithms , Antitubercular Agents/chemistry
10.
J Chem Inf Model ; 49(6): 1428-36, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19422246

ABSTRACT

A novel 4D-QSAR approach which makes use of the molecular dynamics (MD) trajectories and topology information retrieved from the GROMACS package is presented in this study. This new methodology, named LQTA-QSAR (LQTA, Laboratório de Quimiometria Teórica e Aplicada), has a module (LQTAgrid) that calculates intermolecular interaction energies at each grid point considering probes and all aligned conformations resulting from MD simulations. These interaction energies are the independent variables or descriptors employed in a QSAR analysis. The comparison of the proposed methodology to other 4D-QSAR and CoMFA formalisms was performed using a set of forty-seven glycogen phosphorylase b inhibitors (data set 1) and a set of forty-four MAP p38 kinase inhibitors (data set 2). The QSAR models for both data sets were built using the ordered predictor selection (OPS) algorithm for variable selection. Model validation was carried out applying y-randomization and leave-N-out cross-validation in addition to the external validation. PLS models for data set 1 and 2 provided the following statistics: q(2) = 0.72, r(2) = 0.81 for 12 variables selected and 2 latent variables and q(2) = 0.82, r(2) = 0.90 for 10 variables selected and 5 latent variables, respectively. Visualization of the descriptors in 3D space was successfully interpreted from the chemical point of view, supporting the applicability of this new approach in rational drug design.


Subject(s)
Quantitative Structure-Activity Relationship , Algorithms , Internet , Models, Molecular , Molecular Conformation , Solvents/chemistry
11.
J Chem Inf Model ; 49(4): 1070-8, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19296716

ABSTRACT

Thymidine monophosphate kinase (TMPK) has emerged as an attractive target for developing inhibitors of Mycobacterium tuberculosis growth. In this study the receptor-independent (RI) 4D-QSAR formalism has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 5'-thiourea-substituted alpha-thymidine inhibitors. Models were developed for the entire training set and for a subset of the training set consisting of the most potent inhibitors. The optimized (RI) 4D-QSAR models are statistically significant (r(2) = 0.90, q(2) = 0.83 entire set, r(2) = 0.86, q(2) = 0.80 high potency subset) and also possess good predictivity based on test set predictions. The most and least potent inhibitors, in their respective postulated active conformations derived from the models, were docked in the active site of the TMPK crystallographic structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. This model identifies new regions of the inhibitors that contain pharmacophore sites, such as the sugar-pyrimidine ring structure and the region of the 5'-arylthiourea moiety. These new regions of the ligands can be further explored and possibly exploited to identify new, novel, and, perhaps, better antituberculosis inhibitors of TMPKmt. Furthermore, the 3D-pharmacophores defined by these models can be used as a starting point for future receptor-dependent antituberculosis drug design as well as to elucidate candidate sites for substituent addition to optimize ADMET properties of analog inhibitors.


Subject(s)
Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Nucleoside-Phosphate Kinase/antagonists & inhibitors , Thiourea/chemistry , Thymidine/analogs & derivatives , Thymidine/chemical synthesis , Algorithms , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Ligands , Models, Molecular , Molecular Conformation , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/enzymology , Quantitative Structure-Activity Relationship , Reproducibility of Results , Thymidine/pharmacology
12.
Mol Divers ; 12(1): 47-59, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18373208

ABSTRACT

Worldwide, tuberculosis (TB) is the leading cause of death among curable infectious diseases. Multidrug-resistant Mycobacterium tuberculosis is an emerging problem of great importance to public health, and there is an urgent need for new anti-TB drugs. In the present work, classical 2D quantitative structure-activity relationships (QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 91 isoniazid derivatives. Significant statistical models (classical QSAR, q (2) = 0.68 and r (2) = 0.72; HQSAR, q (2) = 0.63 and r (2) = 0.86) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 24 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, r(2)(pred) = 0.87; classical QSAR, r(2)(pred) = 0.75).


Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Isoniazid/chemistry , Isoniazid/pharmacology , Quantitative Structure-Activity Relationship , Isoniazid/analogs & derivatives
13.
Anal Chim Acta ; 595(1-2): 216-20, 2007 Jul 09.
Article in English | MEDLINE | ID: mdl-17606003

ABSTRACT

The variables that influence the tablets obtained by direct compression method deserve to be studied to minimize formulations costs and to improve the physicochemical and biopharmaceutical properties of the compacts. Here, we explore the adjuvants effects on amoxicillin tablet formulations considering multiple responses, and indicate the most suitable formulation composition. A 2(3) full factorial design was built to different amoxicillin formulations, each one containing three replicate batches, and eight responses (physicochemical and biopharmaceutical parameters) were obtained. The microcrystalline cellulose (MCC) type Avicel PH-102 (low) or PH-200 (high), the absence (low) or presence (high) of spray-dried lactose (LAC), and the absence (low) or presence (high) of disintegrant (DIS) were the levels investigated. The more relevant responses to the distinct formulations from the experimental design were hardness, friability, and the amount of amoxicillin dissolved during the first hour. PCA biplot indicated high values of amount of drug dissolved in 60 min as advantageous responses for the investigated amoxicillin tablet formulations and high values of friability as not desirable. Considering the individual response evaluation, the most suitable amoxicillin tablet formulation should present in its composition the MCC type Avicel PH-102 (low level) and the superdisintegrant agent (DIS high level), croscarmellose sodium, but no LAC (low level).


Subject(s)
Amoxicillin/analysis , Amoxicillin/chemistry , Chemistry, Pharmaceutical/methods , Amoxicillin/standards , Biopharmaceutics/standards , Carboxymethylcellulose Sodium/standards , Chemistry, Pharmaceutical/standards , Chemistry, Physical/standards , Compressive Strength , Solubility , Tablets
14.
J Med Chem ; 47(15): 3755-64, 2004 Jul 15.
Article in English | MEDLINE | ID: mdl-15239654

ABSTRACT

A 4D-QSAR analysis was carried out for a set of 37 hydrazides whose minimum inhibitory concentrations against M. tuberculosis var. bovis were evaluated. These ligands are thought to act like isoniazid in mycolic acid biosynthesis. Results indicate that nonpolar groups in the acyl moiety of ligands markedly decrease biological activity. Molecular modifications of the ligand NAD moiety, including nonpolar groups and hydrogen bond donor and acceptor groups, seemingly improve ligand interactions with amino acid residues of the InhA active site.


Subject(s)
Antitubercular Agents/chemistry , Isoniazid/analogs & derivatives , Isoniazid/chemistry , Quantitative Structure-Activity Relationship , Antitubercular Agents/pharmacology , Binding Sites , Isoniazid/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Mycobacterium tuberculosis/drug effects
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