Santos MA

References (26)

Title : New Multitarget Rivastigmine-Indole Hybrids as Potential Drug Candidates for Alzheimer's Disease - Bon_2024_Pharmaceutics_16_
Author(s) : Bon L , Banas A , Dias I , Melo-Marques I , Cardoso SM , Chaves S , Santos MA
Ref : Pharmaceutics , 16 : , 2024
Abstract : Alzheimer's disease (AD) is the most common form of dementia with no cure so far, probably due to the complexity of this multifactorial disease with diverse processes associated with its origin and progress. Several neuropathological hallmarks have been identified that encourage the search for new multitarget drugs. Therefore, following a multitarget approach, nine rivastigmine-indole (RIV-IND) hybrids (5a1-3, 5b1-3, 5c1-3) were designed, synthesized and evaluated for their multiple biological properties and free radical scavenging activity, as potential multitarget anti-AD drugs. The molecular docking studies of these hybrids on the active center of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) suggest their capacity to act as dual enzyme inhibitors with probable greater disease-modifying impact relative to AChE-selective FDA-approved drugs. Compounds 5a3 (IC(50) = 10.9 microM) and 5c3 (IC(50) = 26.8 microM) revealed higher AChE inhibition than the parent RIV drug. Radical scavenging assays demonstrated that all the hybrids containing a hydroxyl substituent in the IND moiety (5a2-3, 5b2-3, 5c2-3) have good antioxidant activity (EC(50) 7.8-20.7 microM). The most effective inhibitors of Abeta(42) self-aggregation are 5a3, 5b3 and 5c3 (47.8-55.5%), and compounds 5b2 and 5c2 can prevent the toxicity induced by Abeta(1-42) to cells. The in silico evaluation of the drug-likeness of the hybrids also showed that all the compounds seem to have potential oral availability. Overall, within this class of RIV-IND hybrids, 5a3 and 5c3 appear as lead compounds for anti-AD drug candidates, deserving further investigation.
ESTHER : Bon_2024_Pharmaceutics_16_
PubMedSearch : Bon_2024_Pharmaceutics_16_
PubMedID: 38399339

Title : Rivastigmine-Benzimidazole Hybrids as Promising Multitarget Metal-Modulating Compounds for Potential Treatment of Neurodegenerative Diseases - Vicente-Zurdo_2023_Int.J.Mol.Sci_24_
Author(s) : Vicente-Zurdo D , Brunetti L , Piemontese L , Guedes B , Cardoso SM , Chavarria D , Borges F , Madrid Y , Chaves S , Santos MA
Ref : Int J Mol Sci , 24 : , 2023
Abstract : With the goal of combating the multi-faceted Alzheimer's disease (AD), a series of Rivastigmine-Benzimidazole (RIV-BIM) hybrids was recently reported by us as multitarget-directed ligands, thanks to their capacity to tackle important hallmarks of AD. In particular, they exhibited antioxidant activity, acted as cholinesterase inhibitors, and inhibited amyloid-beta (Abeta) aggregation. Herein, we moved forward in this project, studying their ability to chelate redox-active biometal ions, Cu(II) and Fe(III), with widely recognized roles in the generation of oxidative reactive species and in protein misfolding and aggregation in both AD and Parkinson's disease (PD). Although Cu(II) chelation showed higher efficiency for the positional isomers of series 5 than those of series 4 of the hybrids, the Abeta-aggregation inhibition appears more dependent on their capacity for fibril intercalation than on copper chelation. Since monoamine oxidases (MAOs) are also important targets for the treatment of AD and PD, the capacity of these hybrids to inhibit MAO-A and MAO-B was evaluated, and they showed higher activity and selectivity for MAO-A. The rationalization of the experimental evaluations (metal chelation and MAO inhibition) was supported by computational molecular modeling studies. Finally, some compounds showed also neuroprotective effects in human neuroblastoma (SH-SY5Y cells) upon treatment with 1-methyl-4-phenylpyridinium (MPP(+)), a neurotoxic metabolite of a Parkinsonian-inducing agent.
ESTHER : Vicente-Zurdo_2023_Int.J.Mol.Sci_24_
PubMedSearch : Vicente-Zurdo_2023_Int.J.Mol.Sci_24_
PubMedID: 37176018

Title : Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease - Brunetti_2022_Eur.J.Med.Chem_237_114358
Author(s) : Brunetti L , Leuci R , Carrieri A , Catto M , Occhineri S , Vinci G , Gambacorta L , Baltrukevich H , Chaves S , Laghezza A , Altomare CD , Tortorella P , Santos MA , Loiodice F , Piemontese L
Ref : Eur Journal of Medicinal Chemistry , 237 :114358 , 2022
Abstract : Alzheimer's disease (AD) is a widespread multifactorial aging-related pathology, which includes cholinergic deficit among its main causes. Following a multi-target design strategy, the structure of the approved drug donepezil was taken as the starting point for generating some new potential multi-functional compounds. Therefore, a series of twenty molecular hybrids were synthesized and assayed against three different enzymes, namely the well-established targets acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the innovative one fatty acid amide hydrolase (FAAH). In silico studies confirmed the interaction of benzylpiperidine and the benzylpiperazine isostere with the catalytic anionic site (CAS) of AChE, while the aryloxycarbonyl portion appeared to be important for the interaction with the peripheral site (PAS). A QSAR study was carried out on AChE inhibition data, which revealed that the inhibition potency seems to depend upon the length of the spacer and the number of polar atoms. The docking poses of selected compounds within BChE and FAAH were also calculated. Furthermore, pharmacokinetics and drug-likeness properties were assessed by chemoinformatic tools. Several piperidine derivatives (in particular compound 10) showed interesting profiles as multi-target directed agents, while the lead piperazine derivative 12 (SON38) was found to be a more potent and selective AChE inhibitor (IC(50) = 0.8 nM) than donepezil, besides being able to bind bivalent copper cations (pCu = 7.9 at physiological pH). Finally, the selected lead compounds (10 and 12, SON38) did not show significant cytotoxicity on SH-SY5Y and HepG2 cells at the highest tested concentration (100 microM) in a MTT assay.
ESTHER : Brunetti_2022_Eur.J.Med.Chem_237_114358
PubMedSearch : Brunetti_2022_Eur.J.Med.Chem_237_114358
PubMedID: 35462163

Title : Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer's Disease - Vicente-Zurdo_2022_Biomedicines_10_1510
Author(s) : Vicente-Zurdo D , Rosales-Conrado N , Leon-Gonzalez ME , Brunetti L , Piemontese L , Pereira-Santos AR , Cardoso SM , Madrid Y , Chaves S , Santos MA
Ref : Biomedicines , 10 :1510 , 2022
Abstract : Alzheimer's disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV-BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid beta-peptide (Abeta) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Abeta(42) aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC(50) = 32.1 microM), but compounds of series 5 are better inhibitors of BChE (IC(50) = 0.9-1.7 microM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1-58.7%) and Cu(II)-induced (40.3-60.8%) Abeta aggregation and also to narrow (22.4-42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Abeta(42) and oxidative stress. Therefore, RIV-BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.
ESTHER : Vicente-Zurdo_2022_Biomedicines_10_1510
PubMedSearch : Vicente-Zurdo_2022_Biomedicines_10_1510
PubMedID: 35884815

Title : Novel Phenothiazine\/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer's Disease - Carocci_2022_Antioxidants.(Basel)_11_
Author(s) : Carocci A , Barbarossa A , Leuci R , Carrieri A , Brunetti L , Laghezza A , Catto M , Limongelli F , Chaves S , Tortorella P , Altomare CD , Santos MA , Loiodice F , Piemontese L
Ref : Antioxidants (Basel) , 11 : , 2022
Abstract : Alzheimer's disease (AD) is a complex multi-factorial neurodegenerative disorder for which only few drugs (including donepezil, DPZ) are available as symptomatic treatments; thus, researchers are focusing on the development of innovative multi-target directed ligands (MTDLs), which could also alter the course of the disease. Among other pathological factors, oxidative stress has emerged as an important factor in AD that could affect several pathways involved in the onset and progression of the pathology. Herein, we propose a new series of hybrid molecules obtained by linking a phenothiazine moiety, known for its antioxidant properties, with N-benzylpiperidine or N-benzylpiperazine fragments, mimicking the core substructure of DPZ. The investigation of the resulting hybrids showed, in addition to their antioxidant properties, their activity against some AD-related targets, such as the inhibition of cholinesterases (both AChE and BChE) and in vitro Abeta(1-40) aggregation, as well as the inhibition of the innovative target fatty acid amide hydrolase (FAAH). Furthermore, the drug-likeness properties of these compounds were assessed using cheminformatic tools. Compounds 11d and 12d showed the most interesting multi-target profiles, with all the assayed activities in the low micromolar range. In silico docking calculations supported the obtained results. Compound 13, on the other hand, while inactive in the DPPH assay, showed the best results in the in vitro antioxidant cell assays conducted on both HepG2 and SHSY-5Y cell lines. These results, paired with the low or absent cytotoxicity of these compounds at tested concentrations, allow us to aim our future research at the study of novel and effective drugs and pro-drugs with similar structural characteristics.
ESTHER : Carocci_2022_Antioxidants.(Basel)_11_
PubMedSearch : Carocci_2022_Antioxidants.(Basel)_11_
PubMedID: 36139705

Title : Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease - Queda_2021_Molecules_26_
Author(s) : Queda F , Cal S , Gwizdala K , Magalhaes JD , Cardoso SM , Chaves S , Piemontese L , Santos MA
Ref : Molecules , 26 : , 2021
Abstract : Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-beta (Abeta) aggregation. Some of these hybrids also prevented Abeta-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC(50) 1.6 microM); Abeta aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.
ESTHER : Queda_2021_Molecules_26_
PubMedSearch : Queda_2021_Molecules_26_
PubMedID: 33809771

Title : Derivatives of Tenuazonic Acid as Potential New Multi-Target Anti-Alzheimer's Disease Agents - Poliseno_2021_Biomolecules_11_
Author(s) : Poliseno V , Chaves S , Brunetti L , Loiodice F , Carrieri A , Laghezza A , Tortorella P , Magalhaes JD , Cardoso SM , Santos MA , Piemontese L
Ref : Biomolecules , 11 : , 2021
Abstract : Alzheimer's disease (AD) is generally recognized as a multifactorial neurodegenerative pathology with an increasing impact on society. Tenuazonic acid (TA) is a natural compound that was recently identified as a potential multitarget ligand with anti-cholinesterase, anti-amyloidogenic and antioxidant activities. Using its structure as a chemical scaffold, we synthesized and evaluated new derivatives (1-5), including tenuazonic-donepezil (TA-DNP) hybrids (4 and 5) due to the clinical importance of the anti-AD drug donepezil. These novel compounds all achieved activity in the micromolar range towards all selected targets and demonstrated to be potentially orally absorbed. Moreover, a selected compound (1) was further investigated as a chelating agent towards copper (II), zinc (II) and iron (III) and showed good chelating ability (pFe = 16.6, pCu = 11.6, pZn = 6.0 at pH 7.4). Therefore, the TA motif can be considered an interesting building block in the search for innovative multi-functional anti-neurodegenerative drugs, as exemplified by hybrid 5, a promising non-cytotoxic lead compound adequate for the early stages of AD, and capable of ameliorating the oxidative status of SH-SY5Y human neuroblastoma cells.
ESTHER : Poliseno_2021_Biomolecules_11_
PubMedSearch : Poliseno_2021_Biomolecules_11_
PubMedID: 33467709

Title : Recent Multi-Target Approaches on the Development of Anti-Alzheimer`s Agents Integrating Metal Chelation Activity - Chaves_2021_Curr.Med.Chem__
Author(s) : Chaves S , Varnagy K , Santos MA
Ref : Curr Med Chem , : , 2021
Abstract : Alzheimers disease (AD) is the most common and severe age-dependent neurodegenerative disorder, worldwide. Notwithstanding the large amount of research dedicated to both the elucidation of this pathology and the development of an effective drug, the multifaceted nature and complexity of the disease are certainly a rationale for the absence of cure so far. Current available drugs are used, mainly, to compensate the decline of the neurotransmitter acetylcholine by acetylcholinesterase (AChE) inhibition, though they only provide temporary symptomatic benefits and cannot stop AD progression. Although the multiple factors that contribute to trigger AD onset and progression are not yet fully understood, several pathological features and underneath pathways have been recognized to contribute to its pathology, such as metal dyshomeostasis, protein misfolding, oxidative stress and neurotransmitter deficiencies, some of them being interconnected. Thus, there is a widespread recent interest in the development of multitarget-directed ligands (MTDLs) for simultaneous interaction with several pathological targets of AD. In this review, a selection of the most recent reports (2016-up to present) on metal chelators of MTDLs with multifunctionalities is presented. These compounds enable the hitting of several AD targets or pathways, such as modulation of specific biometal ions (e.g. Cu, Fe, Zn) and of protein misfolding (beta-amyloid and tau protein), anti-oxidant activity and AChE inhibition. The properties found for these hybrids are discussed in comparison with the original reference compounds, some MTDLs being outlined as leading compounds for pursuing future studies in view of efficient potential applications in AD therapy.
ESTHER : Chaves_2021_Curr.Med.Chem__
PubMedSearch : Chaves_2021_Curr.Med.Chem__
PubMedID: 33602068

Title : Novel tacrine-benzofuran hybrids as potential multi-target drug candidates for the treatment of Alzheimer's Disease - Fancellu_2020_J.Enzyme.Inhib.Med.Chem_35_211
Author(s) : Fancellu G , Chand K , Tomas D , Orlandini E , Piemontese L , Silva DF , Cardoso SM , Chaves S , Santos MA
Ref : J Enzyme Inhib Med Chem , 35 :211 , 2020
Abstract : Pursuing the widespread interest on multi-target drugs to combat Alzheimer s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Abeta aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Abeta1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.
ESTHER : Fancellu_2020_J.Enzyme.Inhib.Med.Chem_35_211
PubMedSearch : Fancellu_2020_J.Enzyme.Inhib.Med.Chem_35_211
PubMedID: 31760822

Title : Donepezil-based hybrids as multifunctional anti-Alzheimer's disease chelating agents: Effect of positional isomerization - Costa_2020_J.Inorg.Biochem_206_111039
Author(s) : Costa M , Josselin R , Silva DF , Cardoso SM , May NV , Chaves S , Santos MA
Ref : J Inorg Biochem , 206 :111039 , 2020
Abstract : The intricate and multifactorial nature of Alzheimer's disease (AD) requires the development of compounds able to hit different pathophysiological targets, such as cholinergic dysfunction, deposits of amyloid beta (Abeta) peptide and metal dyshomeostasis. In order to continue the search for new anti-AD drugs, a design strategy was once more followed based on repositioning donepezil (DNP) drug, by ortho-attaching a benzylpiperidine mimetic of DNP moiety to a hydroxyphenyl-benzimidazole (BIM) chelating unit (compound 1). Herein, compound 1 and a positional isomer 2 are compared in terms of their potential multiple properties: both present good acetylcholinesterase (AChE) inhibition (low mumolar range) and are moderate/good inhibitors of Abeta self- and Cu-mediated aggregation, the inhibition process being mainly due to ligand intercalation between the beta-sheets of the fibrils; compound 1 has a higher chelating capacity towards Cu(2+) and Zn(2+) (pCu = 14.3, pZn = 6.4, pH 7.4, CL/CM = 10, CM = 10(-6) M) than 2 (pCu = 10.7, pZn = 6.3), attributed to its ability to establish a tridentate (N,O,O) coordination to the metal ion. Both compounds are eligible as drug candidates for oral administration but compound 1 shows improved neuroprotective role by completely preventing Abeta-induced cell toxicity.
ESTHER : Costa_2020_J.Inorg.Biochem_206_111039
PubMedSearch : Costa_2020_J.Inorg.Biochem_206_111039
PubMedID: 32171933

Title : Deep Eutectic Solvents as Effective Reaction Media for the Synthesis of 2-Hydroxyphenylbenzimidazole-based Scaffolds en Route to Donepezil-Like Compounds - Piemontese_2020_Molecules_25_
Author(s) : Piemontese L , Sergio R , Rinaldo F , Brunetti L , Perna FM , Santos MA , Capriati V
Ref : Molecules , 25 : , 2020
Abstract : An unsubstituted 2-hydroxyphenylbenzimidazole has recently been included as a scaffold in a series of hybrids (including the hit compound PZ1) based on the framework of the acetylcholinesterase (AChE) inhibitor Donepezil, which is a new promising multi-target ligand in Alzheimer's disease (AD) treatment. Building upon these findings, we have now designed and completed the whole synthesis of PZ1 in the so-called deep eutectic solvents (DESs), which have emerged as an unconventional class of bio-renewable reaction media in green synthesis. Under optimized reaction conditions, the preparation of a series of 2-hydroxyphenylbenzimidazole-based nuclei has also been perfected in DESs, and comparison with other routes which employ toxic and volatile organic solvents (VOCs) provided. The functionalization of the aromatic ring can have implications on some important biological properties of the described derivatives and will be the subject of future studies of structure-activity relationships (SARs).
ESTHER : Piemontese_2020_Molecules_25_
PubMedSearch : Piemontese_2020_Molecules_25_
PubMedID: 32013037

Title : Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease - Chaves_2020_Molecules_25_
Author(s) : Chaves S , Resta S , Rinaldo F , Costa M , Josselin R , Gwizdala K , Piemontese L , Capriati V , Pereira-Santos AR , Cardoso SM , Santos MA
Ref : Molecules , 25 : , 2020
Abstract : A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer's disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and beta-amyloid (Abeta) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Abeta-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.
ESTHER : Chaves_2020_Molecules_25_
PubMedSearch : Chaves_2020_Molecules_25_
PubMedID: 32098407

Title : New Multitarget Hybrids Bearing Tacrine and Phenylbenzothiazole Motifs as Potential Drug Candidates for Alzheimer's Disease - Rajeshwari_2019_Molecules_24_587
Author(s) : Rajeshwari R , Chand K , Candeias E , Cardoso SM , Chaves S , Santos MA
Ref : Molecules , 24 : , 2019
Abstract : Research on neurodegenerative brain disorders, namely the age-dependent Alzheimer's disease (AD), has been intensified in the last decade due to the absence of a cure and the recognized increasing of life expectancy for populations. To address the multifactorial nature and complexity of AD, a multi-target-directed ligand approach was herein employed, by designing a set of six selected hybrids (14(-)19) that combine in the same entity two pharmacophores: tacrine (TAC) and 2-phenylbenzothiazole (PhBTA). The compounds contain a methoxy substituent at the PhBTA moiety and have a variable length linker between that and the TAC moiety. The docking studies showed that all the compounds assure a dual-binding mode of acetylcholinesterase (AChE) inhibition, establishing pi-stacking and H-bond interactions with aminoacid residues at both active binding sites of the enzyme (CAS and PAS). The bioassays revealed that the designed compounds display excellent AChE inhibitory activity in the sub-micromolar range (0.06(-)0.27 muM) and moderate inhibition values for amyloid-beta (Abeta) self-aggregation (27(-)44.6%), compounds 14 and 15 being the lead compounds. Regarding neuroprotective effects in neuroblastoma cells, compounds 15, 16 and 19 revealed the capacity to prevent Abeta-induced toxicity, but compound 16 showed the highest neuroprotective effect. Overall these hybrid compounds, in particular 15 and 16, with promising multitarget anti-AD ability, encourage further pursuing studies on this type of TAC-PhBTA derivatives for potential AD therapy.
ESTHER : Rajeshwari_2019_Molecules_24_587
PubMedSearch : Rajeshwari_2019_Molecules_24_587
PubMedID: 30736397

Title : Tacrine-deferiprone hybrids as multi-target-directed metal chelators against Alzheimer's disease: a two-in-one drug - Chand_2018_Metallomics_10_1460
Author(s) : Chand K , Rajeshwari , Candeias E , Cardoso SM , Chaves S , Santos MA
Ref : Metallomics , 10 :1460 , 2018
Abstract : Alzheimer's disease (AD) is a severe age-dependent neurodegenerative disorder affecting several million people worldwide. So far, there is no adequate medication to prevent or slow down the progression of the disease, only medication with palliative effects allowing temporary symptomatic reliefs. As part of our continuing efforts into the development of innovative drugs following a polypharmacological strategy, we decided to use a former anti-AD palliative drug (tacrine) and to reposition it by hybridization with a metal chelating drug (deferiprone, DFP). This combination endows the hybrids with good capacity to inhibit acetylcholinesterase (low micromolar range) and self-/Cu-induced Abeta aggregation (up to ca. 90%) as well as a good radical scavenging ability (micromolar range) and metal (M) chelating capacity, with pM (pM = -log[M], CL/CM = 10, CM = 10(-6) M at pH = 7.4, M = Fe, Cu, Zn) values close to those of DFP. The most promising compounds have 2-hydroxypropyl linkers, and a selection of compounds have demonstrated neuroprotective roles in neuroblastoma cells treated with Abeta1-42 and ascorbate/iron stressors. Consequently, these hybrids can be considered as attractive multipotent therapeutic molecules that will eventually play key roles against AD progression, namely in the control of cholinergic dysfunction, amyloid peptide aggregation, oxidative stress, and metal modulation, besides presenting a good pharmacokinetic profile.
ESTHER : Chand_2018_Metallomics_10_1460
PubMedSearch : Chand_2018_Metallomics_10_1460
PubMedID: 30183790

Title : Hydroxypyridinone-benzofuran hybrids with potential protective roles for Alzheimer s disease therapy - Hiremathad_2017_J.Inorg.Biochem_179_82
Author(s) : Hiremathad A , Chand K , Tolayan L , Rajeshwari , Keri RS , Esteves AR , Cardoso SM , Chaves S , Santos MA
Ref : J Inorg Biochem , 179 :82 , 2017
Abstract : A series of (3-hydroxy-4-pyridinone)-benzofuran hybrids have been developed and studied as potential multitargeting drugs for Alzheimer's disease (AD). Their design envisaged mainly to mimic the donepezil drug, a marketed inhibitor of acetylcholinesterase (AChE), and to endow the conjugate molecules with extra-properties such as metal chelation, radical scavenging and inhibition of amyloid peptide (Abeta) aggregation. Thus, a set of eleven new hybrid compounds was developed and evaluated for chemical and biological properties, in solution and in neuronal cell environment. The results are discussed in terms of the type of substituents on both main moieties and the linker size. The closest similarity with donepezil, in terms of AChE inhibitory activity, was obtained for the O-benzyl-hydroxypyridinone hybrids containing a 2-methylene linker, although still less active than the drug. However, the free-hydroxypyridinone hybrids present higher activity for the Abeta aggregation inhibition, metal chelating capacity and radical scavenging activity. Overall, some compounds demonstrated capacity to exert a multiple action by hitting three- (7d) or four- (8d, 8f) pathophysiological targets of AD. Furthermore, the compounds showed neuroprotective effects in neuronal cells subjected to model stressors of AD, but not significant dependence on the substituent groups. Importantly, the compounds evidenced drug-likeness properties, including good membrane permeability.
ESTHER : Hiremathad_2017_J.Inorg.Biochem_179_82
PubMedSearch : Hiremathad_2017_J.Inorg.Biochem_179_82
PubMedID: 29182921

Title : Tacrine-(hydroxybenzoyl-pyridone) hybrids as potential multifunctional anti-Alzheimer's agents: AChE inhibition, antioxidant activity and metal chelating capacity - Chand_2016_J.Inorg.Biochem_163_266
Author(s) : Chand K , Alsoghier HM , Chaves S , Santos MA
Ref : J Inorg Biochem , 163 :266 , 2016
Abstract : Three novel potentially site-activated multitarget tacrine-(hydroxybenzoyl-pyridone) (TAC-HBP) hybrids were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors, antioxidants and biometal chelators. All of them are dual-binding site AChE inhibitors with activity in sub-micromolar range (IC50=0.57-0.78muM), which is comparable to the parent tacrine, and have good 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity (EC50=204-249muM) conferred by the hydroxybenzoyl-pyridone (HBP) moiety. Their chelating capacity towards redox-active and/or amyloid-beta-binding metal ions (Fe(III), Cu(II)), Zn(II)) was evaluated by using 2'-hydroxy-4'-methoxybenzoyl-2-pyridone derivative as a model compound in 30% w/w DMSO/water medium. It was proved that the HBP moiety acts as a moderate/good chelator of these biometals (pFe=13.9, pCu=6.0 and pZn=6.0 at pH6.0, CL/CM=10, CM=10-6M), being able to form complexes with beta-phenol-keto coordination mode, and that this chelating ability is preserved in the TAC-HBP hybrids.
ESTHER : Chand_2016_J.Inorg.Biochem_163_266
PubMedSearch : Chand_2016_J.Inorg.Biochem_163_266
PubMedID: 27235273

Title : New Tacrine Hybrids with Natural-Based Cysteine Derivatives as Multitargeted Drugs for Potential Treatment of Alzheimer's Disease - Keri_2016_Chem.Biol.Drug.Des_87_101
Author(s) : Keri RS , Quintanova C , Chaves S , Silva DF , Cardoso SM , Santos MA
Ref : Chemical Biology Drug Des , 87 :101 , 2016
Abstract : Alzheimer's disease (AD) is a devastating age-dependent neurodegenerative disorder. The main hallmarks are impairment of cholinergic system and accumulation in brain of beta-amyloid (Abeta) aggregates, which have been associated with oxidative damage and dyshomeostasis of redox-active biometals. The absence of an efficient treatment that could delay or cure AD has been attributed to the complexity and multifactorial nature of this disease. With this in mind and the recent interest on natural-based drugs, we have explored a set of natural-based hybrid compounds by conjugation of a tacrine moiety with an S-allylcysteine (garlic constituent) or S-propargylcysteine moiety aimed at improving the cholinergic system and neuroprotective capacity. The docking modeling studies allowed the selection of linkers to optimize the bimodal drug interaction with acetylcholinesterase enzyme (AChE) active site. The compounds were evaluated for some representative biological properties, including AChE activity and Abeta aggregation inhibition, as well as for their neuroprotective activity to Abeta- and ROS-induced cellular toxicity. The most promising results were achieved by compounds 9d for the AChE inhibition and 9l for the remarkable prevention of superoxide production and Abeta-induced cellular toxicity.
ESTHER : Keri_2016_Chem.Biol.Drug.Des_87_101
PubMedSearch : Keri_2016_Chem.Biol.Drug.Des_87_101
PubMedID: 26256122

Title : Copper(II) complexation of tacrine hybrids with potential anti-neurodegenerative roles - Quintanova_2015_J.Inorg.Biochem_151_58
Author(s) : Quintanova C , Keri RS , Chaves S , Santos MA
Ref : J Inorg Biochem , 151 :58 , 2015
Abstract : The complexity and multifactorial nature of neurodegenerative diseases turn quite difficult the development of adequate drugs for their treatment. Multi-target analogues, in conjugation with natural moieties, have been developed in order to combine acetylcholinesterase (AChE) inhibition with antioxidant properties, metal-binding capacity and inhibition of amyloid-beta (Abeta) aggregation. Due to the recent interest on natural-based drugs and also the importance of studying the role of transition metal ions in the disease process, we herein evaluate the copper chelating capacity and inhibitory ability for self- and Cu-induced Abeta1-42 aggregation of two nature-base hybrid model compounds obtained from conjugation of a tacrine moiety with a S-allylcystein (1) or S-propargylcystein (2) moiety. Both compounds show a moderate chelating power towards Cu(II) (pCu 7.13-7.51, CL/CCu=10, CCu=10(-6)M, pH7.4), with predominant formation of 1:1 complex species (CuL, CuH-1L) for which the coordination sphere involves the N-amide and the NH2 amine of the cysteine derivative as well as the NH of tacrine. The compounds are able to improve the inhibition of Abeta aggregation in the presence of Cu(II) and this is slightly more relevant for the allyl derivative (1), a stronger copper chelator, than for the propargyl (2). Moreover, the presence of a chloro atom in the tacrine moiety and the size of the chain length between the two NH groups appeared also to improve the inhibition capacity for Abeta aggregation.
ESTHER : Quintanova_2015_J.Inorg.Biochem_151_58
PubMedSearch : Quintanova_2015_J.Inorg.Biochem_151_58
PubMedID: 26119099

Title : Susceptibility profile of Aedes aegypti from Santiago Island, Cabo Verde, to insecticides - Rocha_2015_Acta.Trop_152_66
Author(s) : Rocha HD , Paiva MH , Silva NM , de Araujo AP , Camacho DD , Moura AJ , Gomez LF , Ayres CF , Santos MA , Camacho Ddos R
Ref : Acta Trop , 152 :66 , 2015
Abstract : In 2009, Cabo Verde diagnosed the first dengue cases, with 21,137 cases reported and Aedes aegypti was identified as the vector. Since the outbreak, chemical insecticides and source reduction were used to control the mosquito population. This study aimed to assess the susceptibility of A. aegypti populations from Santiago, Cabo Verde to insecticides and identify the mechanisms of resistance. Samples of A. aegypti eggs were obtained at two different time periods (2012 and 2014), using ovitraps in different locations in Santiago Island to establish the parental population. F1 larvae were exposed to different concentrations of insecticides (Bacillus thuringiensis var israelensis (Bti), diflubenzuron and temephos) to estimate the lethal concentrations (LC90) and calculate the respective rate of resistance (RR90). Semi-field tests using temephos-ABATE((R)) were performed to evaluate the persistence of the product. Bottle tests using female mosquitoes were carried out to determine the susceptibility to the adulticides malathion, cypermethrin and deltamethrin. Biochemical and molecular tests were performed to investigate the presence of metabolic resistance mechanisms, associated with the enzymes glutathione S-transferases (GSTs), esterases and mixed-function oxidases (MFO) and to detect mutations or alterations in the sodium channel and acetylcholinesterase genes. A. aegypti mosquitoes from Santiago exhibited resistance to deltamethrin, cypermethrin (mortality<80%) and temephos (RR90=4.4) but susceptibility to malathion (mortality>/=98%), Bti and diflubenzuron. The low level of resistance to temephos did not affect the effectiveness of Abate((R)). The enzymatic analysis conducted in 2012 revealed slight changes in the activities of GST (25%), MFO (18%), alpha-esterase (19%) and beta-esterase (17%), but no significant changes in 2014. Target site resistance mutations were not detected. Our results suggest that the A. aegypti population from Santiago is resistant to two major insecticides used for vector control, deltamethrin and temephos. To our knowledge, this is the first report of temephos resistance in an African A. aegypti population. The low level of temephos resistance was maintained from 2012-2014, which suggested the imposition of selective pressure, although it was not possible to identify the resistance mechanisms involved. These data show that the potential failures in the local mosquito control program are not associated with insecticide resistance.
ESTHER : Rocha_2015_Acta.Trop_152_66
PubMedSearch : Rocha_2015_Acta.Trop_152_66
PubMedID: 26307496

Title : Insights into neurosensory toxicity of mercury in fish eyes stemming from tissue burdens, oxidative stress and synaptic transmission profiles - Pereira_2015_Mar.Environ.Res_113_70
Author(s) : Pereira R , Guilherme S , Brandao F , Raimundo J , Santos MA , Pacheco M , Pereira P
Ref : Mar Environ Research , 113 :70 , 2015
Abstract : This study aims to contribute to fill a knowledge gap related with Hg effects in fish eyes. As a pioneering strategy, Hg bioaccumulation in eye wall of the wild grey mullet (Liza aurata) was assessed, together with oxidative stress and synaptic transmission profiles. This approach was complemented by the characterisation of environmental contamination (both in water and sediment). Sampling was conducted in winter and summer in two sites of a Portuguese coastal lagoon (Aveiro lagoon): Largo do Laranjo (LAR) - located in an Hg contaminated/confined area; Sao Jacinto (SJ) - closer to the lagoon inlet and selected as reference site. Levels of total Hg (tHg), inorganic Hg (iHg) and methylmercury (MeHg) in eye wall were higher at LAR than SJ, both in winter and summer, reflecting the environmental contamination patterns. Moreover, fish caught at LAR in winter showed a significant decrease of catalase and superoxide dismutase activities, in line with the occurrence of peroxidative damage. A different spatial pattern was recorded in summer, being characterised by the increment of glutathione peroxidase and glutathione reductase activities at LAR, as well as total glutathione content, preventing the occurrence of lipid peroxidation. Also in summer, a significant decrease of acetylcholinesterase activity was recorded in fish eyes at LAR, pointed out Hg as an anticholinergic agent. Besides Hg, water salinity had probably an indirect effect on spatial and winter-summer variation patterns of AChE. Current data pointed out that Hg (in iHg and MeHg forms) could exert ocular toxicity both by the promotion of oxidative stress and by the interference with neurotransmission processes.
ESTHER : Pereira_2015_Mar.Environ.Res_113_70
PubMedSearch : Pereira_2015_Mar.Environ.Res_113_70
PubMedID: 26610197

Title : Multifunctional iron-chelators with protective roles against neurodegenerative diseases - Nunes_2013_Dalton.Trans_42_6058
Author(s) : Nunes A , Marques SM , Quintanova C , Silva DF , Cardoso SM , Chaves S , Santos MA
Ref : Dalton Trans , 42 :6058 , 2013
Abstract : The multifactorial nature of Alzheimer's disease (AD), and the absence of a disease modifying drug, makes the development of new multifunctional drugs an attractive therapeutic strategy. Taking into account the hallmarks of AD patient brains, such as low levels of acetylcholine, misfolding of proteins and associated beta-amyloid (Abeta) aggregation, oxidative stress and metal dyshomeostasis, we have developed a series of compounds that merge three different approaches: metal attenuation, anti-Abeta aggregation and anti-acetylcholinesterase activity. Therefore, 3-hydroxy-4-pyridinone (3,4-HP) and benzothiazole molecular moieties were selected as starting frameworks due to their well known affinity for iron and Abeta peptides, respectively. The linkers between these two main functional groups were selected on the basis of virtual screening, so that the final molecule could further inhibit the acetylcholinesterase, responsible for the cholinergic losses. We describe herein the design and synthesis of the new hybrid compounds, followed by the assessment of solution properties, namely iron chelation and anti-oxidant capacity. The compounds were bioassayed for their capacity to inhibit AChE, as well as self- and Zn mediated-Abeta(1-42) aggregation. Finally, we assessed their effects on the viability of neuronal cells stressed with Abeta(42).
ESTHER : Nunes_2013_Dalton.Trans_42_6058
PubMedSearch : Nunes_2013_Dalton.Trans_42_6058
PubMedID: 23487286

Title : Design, synthesis and neuroprotective evaluation of novel tacrine-benzothiazole hybrids as multi-targeted compounds against Alzheimer's disease - Keri_2013_Bioorg.Med.Chem_21_4559
Author(s) : Keri RS , Quintanova C , Marques SM , Esteves AR , Cardoso SM , Santos MA
Ref : Bioorganic & Medicinal Chemistry , 21 :4559 , 2013
Abstract : Alzheimer's disease (AD) is a multifactorial disorder with several target proteins contributing to its etiology. In search for multifunctional anti-AD drug candidates, taking into account that the acetylcholinesterase (AChE) and beta-amyloid (Abeta) aggregation are particularly important targets for inhibition, the tacrine and benzothiazole (BTA) moieties were conjugated with suitable linkers in a novel series of hybrids. The designed compounds (7a-7e) were synthesized and in vitro as well as in ex vivo evaluated for their capacity for the inhibition of acetylcholinesterase (AChE) and Abeta self-induced aggregation, and also for the protection of neuronal cells death (SHSY-5Y cells, AD and MCI cybrids). All the tacrine-BTA hybrids displayed high in vitro activities, namely with IC50 values in the low micromolar to sub-micromolar concentration range towards the inhibition of AChE, and high percentages of inhibition of the self-induced Abeta aggregation. Among them, compound 7a, with the shortest linker, presented the best inhibitory activity of AChE (IC50=0.34muM), while the highest activity as anti-Abeta42 self-aggregation, was evidenced for compound 7b (61.3%, at 50muM. The docking studies demonstrated that all compounds are able to interact with both catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Our results show that compounds 7d and 7e improved cell viability in cells treated with Abeta42 peptide. Overall, these multi-targeted hybrid compounds appear as promising lead compounds for the treatment of Alzheimer's disease.
ESTHER : Keri_2013_Bioorg.Med.Chem_21_4559
PubMedSearch : Keri_2013_Bioorg.Med.Chem_21_4559
PubMedID: 23768661

Title : Bifunctional phenolic-choline conjugates as anti-oxidants and acetylcholinesterase inhibitors - Sebestik_2011_J.Enzyme.Inhib.Med.Chem_26_485
Author(s) : Sebestik J , Marques SM , Fale PL , Santos S , Arduino DM , Cardoso SM , Oliveira CR , Serralheiro ML , Santos MA
Ref : J Enzyme Inhib Med Chem , 26 :485 , 2011
Abstract : Because of the complex cascade of molecular events that can occur in the brain of an Alzheimer's disease (AD) patient, the therapy of this neurodegenerative disease seems more likely to be achieved by multifunctional drugs. Herein, a new series of dual-targeting ligands have been developed and in vitro bioevaluated. Their architecture is based on conjugating the acetylcholinesterase inhibition and anti-oxidant properties in one molecular entity. Specifically, a series of naturally occurring phenolic acids with recognized anti-oxidant properties (derivatives of caffeic acid, rosmarinic acid, and trolox) have been conjugated with choline to account for the recognition by acetylcholinesterase (AChE). The synthesized hybrid compounds evidenced AChE inhibitory capacity of micromolar range (rationalized by molecular modeling studies) and good antioxidant properties. Their effects on human neuroblastoma cells, previously treated with beta-amyloid peptides and 1-methyl-4-phenylpyridinium ion neurotoxins (to simulate AD and Parkinson's disease, respectively), also demonstrated a considerable capacity for protection against the cytotoxicity of these stressors.
ESTHER : Sebestik_2011_J.Enzyme.Inhib.Med.Chem_26_485
PubMedSearch : Sebestik_2011_J.Enzyme.Inhib.Med.Chem_26_485
PubMedID: 21067438

Title : Evolution of pathogenicity and sexual reproduction in eight Candida genomes - Butler_2009_Nature_459_657
Author(s) : Butler G , Rasmussen MD , Lin MF , Santos MA , Sakthikumar S , Munro CA , Rheinbay E , Grabherr M , Forche A , Reedy JL , Agrafioti I , Arnaud MB , Bates S , Brown AJ , Brunke S , Costanzo MC , Fitzpatrick DA , de Groot PW , Harris D , Hoyer LL , Hube B , Klis FM , Kodira C , Lennard N , Logue ME , Martin R , Neiman AM , Nikolaou E , Quail MA , Quinn J , Santos MC , Schmitzberger FF , Sherlock G , Shah P , Silverstein KA , Skrzypek MS , Soll D , Staggs R , Stansfield I , Stumpf MP , Sudbery PE , Srikantha T , Zeng Q , Berman J , Berriman M , Heitman J , Gow NA , Lorenz MC , Birren BW , Kellis M , Cuomo CA
Ref : Nature , 459 :657 , 2009
Abstract : Candida species are the most common cause of opportunistic fungal infection worldwide. Here we report the genome sequences of six Candida species and compare these and related pathogens and non-pathogens. There are significant expansions of cell wall, secreted and transporter gene families in pathogenic species, suggesting adaptations associated with virulence. Large genomic tracts are homozygous in three diploid species, possibly resulting from recent recombination events. Surprisingly, key components of the mating and meiosis pathways are missing from several species. These include major differences at the mating-type loci (MTL); Lodderomyces elongisporus lacks MTL, and components of the a1/2 cell identity determinant were lost in other species, raising questions about how mating and cell types are controlled. Analysis of the CUG leucine-to-serine genetic-code change reveals that 99% of ancestral CUG codons were erased and new ones arose elsewhere. Lastly, we revise the Candida albicans gene catalogue, identifying many new genes.
ESTHER : Butler_2009_Nature_459_657
PubMedSearch : Butler_2009_Nature_459_657
PubMedID: 19465905
Gene_locus related to this paper: canal-ATG15 , canal-bna7 , canal-c4yl13 , canal-LIP1 , canal-LIP2 , canal-LIP3 , canal-LIP4 , canal-LIP5 , canal-LIP6 , canal-LIP7 , canal-LIP8 , canal-LIP9 , canal-LIP10 , canal-ppme1 , canal-q5a0c9 , canal-q5a2i9 , canal-q5a042 , canal-q5ad17 , canal-q5aeu3 , canal-q5afp8 , canal-q5ag57 , canal-q5ai09 , canal-q5ai12 , canal-q5ajt3 , canal-q5akz5 , canal-q5apu4 , canal-q59l46 , canal-q59m48 , canal-q59nw6 , canal-q59u61 , canal-q59u64 , canal-q59vp0 , canal-q59y97 , canaw-c4ykb1 , canaw-c4yrn6 , canaw-c4yrn9 , canaw-c4yrr3 , canaw-c4yrv3 , canaw-c4ys26 , cantt-c5m3d7 , cantt-c5m3y5 , cantt-c5m4x0 , cantt-c5m5e8 , cantt-c5m5w2 , cantt-c5m8s7 , cantt-c5m9c2 , cantt-c5m465 , cantt-c5m751 , cantt-c5m793 , cantt-c5m893 , cantt-c5ma78 , cantt-c5mag0 , cantt-c5mbb8 , cantt-c5mc53 , cantt-c5md87 , cantt-c5mdy3 , cantt-c5mey7 , cantt-c5mfg0 , cantt-c5mfh8 , cantt-c5mg56 , cantt-c5mgj0 , cantt-c5mh75 , cantt-c5mh80 , cantt-c5mh89 , cantt-c5mhh0 , cantt-c5mhn5 , cantt-c5mij5 , cantt-c5min7 , clal4-c4xvt8 , clal4-c4xwy4 , clal4-c4xy03 , clal4-c4xyx9 , clal4-c4xzz1 , clal4-c4y3e1 , clal4-c4y4f2 , clal4-c4y4w8 , clal4-c4y5j4 , clal4-c4y5j9 , clal4-c4y7z7 , clal4-c4y8q1 , clal4-c4y035 , clal4-c4y481 , clal4-c4y538 , clal4-c4y898 , clal4-c4yas2 , clal4-c4yba6 , clal4-c4yba7 , clal4-c4yc85 , lodel-a5drz3 , lodel-a5ds97 , lodel-a5dsc0 , lodel-a5duu4 , lodel-a5duy7 , lodel-a5dv03 , lodel-a5dv46 , lodel-a5dw16 , lodel-a5dwv7 , lodel-a5dww6 , lodel-a5dxf3 , lodel-a5e0z5 , lodel-a5e1c1 , lodel-a5e1l4 , lodel-a5e1p3 , lodel-a5e2s1 , lodel-a5e2t8 , lodel-a5e2v2 , lodel-a5e4u8 , lodel-a5e5a9 , lodel-a5e5k1 , lodel-a5e5z7 , lodel-a5e6w1 , lodel-a5e028 , lodel-atg15 , lodel-kex1 , picgu-a5d9u2 , picgu-a5dav0 , picgu-a5dbk0 , picgu-a5dc45 , picgu-a5dc73 , picgu-a5dc74 , picgu-a5dc75 , picgu-a5ddt8 , picgu-a5dev7 , picgu-a5dh90 , picgu-a5dhe3 , picgu-a5di38 , picgu-a5dj06 , picgu-a5dkd8 , picgu-a5dle9 , picgu-a5dlj5 , picgu-a5dm19 , picgu-a5dn92 , picgu-a5dnr3 , picgu-a5dnt6 , picgu-a5dqu5 , picgu-a5dr14 , picgu-a5drl3 , picgu-atg15 , picgu-bna7 , picgu-a5d9q3 , picgu-a5dag9 , clal4-c4y5a2 , clal4-c4y0l0 , cantt-c5mcb1 , clal4-c4y8j2 , cantt-c5m494 , clals-a0a202gac7 , canal-hda1 , picgu-a5dks8 , lodel-a5drs6 , canpc-g8bbk1 , cantt-kex1 , clal4-kex1 , picgu-kex1

Title : A single amino acid substitution in one of the lipases of Aspergillus nidulans confers resistance to the antimycotic drug undecanoic acid - Brito-Madurro_2008_Biochem.Genet_46_557
Author(s) : Brito-Madurro AG , Prade RA , Madurro JM , Santos MA , Peres NT , Cursino-Santos JR , Martinez-Rossi NM , Rossi A
Ref : Biochemical Genetics , 46 :557 , 2008
Abstract : A plausible approach to evaluate the inhibitory action of antifungals is through the investigation of the fungal resistance to these drugs. We describe here the molecular cloning and initial characterization of the A. nidulans lipA gene, where mutation (lipA1) conferred resistance to undecanoic acid, the most fungitoxic fatty acid in the C(7:0)-C(18:0) series. The lipA gene codes for a putative lipase with the sequence consensus GVSIS and WIFGGG as the catalytic signature. Comparison of the wild-type and LIP1 mutant strain nucleotide sequences showed a G --> A change in lipA1 allele, which results in a Glu(214) --> Lys substitution in LipA protein. This ionic charge change in a conserved LipA region, next to its catalytic site, may have altered the catalytic properties of this enzyme resulting in resistance to undecanoic acid.
ESTHER : Brito-Madurro_2008_Biochem.Genet_46_557
PubMedSearch : Brito-Madurro_2008_Biochem.Genet_46_557
PubMedID: 18516670

Title : Complete DNA sequence of yeast chromosome XI - Dujon_1994_Nature_369_371
Author(s) : Dujon B , Alexandraki D , Andre B , Ansorge W , Baladron V , Ballesta JP , Banrevi A , Bolle PA , Bolotin-Fukuhara M , Bossier P , Bou G , Boyer J , Bultrago MJ , Cheret G , Colleaux L , Dalgnan-Fornler B , del Rey F , Dlon C , Domdey H , Dsterhoft A , Dsterhus S , Entlan KD , Erfle H , Esteban PF , Feldmann H , Fernandes L , Robo GM , Fritz C , Fukuhara H , Gabel C , Gaillon L , Carcia-Cantalejo JM , Garcia-Ramirez JJ , Gent NE , Ghazvini M , Goffeau A , Gonzalez A , Grothues D , Guerreiro P , Hegemann J , Hewitt N , Hilger F , Hollenberg CP , Horaitis O , Indge KJ , Jacquier A , James CM , Jauniaux C , Jimenez A , Keuchel H , Kirchrath L , Kleine K , Ktter P , Legrain P , Liebl S , Louis EJ , Maia e Silva A , Marck C , Monnier AL , Mostl D , Mller S , Obermaier B , Oliver SG , Pallier C , Pascolo S , Pfeiffer F , Philippsen P , Planta RJ , Pohl FM , Pohl TM , Pohlmann R , Portetelle D , Purnelle B , Puzos V , Ramezani Rad M , Rasmussen SW , Remacha M , Revuelta JL , Richard GF , Rieger M , Rodrigues-Pousada C , Rose M , Rupp T , Santos MA , Schwager C , Sensen C , Skala J , Soares H , Sor F , Stegemann J , Tettelin H , Thierry A , Tzermia M , Urrestarazu LA , van Dyck L , Van Vliet-Reedijk JC , Valens M , Vandenbo M , Vilela C , Vissers S , von Wettstein D , Voss H , Wiemann S , Xu G , Zimmermann J , Haasemann M , Becker I , Mewes HW
Ref : Nature , 369 :371 , 1994
Abstract : The complete DNA sequence of the yeast Saccharomyces cerevisiae chromosome XI has been determined. In addition to a compact arrangement of potential protein coding sequences, the 666,448-base-pair sequence has revealed general chromosome patterns; in particular, alternating regional variations in average base composition correlate with variations in local gene density along the chromosome. Significant discrepancies with the previously published genetic map demonstrate the need for using independent physical mapping criteria.
ESTHER : Dujon_1994_Nature_369_371
PubMedSearch : Dujon_1994_Nature_369_371
PubMedID: 8196765
Gene_locus related to this paper: yeast-mgll