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This review reports on the latest developments (since 2014) in the chemistry of cholesterol and its applications in different research fields. These applications range from drug delivery or bioimaging applications to cholesterol-based liquid crystals and gelators. A brief overview of the most recent synthetic procedures to obtain new cholesterol derivatives is also provided, as well as the latest anticancer, antimicrobial, and antioxidant new cholesterol-based derivatives. This review discusses not only the synthetic details of the preparation of new cholesterol derivatives or conjugates, but also gives a short summary concerning the specific application of such compounds ; Thanks are due to the University of Aveiro, Instituto Politécnico de Bragança, FCT/MEC for financial support of the QOPNA (FCT UID/QUI/00062/2013) and CIMO (UID/AGR/00690/2013) research units, through national funds, and where applicable cofinanced by the FEDER, within the PT2020 Partnership Agreement; and also to the Portuguese NMR Network. This work was also supported by the Integrated Programme of SR&TD "pAGE–Protein aggregation Across the Lifespan" (reference CENTRO-01-0145-FEDER-000003), co-funded by the Centro 2020 program, Portugal 2020, European Union, through the European Regional Development Fund. H. M. T. Albuquerque thanks the pAGE project for his Post-Doc grant (BPD/UI98/4861/2017). ; info:eu-repo/semantics/publishedVersion

Chromones are a well-known class of naturally occurring oxygencontaining heterocyclic compounds; many of them playing important biological functions in nature [1]. Although 2-methylchromones are one of the scarcest classes of natural chromones, their synthesis and reactivity is well studied. They can participate in several chemical transformations such as oxidation, thiation, hydrogenation, photolysis, cycloaddition and condensation reactions, being useful targets in the synthesis of novel heterocyclic compounds [2]. The acidity of the 2- methyl group, due to the low electron density at C-2 caused by oxygen atom and the α,β-unsaturated ketone system, led us to explore the condensation of 2-methylchromones [3] with propargyl aldehydes [4]. ; University of Aveiro, Fundação para a Ciência e Tecnologia (FCT, Portugal), European Union, QREN, FEDER and COMPETE for funding the QOPNA Research Unit (project PEst-C/QUI/UI0062/2011) and the Portuguese National NMR Network. Hélio Albuquerque also thanks FCT for his fellowship (SFRH/BI/51556/2011).

Chromones are a family of oxygen-containing heterocyclic compounds that have been shown particular relevant biological activity. In what concerns to 2-methylchromones, their reactivity is well-known and allowed to exploit many different kinds of chemical reactions. The acidic character of the 2-methyl group, due to the low electron density at C-2 caused by carbonyl group enable this class of compounds to undergo oxidation, photolysis, cycloaddition and condensation reactions ; University of Aveiro, Funda9ao para a Ciencia e Tecnologia (FCT, Portugal), European Union, QREN, FEDER and COMPETE for funding the QOPNA Research Unit (project PEst-C/QUI/UI0062/2011) and the Portuguese National NMR Network. Hello Albuquerque also thanks FCT for his fellowship (SFRH/Bl/51556/2011 ).

Chromones are a well-known class of naturally occurring oxygen-containing heterocyclic compounds; many of them playing important biological functions in nature.[IJ Although 2- methylchromones are one of the scarcest classes of natural chromones, their synthesis and reactivity is well studied. They can participate in several chemical transformations such as oxidation, thiation, hydrogenation, photolysis, cycloaddition and condensation reactions, being useful targets in the synthesis of novel heterocyclic compounds. [lJ The acidity of the 2-methyl group, due to the low electron density at C-2 caused by oxygen atom and the α, β-unsaturated ketone system, led us to explore the condensation of 2-methylchromone 2 with propargyl aldehydes 3 in order to obtain new (£)-2-( 4-arylbut-1-en-3-ynyl)-4Hchromen- 4-ones 4 (Scheme 1). The starting material, 2-methyl-chromone 2 was prepared in a three step sequence starting from 2 '-hydroxyacetophenone 1 while the propargyl aldehydes 3were obtained from the reaction of the appropriate iodobenzene with propargyl alcohol and subsequent oxidation. In this communication we will present the synthetic details of all described transformations as well as the structural characterization (by 1 D and 2D NMR studies) of the new synthesized compounds. ; University of Aveiro, Fundat;iio para a Ciencia e Tecnologia (FCT, Portugal), European Union, QREN, FEDER and COMPETE for funding the QOPNA Research Unit (project PEst-CIQUJ/UJ0062/2011) and the Portuguese National NMR Network. Helio Albuquerquealso thanks FCT for his fel/owship(SFRH/BI/51556/20 11).

Chromones are a family of oxygen-containing heterocyclic compounds that have been shown particular relevant biological activity. In what concerns to 2-methylchromones, their reactivity is well-known and allowed to exploit many different kinds of chemical reactions. The acidic character of the 2-methyl group, due to the low electron density at C-2 caused by carbonyl group enable this class of compounds to undergo oxidation, photolysis, cycloaddition and condensation reactions ; University of Aveiro, Funda9ao para a Ciencia e Tecnologia (FCT, Portugal), European Union, QREN, FEDER and COMPETE for funding the QOPNA Research Unit (project PEst-C/QUI/UI0062/2011) and the Portuguese National NMR Network. Hello Albuquerque also thanks FCT for his fellowship (SFRH/Bl/51556/2011 ).

P rotein aggregation is a biological process in which misfolded proteins aggregate and accumulate in intra- or extracellular media. Protein aggregation is intimately linked to the pathogenesis of many neurodegenerative diseases (such as Alzheimer's, Huntington, Parkinson's and prion diseases) but also in cancer and cardiovascular pathologies (e.g. atherosclerosis, heart failure and ischemic heart disease).1 However, it is not fully understood how aggregates are formed and how the complex network of chaperones, the proteasome, autophagy and other regulatory factors are involved in their clearance.1 Nevertheless, it is well accepted that lowering protein aggregates back to "normal" levels in cells could be an important therapeutic strategy to control or modulate neurodegenerative diseases.2 In 2015, lanosterol was reported to reverse protein aggregation of crystallin clumps in mouse cataracts, due to its amphiphilic nature, being able to intercalate into and coat hydrophobic areas of large protein aggregates, making these water soluble again.3 Taking into consideration this discovery, we believe that other steroids, such cholesterol (with the appropriate chemical modification),4 can be good lead candidates to lower several types of protein aggregates. In this project a series of new hybrid-steroidal compounds was designed and synthesized, to address protein aggregates in different models and using techniques such as a high-throughput screening (HTS) (Figure 1). The design and synthetic strategy of the compounds, as well as the preliminary disaggregation results in different types of in vitro and ex vivo aggregation models will be discussed and rationalized in terms of structure-activity relationship, whenever possible. ; Thanks are due to University of Aveiro, FCT/MEC, Centro 2020 and Portugal2020, the COMPETE program, and the European Union (FEDER program) via the financial support to the QOPNA research project (FCT UID/QUI/00062/2019), to the IBiMed Research Unit (UID/BIM/04501/2013), to the Portuguese NMR Network, and to the PAGE project "Protein aggregation across the lifespan" (CENTRO-01-0145-FRDER-000003), including H. M. T. Albuquerque Post-Doctoral grant (BPD/UI98/4861/2017) and R. Nunes da Silva Post-Doctoral grant (BPD/UI98/6327/2018). ; info:eu-repo/semantics/publishedVersion

Chromone and xanthone derivativas are well-known for their outstanding antioxidant properties. ln an effort to develop new antioxidants with improved efficacy, here we cteveloped a new synthetic strategy to prepare hydroxylated chromones 3 and xanthones 4 with extended conjugated rr-systems. The synthetic strategy involved the aldolcondensation of 2-methylchromones 1 with cinnamaldehyde 2 to give chromones 3. Subsequent electrocyclization and oxidation of chromones 3 afforded xanthones 4 (Fig. 1 ). The scavenging activities of both derivativas 3 and 4 were addressed against both reactive oxygen species (ROS) and reactive nitrogen species (RNS). Ali tested compounds exhibited scavenger effects dependent on the concentration, with ICso values found in the micromolar range [1]. ; Sincere thanks are expressed to Faculdade de Farmácia da Universidade do Porto, Universidade de Aveiro, Instituto Politécnico de Bragança, Fundação para a Ciência e a Tecnologia (FCT, Portugal), European Union, QREN, FEDER and COMPETE funding UCIBIOREQUIMTE (FCT UID/Multi/04378/2013) and OOPNA (FCT UID/QUI/00062/2013) Research Units and also to the Portuguesa National NMR Network (RNRMN). ; info:eu-repo/semantics/publishedVersion

Reversing protein aggregation within cells may be an important tool to fight protein-misfolding disorders such as Alzheimer's, Parkinson's, and cardiovascular diseases. Here we report the design and synthesis of a family of steroid−quinoline hybrid compounds based on the framework combination approach. This set of hybrid compounds effectively inhibited Aβ1−42 self-aggregation in vitro by delaying the exponential growth phase and/or reducing the quantity of fibrils in the steady state. Their disaggregation efficacy was further demonstrated against preaggregated Aβ1−42 peptides in cellular assays upon their endocytosis by neuroblastoma cells, as they reverted both the number and the average area of fibrils back to basal levels. The antiaggregation effect of these hybrids was further tested and demonstrated in a cellular model of general protein aggregation expressing a protein aggregation fluorescent sensor. Together, our results show that the new cholesterol−quinoline hybrids possess wide and marked disaggregation capacities and are therefore promising templates for the development of new drugs to deal with conformational disorders. ; Thanks are due to the University of Aveiro, FCT/MEC, Centro 2020 and Portugal2020, the COMPETE Program, and the European Union (FEDER Program) via the financial support to the research units LAQV-REQUIMTE (UIDB/50006/2020), IBiMED (UID/BIM/04501/2019) and CICECO- Aveiro Institute of Materials (UID/CTM/50011/2019), financed by national funds through the FCT/MCTES, to the Portuguese NMR Network, to the ThiMES Project (POCI-01- 0145-FEDER-016630), and to the PAGE Project "Protein Aggregation Across the Lifespan" (CENTRO-01-0145- FEDER-000003), including postdoctoral grants to H.M.T.A. (BPD/UI98/4861/2017) and R.N.d.S. (BPD/UI98/6327/2018). M.P. was supported by Ph.D. Grant SFRH/BD/135655/2018. A.R.S. and S.G. were supported by national funds (OE) through FCT, I.P., in the scope of the framework contract foreseen in numbers 4, 5, and 6 of Article 23 of the Decree-Law 57/2016 of August ...