Chemistry and personalized medicine – the research and development future of Europe

Personalized medicine may represent a dramatic change of paradigm in the medium-term future. For a chemist, personalized medicine means the definition and understanding of any disease on molecular level for each individual or group of individuals (personalized diagnosis) ideally leading to the design of a drug that efficiently counteracts or prevents any molecular dysfunction, ie, a personalized drug without side effects. The interdisciplinary research required for personalized medicine should overcome a myriad of obstacles not the least being to find specific biomarkers and targets for each individual or group of individuals suffering from a given disease. Chemists enter then into action and will model/ design drugs and drug delivery pathways for a personalized therapy. They will either tap into the numerous drugs candidates, which were abandoned at some stage of clinical trials, or synthesize new drugs, mainly those “small molecules” mimicking the activity of natural products. This view has obvious economic, ethical, and social implications, beyond scientific challenges. All stakeholders will have to take them into account. Policy makers will have to examine all disciplines of regulatory science among which the thorny economics (cost-benefit analysis of specific research and development projects) are of paramount importance and critical to the development of personalized medicine

Chemistry and personalized medicine – the research and development future of Europe

Personalized medicine may represent a dramatic change of paradigm in the medium-term future. For a chemist, personalized medicine means the definition and understanding of any disease on molecular level for each individual or group of individuals (personalized diagnosis) ideally leading to the design of a drug that efficiently counteracts or prevents any molecular dysfunction, ie, a personalized drug without side effects. The interdisciplinary research required for personalized medicine should overcome a myriad of obstacles not the least being to find specific biomarkers and targets for each individual or group of individuals suffering from a given disease. Chemists enter then into action and will model/ design drugs and drug delivery pathways for a personalized therapy. They will either tap into the numerous drugs candidates, which were abandoned at some stage of clinical trials, or synthesize new drugs, mainly those “small molecules” mimicking the activity of natural products. This view has obvious economic, ethical, and social implications, beyond scientific challenges. All stakeholders will have to take them into account. Policy makers will have to examine all disciplines of regulatory science among which the thorny economics (cost-benefit analysis of specific research and development projects) are of paramount importance and critical to the development of personalized medicine

Self-Renewal Signalling in Presenescent Tetraploid IMR90 Cells

Endopolyploidy and genomic instability are shared features of both stress-induced cellular senescence and malignant growth. Here, we examined these facets in the widely used normal human fibroblast model of senescence, IMR90. At the presenescence stage, a small (2–7%) proportion of cells overcome the 4n-G1 checkpoint, simultaneously inducing self-renewal (NANOG-positivity), the DNA damage response (DDR; γ-H2AX-positive foci), and senescence (p16inka4a- and p21CIP1-positivity) signalling, some cells reach octoploid DNA content and divide. All of these markers initially appear and partially colocalise in the perinucleolar compartment. Further, with development of senescence and accumulation of p16inka4a and p21CIP1, NANOG is downregulated in most cells. The cells increasingly arrest in the 4n-G1 fraction, completely halt divisions and ultimately degenerate. A positive link between DDR, self-renewal, and senescence signalling is initiated in the cells overcoming the tetraploidy barrier, indicating that cellular and molecular context of induced tetraploidy during this period of presenescence is favourable for carcinogenesis

Intramolecular C-H⋯O hydrogen bonding in 1,4-dihydropyridine derivatives

The diastereotopy of the methylene protons at positions 2 and 6 in 1,4-dihydropiridine derivatives with various substituents has been investigated. NMR spectroscopy and quantum chemistry calculations show that the CH⋯O intramolecular hydrogen bond is one of the factors amplifying the chemical shift differences in the 1H-NMR spectra.publishersversionPeer reviewe

A 1,4-dihydropyridine derivative reduces DNA damage and stimulates DNA repair in human cells in vitro

Abstract Compounds of the 1,4-dihydropyridine (1,4-DHP) series have been shown to reduce spontaneous, alkylation-and radiationinduced mutation rates in animal test systems. Here we report studies using AV-153, the 1,4-DHP derivative that showed the highest antimutagenic activity in those tests, to examine if it modulates DNA repair in human peripheral blood lymphocytes and in two human lymphoblastoid cell lines, Raji and HL-60. AV-153 caused a 50% inhibition of growth (IC 50 ) of Raji and HL-60 cells at 14.9 ± 1.2 and 10.3 ± 0.8 mM, respectively, but did not show a cytotoxic effect at concentrations <100 M. Alkaline single-cell gel electrophoresis (comet) assays showed that AV-153 reduced the number of DNA strand breaks in untreated cells and also in cells exposed to 2 Gy of gamma-radiation, 100 M ethylmethane sulfonate (EMS), or 100 M H 2 O 2 . DNA damage was reduced by up to 87% at AV-153 concentrations between 1 and 10 nM, and a positive dose-effect relationship was seen between 0.01 and 1 nM. Comparison of the kinetics of DNA strand-break rejoining in the presence and absence of AV-153 revealed a considerable influence on the rate of repair. In view of the resemblance of this compound's structure to that of dihydronicotinamide, a substrate for poly(ADP-rybose)polymerase, the modulation of DNA repair by AV-153 could involve an influence on poly(ADP)ribosylation

1,4-Dihydropyridine Derivatives: Dihydronicotinamide Analogues—Model Compounds Targeting Oxidative Stress

Many 1,4-dihydropyridines (DHPs) possess redox properties. In this review DHPs are surveyed as protectors against oxidative stress (OS) and related disorders, considering the DHPs as specific group of potential antioxidants with bioprotective capacities. They have several peculiarities related to antioxidant activity (AOA). Several commercially available calcium antagonist, 1,4-DHP drugs, their metabolites, and calcium agonists were shown to express AOA. Synthesis, hydrogen donor properties, AOA, and methods and approaches used to reveal biological activities of various groups of 1,4-DHPs are presented. Examples of DHPs antioxidant activities and protective effects of DHPs against OS induced damage in low density lipoproteins (LDL), mitochondria, microsomes, isolated cells, and cell cultures are highlighted. Comparison of the AOA of different DHPs and other antioxidants is also given. According to the data presented, the DHPs might be considered as bellwether among synthetic compounds targeting OS and potential pharmacological model compounds targeting oxidative stress important for medicinal chemistry

1,4 dihidropiridinski derivati povećavaju ekspresiju gena Psma3, Psmb5 i Psmc6 u glasničkoj RNA štakora

The ubiquitin-proteasome system modifies different cellular and protein functions. Its dysregulation may lead to disrupted proteostasis associated with multiple pathologies and aging. Pharmacological regulation of proteasome functions is already an important part of the treatment of several diseases. 1,4-dihydropyridine (1,4-DHP) derivatives possess different pharmacological activities, including antiaging and neuroprotective. The aim of this study was to investigate the effects of several 1,4-DHP derivatives on mRNA expression levels of proteasomal genes Psma3, Psmb5, and Psmc6 in several organs of rats. Rats were treated with metcarbatone, etcarbatone, glutapyrone, styrylcarbatone, AV-153-Na, or AV-153-Ca per os for three days. mRNA expression levels were determined with real-time polymerase chain reaction (PCR). For AV-153-Na and AV-153-Ca, we also determined the expression of the Psma6 gene. In the kidney, metcarbatone, etcarbatone, styrylcarbatone, and AV-153-Na increased the expression of all analysed genes. Glutapyrone increased the expression of Psmb5 and Psmc6 but did not affect the expression of Psma3. In the blood, glutapyrone increased Psmb5 expression. In the liver, AV-153-Na increased the expression of Psma6 and Psmc6 but lowered the expression of Psmb5, while AV-153-Ca only increased Psma6 expression. The ability of 1,4-DHP derivatives to increase the expression of proteasome subunit genes might hold a therapeutic potential in conditions associated with impaired proteasomal functions, but further research is needed.Ubikvitin-proteasomski sustav utječe na različite funkcije bjelančevina i stanica. Poremećaji u njegovoj regulaciji mogu dovesti do poremećaja u proteostazi koji su povezani s nastankom različitih bolesti i sa starenjem, ali se sustav može regulirati u liječenju pojedinih bolesti lijekovima poput 1,4 dihidropiridinskih (1,4 DHP) derivata, koji štite živčani sustav i usporavaju starenje. Cilj ovoga istraživanja bio je utvrditi djelovanje nekoliko 1,4 DHP derivata na ekspresiju glasničke RNA (mRNA) u proteasomskim genima Psma3, Psmb5 i Psmc6 u više štakorskih organa. Štakori su tri dana dobivali oralne doze metkarbatona, etkarbatona, glutapirona, stirilkarbatona, AV-153-Na ili AV-153-Ca, a genska se ekspresija u mRNA utvrdila polimeraznom lančanom reakcijom u stvarnom vremenu (engl. real-time polymerase chain reaction, krat. PCR). Osim toga, utvrdili smo djelovanje derivata AV‑153‑Na i AV‑153‑Ca na ekspresiju gena Psma6. U bubrezima su metkarbaton, etkarbaton, stirilkarbatoni AV‑153‑Na povećali ekspresiju svih analiziranih gena. Glutapiron je povećao ekspresiju Psmb5 i Psmc6, ali ne i Psma3. U krvi je glutapiron povećao gensku ekspresiju Psmb5. U jetrima je AV‑153‑Na povećao ekspresiju Psma6 i Psmc6, istodobno smanjivši ekspresiju Psmb5. AV‑153‑Ca utjecao je samo na Psma6, povećavši mu ekspresiju. Sposobnost 1,4-DHP derivata da povećaju gensku ekspresiju proteasomskih podjediničnih proteina obećava u smislu mogućnosti liječenja bolesti povezanih s poremećenom proteasomskom funkcijom, no nužna su daljnja istraživanja

Kratki pregled genotoksičnoga i genoprotektivnoga djelovanja derivata 1,4-dihidropiridina

This review summarises current knowledge about the genotoxic and genoprotective effects of 1,4-dihydropyridines (DHP) with the main focus on the water-soluble 1,4-DHPs. Most of these water-soluble compounds manifest very low calcium channel blocking activity, which is considered “unusual” for 1,4-DHPs. Glutapyrone, diludine, and AV-153 decrease spontaneous mutagenesis and frequency of mutations induced by chemical mutagens. AV-153, glutapyrone, and carbatones protect DNA against the damage produced by hydrogen peroxide, radiation, and peroxynitrite. The ability of these molecules to bind to the DNA may not be the only mechanism of DNA protection, as other mechanisms such as radical scavenging or binding to other genotoxic compounds may take place and enhance DNA repair. These uncertainties and reports of high 1,4-DHP concentrations damaging the DNA call for further in vitro and in vivo preclinical research, pharmacokinetic in particular, as it can help pinpoint the exact mechanism(s) of the genotoxic and/or genoprotective action of 1,4-DHPs.Ovaj pregledni rad donosi sažetak onoga što smo dosad naučili o genotoksičnom i genoprotektivnom djelovanju 1,4-dihidropiridina (DHP), s posebnom pažnjom na 1,4-DHP-ove topljive u vodi. Većina tih u vodi topljivih spojeva slabo aktivira blokiranje kalcijevih kanala, što se smatra “neuobičajenim” za 1,4-DHP-ove. Glutapiron, diludin i AV-153 ublažavaju spontanu mutagenezu i učestalost mutacija prouzročene kemijskim mutagenima. AV-153, glutapiron i karbatoni štite DNA od oštećenja prouzročenih vodikovim peroksidom, zračenjem i peroksinitritom. Sposobnost tih molekula da se vežu za DNA vjerojatno nije jedini mehanizam njegove zaštite, budući da su mogući i drugi mehanizmi, poput uklanjanja radikala ili vezanja za druge genotoksične spojeve koji pospješuju popravak DNA. Zbog tih nepoznanica i izvještaja da visoke koncentracije 1,4-DHP-ova oštećuju DNA, potrebno je napraviti daljnja neklinička istraživanja in vitro i in vivo, napose ona farmakokinetička, budući da mogu pomoći razaznati točne mehanizme genotoksičnoga i/ili genoprotektivnoga djelovanja derivata 1,4-dihidropiridina

Growth Modulation of Human Cells in Vitro by Mild Oxidative Stress and 1,4-Dihydropyridine Derivative Antioxidants

Reactive oxygen species and lipid peroxidation products are not only cytotoxic but may also modulate signal transduction in cells. Accordingly, antioxidants may be considered as modifiers of cellular redox signaling. Therefore, the effects of two novel synthetic antioxidants, analogues of 1,4-dihydropyridine derivatives, cerebrocrast and Z41-74 were analysed in vitro on human osteosarcoma cell line HOS, the growth of which can be modulated by lipid peroxidation. The cells were pretreated with either cerebrocrast or Z41-74 and afterwards exposed to mild, copper induced lipid peroxidation or to 4-hydroxynonenal (HNE), the end product of lipid peroxidation. The results obtained have shown that both antioxidants exert growth modulating effects interfering with the lipid peroxidation. Namely, cells treated with antioxidants showed increased metabolic rate and cell growth, thereby attenuating the effects of lipid peroxidation. Such biomodulating effects of cerebrocrast and Z41-74 resembled growth modulating effects of HNE, suggesting that the antioxidants could eventually promote cellular adaptation to oxidative stress interacting with redox signaling and hydroxynonenal HNE-signal transduction pathways. This may be of particular relevance for better understanding the beneficial role of hydroxynonenal HNE in cell growth control. Therefore, cerebrocrast and Z41-74 could be convenient to study further oxidative homeostasis involving lipid peroxidation

Growth Modulation of Human Cells in Vitro by Mild Oxidative Stress and 1,4-Dihydropyridine Derivative Antioxidants

Reactive oxygen species and lipid peroxidation products are not only cytotoxic but may also modulate signal transduction in cells. Accordingly, antioxidants may be considered as modifiers of cellular redox signaling. Therefore, the effects of two novel synthetic antioxidants, analogues of 1,4-dihydropyridine derivatives, cerebrocrast and Z41-74 were analysed in vitro on human osteosarcoma cell line HOS, the growth of which can be modulated by lipid peroxidation. The cells were pretreated with either cerebrocrast or Z41-74 and afterwards exposed to mild, copper induced lipid peroxidation or to 4-hydroxynonenal (HNE), the end product of lipid peroxidation. The results obtained have shown that both antioxidants exert growth modulating effects interfering with the lipid peroxidation. Namely, cells treated with antioxidants showed increased metabolic rate and cell growth, thereby attenuating the effects of lipid peroxidation. Such biomodulating effects of cerebrocrast and Z41-74 resembled growth modulating effects of HNE, suggesting that the antioxidants could eventually promote cellular adaptation to oxidative stress interacting with redox signaling and hydroxynonenal HNE-signal transduction pathways. This may be of particular relevance for better understanding the beneficial role of hydroxynonenal HNE in cell growth control. Therefore, cerebrocrast and Z41-74 could be convenient to study further oxidative homeostasis involving lipid peroxidation