Structure–activity relationship of polyamine conjugates for uptake via polyamine transport system

Nazifi, S. Mohamad Reza; Sadeghi‐Aliabadi, Hojjat; Fassihi, Afshin; Saghaie, Lotfollah

doi:10.1007/s11224-018-1175-4

Cited by 10 publications

(2 citation statements)

References 49 publications

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“…In disease models we may pick up isoform-specific transport deficiencies and map possible compensatory changes in the activity of other P 5B ATPase isoforms. Moreover, the broad range of fluorescent polyamines that enter cells via ATP13A2 and/or ATP13A3 suggest that polyamines may be considered as vehicles to take up drugs or other molecular cargo [33]. For instance, polyamine-anthracene conjugates have previously been designed to target cancer cells with an increased polyamine uptake system [34] or Plasmodium falciparum parasites [35].…”

Section: Distinct Polyamine Uptake Kinetics In Atp13a2 and Atp13a3 Cellsmentioning

confidence: 99%

Novel Green Fluorescent Polyamines to Analyze ATP13A2 and ATP13A3 Activity in the Mammalian Polyamine Transport System

et al. 2023

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Cells acquire polyamines putrescine (PUT), spermidine (SPD) and spermine (SPM) via the complementary actions of polyamine uptake and synthesis pathways. The endosomal P5B-type ATPases ATP13A2 and ATP13A3 emerge as major determinants of mammalian polyamine uptake. Our biochemical evidence shows that fluorescently labeled polyamines are genuine substrates of ATP13A2. They can be used to measure polyamine uptake in ATP13A2- and ATP13A3-dependent cell models resembling radiolabeled polyamine uptake. We further report that ATP13A3 enables faster and stronger cellular polyamine uptake than does ATP13A2. We also compared the uptake of new green fluorescent PUT, SPD and SPM analogs using different coupling strategies (amide, triazole or isothiocyanate) and fluorophores (symmetrical BODIPY, BODIPY-FL and FITC). ATP13A2 promotes the uptake of various SPD and SPM analogs, whereas ATP13A3 mainly stimulates the uptake of PUT and SPD conjugates. However, the polyamine linker and coupling position on the fluorophore impacts the transport capacity, whereas replacing the fluorophore affects polyamine selectivity. The highest uptake in ATP13A2 or ATP13A3 cells is observed with BODIPY-FL-amide conjugated to SPD, whereas BODIPY-PUT analogs are specifically taken up via ATP13A3. We found that P5B-type ATPase isoforms transport fluorescently labeled polyamine analogs with a distinct structure–activity relationship (SAR), suggesting that isoform-specific polyamine probes can be designed.

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Section: Distinct Polyamine Uptake Kinetics In Atp13a2 and Atp13a3 Cellsmentioning

confidence: 99%

Novel Green Fluorescent Polyamines to Analyze ATP13A2 and ATP13A3 Activity in the Mammalian Polyamine Transport System

et al. 2023

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“…Алкилированные производные природных и синтетических ПА способны снижать внутриклеточное содержание природных ПА и блокировать рост раковых клеток за счет встраивания в механизмы биосинтеза ПА [1][2][3][4]. Конъюгирование ПА с противоопухолевыми агентами приводит к усилению как терапевтического эффекта, так и селективности действия последних, за счет задействования системы транспорта ПА раковых клеток, которые нуждаются в ПА для быстрой пролиферации [5][6][7][8][9].…”

Section: Introductionunclassified

Amination of epoxides as a convenient approach for lipophilic polyamines synthesis

Eshtukova-Shcheglova

Perevoshchikova

Eshtukov-Shcheglov

et al. 2022

Fine Chem. Technol.

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Objectives. Alkylated derivatives of polyamines are able to block the growth of cancer cells due to their embedding into the polyamine biosynthesis mechanisms. The study aimed to synthesize lipophilic derivatives of norspermine or triethylenetetramine based on the formation of a C–N bond during the opening of the oxirane ring by primary amines to expand a number of synthetic polyamine derivatives with antitumor activity.Methods. The starting compounds—glycidol alcoholate or epichlorohydrin—were reacted with hexadecyl bromide or sodium hexadecanolate to give glycidyl hexadecyl ether. The key reaction for the preparation of lipophilic polyamines was the amination of lipophilic epoxides with polyamines in the presence of calcium triflate. Acylation of the hydroxyl group formed during the opening of oxirane was carried out by the action of 4-dimethylaminopyridine and acetic anhydride. The introduction of an alkyl substituent in the presence of sodium hydride led to intramolecular cyclization with the formation of an oxoazolidine cycle. The regioselectivity of the oxirane ring opening reaction at the C(1) position of glycerol was confirmed by two-dimensional heteronuclear {1H,13C} nuclear magnetic resonance spectroscopy.Results. An approach to the synthesis of novel lipophilic polyamines based on the catalytic amination of epoxides was developed and tested. Compounds based on norspermine and triethylentetramine containing a hydroxyl group at the C(2) atom of the glycerin backbone were obtained. For norspermine derivatives, the hydroxyl group was modified: an acetyl substituent was introduced and a derivative containing an oxoazolidine cycle was obtained.Conclusions. The obtained lipophilic polyamines can be considered as potential antitumor agents, for which cytotoxicity against various cancer cells will be evaluated in the future.

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Synthesis and in vitro cytotoxic activity of dye-linker-macrocycle conjugates with variable linker length and components

Tomczyk,

Matczak,

Skonieczna

et al. 2023

Bioorganic Chemistry

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Structure–activity relationship of polyamine conjugates for uptake via polyamine transport system

Cited by 10 publications

References 49 publications

Novel Green Fluorescent Polyamines to Analyze ATP13A2 and ATP13A3 Activity in the Mammalian Polyamine Transport System

Novel Green Fluorescent Polyamines to Analyze ATP13A2 and ATP13A3 Activity in the Mammalian Polyamine Transport System

Amination of epoxides as a convenient approach for lipophilic polyamines synthesis

Synthesis and in vitro cytotoxic activity of dye-linker-macrocycle conjugates with variable linker length and components

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