Synthesis of novel lipophilic tetraamines with cytotoxic activity

Perevoshchikova, K. A.; Nichugovskiy, Artemiy; Isagulieva, A. K.; Морозова, Н. Г.; Ivanov, Igor; Маслов, М. А.; Shtil, Alexander А.

doi:10.1016/j.mencom.2019.11.003

Cited by 9 publications

(4 citation statements)

References 28 publications

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“…Asymmetric lipophilic PAs were found to be promising antitumor agents. A number of amphiphiles based on triethyltetramine 111a,b, norspermine 112a,b, and spermine 113a-f were synthesized using the Fukuyama reaction [93]. Compounds 111-113 had various long-chain alkyl substituents at the C(1) glycerol atom and PA residues, which could be alkylated at the terminal amino group (Figure 4).…”

Section: Lipophilic Polyaminesmentioning

confidence: 99%

Recent Advances in the Synthesis of Polyamine Derivatives and Their Applications

2021

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Biogenic polyamines (PAs) are involved in the growth and development of normal cells, and their intracellular concentration is stable. The concentration of PAs in cancer cells is significantly increased to promote and sustain their rapid proliferation. Over the years, synthetic PAs, which differ in their structure, have demonstrated high antitumor activity and are involved in clinical trials. The chemical synthesis of PAs and their conjugates require the correct choice of synthetic pathways—methods for constructing conjugates and the orthogonal protection of amino groups. The most common methods of synthesis of PA conjugates are acylation of regioselectively protected PAs or their alkylation under the conditions of the Fukuyama reaction. One of the most promising methods of PA synthesis is the use of a multicomponent Ugi reaction, which allows various PAs to be obtained in high yields. In this review, we describe and analyze various approaches that are used in the synthesis of polyamines and their conjugates.

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Section: Lipophilic Polyaminesmentioning

confidence: 99%

Recent Advances in the Synthesis of Polyamine Derivatives and Their Applications

2021

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“…Most of the known approaches regarding the synthesis of PA derivatives and their conjugates have several disadvantages [ 9 ], namely: (1) multistage synthetic procedures, (2) the introduction of orthogonal protective groups to block internal and terminal nitrogen atoms, (3) the low overall yield of the desired molecules, and (4) complicated purification procedures that are required for highly polar compounds. Following this approach, a synthetic scheme for the preparation of a family of PAs ( 6 ) containing an alkyl diglyceride fragment and an ethyl residue attached to terminal nitrogen atoms was developed in our laboratory [ 10 ]. Within this structure, the long-chain alkyl substituent (C 10 –C 18 ) was placed at the C(1) atom of glycerol, whereas the short-chain ethyl substituent was placed at C(2).…”

Section: Introductionmentioning

confidence: 99%

“…These data have been previously reported for AMXT-1501 with the palmitic acid residue [ 13 ]. In addition, we have previously shown that lipophilic PAs, where the lipophilic part is presented by a diglyceride fragment, also exhibit high anticancer activity [ 10 ]. Considering the results of the mentioned above studies, conjugation of PAs with the diglyceride fragment may have beneficial pharmacological potential.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel Lipophilic Polyamines via Ugi Reaction and Evaluation of Their Anticancer Activity

Nichugovskiy

Maksimova²,

Trapeznikova

et al. 2022

Molecules

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Natural polyamines (PAs) are involved in the processes of proliferation and differentiation of cancer cells. Lipophilic synthetic polyamines (LPAs) induce the cell death of various cancer cell lines. In the current paper, we have demonstrated a new method for synthesis of LPAs via the multicomponent Ugi reaction and subsequent reduction of amide groups by PhSiH3. The anticancer activity of the obtained compounds was evaluated in the A‑549, MCF7, and HCT116 cancer cell lines. For the first time, it was shown that the anticancer activity of LPAs with piperazine fragments is comparable with that of aliphatic LPAs. The presence of a diglyceride fragment in the structure of LPAs appears to be a key factor for the manifestation of high anticancer activity. The findings of the study strongly support further research in the field of LPAs and their derivatives.

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“…Ранее для поиска потенциальных противоопухолевых агентов нами был осуществлен синтез несимметричных конъюгатов ПА и алкильных глицеролипидов (рис. 1), который основан на взаимодействии бромпроизводных диглицеридов с региоселективно защищенными 2-нитробензолсульфониламидными производными ПА, последующем этилированием и удалением защитных групп [12]. Наибольшей противоопухолевой активностью обладали диалкилированные липофильные ПА на основе норспермина и триэтилентетрамина, при этом длина алкильного заместителя при С(1) атоме глицерина практически не влияла на способность соединений вызывать гибель раковых клеток.…”

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 of novel lipophilic tetraamines with cytotoxic activity

Cited by 9 publications

References 28 publications

Recent Advances in the Synthesis of Polyamine Derivatives and Their Applications

Recent Advances in the Synthesis of Polyamine Derivatives and Their Applications

Synthesis of Novel Lipophilic Polyamines via Ugi Reaction and Evaluation of Their Anticancer Activity

Amination of epoxides as a convenient approach for lipophilic polyamines synthesis

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