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.

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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