Anthracycline antitumor antibiotics are one of the promising classes of chemotherapeutic agents for cancer treatment. The main deterrent to their use is high toxicity to a healthy environment, including cumulative cardiotoxicity. In our work, bipharmacophore molecules containing in their structure a fragment of the known anthracycline antibiotics daunorubicin and doxorubicin and natural sesquiterpene lactones were obtained for the first time. When studying the biological activity of the synthesized compounds, it was found that with equal and, in some cases, higher cytotoxicity and glycolysis inhibition by anthracycline antibiotics conjugates with sesquiterpene lactones in comparison with doxo- and daunorubicin, a reduced damaging effect on the functioning of rat heart mitochondria was observed. The results obtained allow us to confirm the assumption that the chemical modification of the anthracycline antibiotics molecules doxo- and daunorubicin by natural sesquiterpene lactones can be a promising strategy for creating potential antitumor chemotherapeutic drugs with a pronounced cytotoxic effect on tumor cells and a reduced damaging effect on healthy cells of the human organism.

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Natural anthracycline antibiotics exhibit high antitumor activity. Their mechanism of action is based on inhibition of nucleic acid synthesis by intercalation between pairs of nitrogenous bases and binding to topoisomerase II [1]. This results in not only high antitumor activity but also low selectivity and side effects [2]. The selectivity can be increased and the side effects decreased by modifying anthracycline antibiotics with natural sesquiterpene lactones. We demonstrated that the Michael reaction [3] can be used to combine into one molecule fragments of the antitumor anthracycline antibiotics daunorubicin (1a) and doxorubicin (1b) and natural alantolactone (2).The antiproliferative activity of the obtained conjugates in vitro in human tumor-cell cultures showed that the conjugate of alantolactone with daunorubicin (3a) was 3-5 times more active with equal toxicity for normal renal epithelium cells. Our results suggested that the new conjugates of sesquiterpene lactones with anthracycline antibiotics were promising for producing more active and less toxic drugs.High-resolution mass spectra were recorded on a Thermo Fisher Exactive Orbitrap mass spectrometer with a mass analyzer using orthogonal ion injection and electrospray ionization. Solutions in MeCN at concentration ~10 5 M were ionized. The resulting m/z value corresponded to a peak for the protonated molecular ion. PMR and 13 C NMR spectra were recorded using TMS as an internal standard on a Bruker Avance III instrument (500.13 and 125.78 MHz). The symbols D and E in the interpreted spectra denoted non-equivalent protons on the same C atom. Equipment of the CCU, IPAC, RAS was used (Contract No. 14.621.21.0008, identifier RFMEFI62114X0008).Preparation of Daunorubicin Base. Daunorubicin hydrochloride (1 g) was dissolved in H 2 O (200 mL) in a separatory funnel and treated with CHCl 3 (100 mL) and NaHCO 3 to transfer the colored anthracycline base into the organic (lower) layer, which was drained off and evaporated. Daunorubicin remaining in the aqueous phase was extracted (3u) with CHCl 3 (50 mL each time).Compound 3a. Alantolactone (100 mg, 0.431 mmol) was dissolved in MeOH (3 mL) and treated with daunorubicin base (250 mg, 0.474 mmol). The course of the reaction was monitored by TLC on Silufol plates using CHCl 3 -MeOH (4:1, R f of 3a, 0.77). When the reaction was finished, the mixture was evaporated at reduced pressure. The residue was rinsed with MeOH and purified by column chromatography over silica gel (15 g) with elution first by CHCl 3 and then by a mixture with

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A method for modifying sesquiterpene lactones using the click chemistry methodology has been developed. A series of conjugates of alantolactone and dehydrocostus lactone with alkoxy substituted benzylazides was obtained and their cytotoxic profile with respect to tumor cells of the A549, SH-SY5Y, Hep-2 and HeLa lines was evaluated. It has been shown that derivatives containing dehydrocostus lactone motif in their structure exhibit the highest cytotoxic activity.