Triphenylphosphine derivatives of allylbenzenes express anti-tumor and adjuvant activity when solubilized with cyclodextrin-based formulations

Zlotnikov, I.D.; Krylov, S.S.; Semenova, M.N.; Semenov, V.V.; Kudryashova, E.V.

Авторы: Zlotnikov Igor D., Krylov Sergey S., Semenova Marina N., Semenov Victor V., Kudryashova Elena V.
Журнал: Pharmaceuticals
Том: 16
Год издания: 2023
Издательство: MDPI
Местоположение издательства: Basel, Switzerland
Первая страница: 3367
Последняя страница: 3390
DOI: 10.3390/ph16121651
Аннотация: Abstract: Allylbenzenes (apiol, dillapiol, myristicin and allyltetramethoxybenzene) are individual 15 components of plant essential oils that demonstrate antitumor activity, and can enhance the anti-16 tumor activity of cytotoxic drugs, such as paclitaxel, doxorubicin, cisplatin, etc. Triphenylphosphine 17 (PPh3) derivatives of allylbenzenes are 2-3 orders of magnitude more potent than original allylbenzenes in terms of IC50. Inhibition of efflux pumps has been reported for allylbenzenes, and PPh3 19 moiety is deemed to be responsible for preferential mitochondrial accumulation and depolarization 20 of mitochondrial membranes. However, due to poor solubility the practical use of these substances 21 has never been an option. Here we show that this problem can be solved by the complex formation 22 with cyclodextrin (CD based molecular containers) and polyanionic heparin, stabilizing the positive 23 charge of PPh3-cation. Such containers can solubilize both allylbenzenes and their PPh3-derivatives 24 up to 0.4mM concentration. Further, we have observed that solubilized PPh3-derivatives indeed 25 work as adjuvants, increasing the antitumor activity of paclitaxel against adenocarcinomic human 26 alveolar basal epithelial cells A549 by an order of magnitude (in terms of IC50), in addition to being 27 quite powerful cytostatics themselves (IC50 in range from 1-10 μM). Even more important, the CD-28 solubilized PPh3-derivatives show pronounced selectivity, being highly toxic for tumor cells line 29 (A549), and minimally toxic for non-tumor cells HEK293T, red blood cells, and sea urchin embryos. 30 Indeed, in many cancers, mitochondrial membrane is more prone to depolarization, as compared to 31 normal cells, which probably explains the observed selectivity of our compounds, since PPh3-derivatives are known to act as mitochondria-targeting agents. According to the MTT test, 100 μM solution of PPh3-derivatives of allylbenzenes causes the death of up to 85% of cancer cells A549, while 34 for non-cancer cells HEK293T only 15-20% of the cells died. The hemolytic index of the studied 35 substances did not exceed 1%, and the thrombogenicity index < 1.5%. Thus, this study outlines the 36 experimental foundation for developing combined cytostatic medications, where effectiveness and 37 selectivity are achieved through decreased concentration of the primary ingredient and the inclusion of adjuvants, which are safe or practically harmless substances.
Добавил в систему: Кудряшова Елена Вадимовна

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№	Имя	Имя файла	Размер	Добавлен
1.	Полный текст	pharmaceuticals-16-01651.pdf	5,2 МБ	27 ноября 2023 [ElenaKudryashova]
2.	Полный текст	TFF_pharmaceuticals-2716345.pdf	2,2 МБ	20 ноября 2023 [ElenaKudryashova]
3.	сертификак публикации	Acceptance-Certificate-pharmaceuticals-2716345.pdf	241,7 КБ	21 ноября 2023 [ElenaKudryashova]

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Triphenylphosphine derivatives of allylbenzenes express anti-tumor and adjuvant activity when solubilized with cyclodextrin-based formulationsстатья

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