No abstract

В обзоре приведены и проанализированы сведения, характеризирующие фармакотерапевтический потенциал оловоорганических соединений (ООС) и токсикологический профиль кандидатов в лекарственные средства (ЛС), изученных на различных видах лабораторных животных. Для ряда ООС установлена противоопухолевая и антиметастатическая активность в экспериментах in vivo на некоторых опухолевых моделях. Результаты анализа литературы будут использованы при планировании дальнейших доклинических исследований субстанций: для выбора наиболее перспективных ООС, оптимального пути введения их в организм, моделей опухолевых процессов и т. д. В качестве потенциально значимых были определены ООС, содержащие антиоксидантный протекторный фрагмент 2,6-ди-трет-бутилфенола, а также модели перевиваемых опухолей — меланома В16 и эпидермоидная карцинома легкого Lewis и агенты для приготовления суспензии (желатин, крахмал).

This review analyzed the literature data on the in vitro preclinical study of the cytotoxic properties of organotin compounds, as well as the main mechanisms of their action. The latter consist in interacting with SH groups of proteins, initiating oxidative stress, binding to DNA, interacting with receptors, as well as activate apoptosis by increasing the expression of caspases, proapoptotic proteins, and decreasing antiapoptotic proteins. Organotin compounds, depending on the donor ligand, exhibit specifi c cytotoxicity towards certain tumor cell lines. The high cytotoxic potential indicates the possibility of further development in vivo and research of organotin compounds as candidates for the creation of drugs for anticancer and antimetastatic therapy.

The aim of the study was to evaluate the safety of the use of organotin compounds containing a fragment of 2,6-di-tert-butylphenol as pharmaceutical substances when administered intragastrically to Wistar outbred rats (females). Material and methods. The objects of the study were three organotin compounds: ((3,5-di-tertbutyl-4-hydroxyphenylthiolate) triphenyltin (Me-5), (3,5-di-tert-butyl-4-hydroxyphenylthiolate)trimethyltin (Me-4), bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate) dimethyltin (Me-3). Acute toxicity study were performed on 106 Wistar rats (female) weighing 190-210 g by "fixed dose" and "up and down" methods according to the OECD protocols. Results. According to the harmonized system of hazard classification and labeling of chemical products (GHS) the studied organotin compounds should be assigned to the following toxicity classes: Me-5 — IV, Me-3 — V, Me-4 — II. Average lethal dose in intragastric administration for Me-5 is LD50 = 955.0 ± 58.3 mg/kg, the value of LD50 for Me-3 is conventionally assumed to be much more than 2000 mg/kg, for Me-4 is in the range of 5 to 50 mg/kg. Discussion. The modification of tin-organic molecules in the course of directed synthesis opens broad prospects for the creation of a new class of anticancer drugs. In the course of the experimental study, the regularities of the "structure-toxicity" relationship of organic tin derivatives were revealed: the introduction of the 2,6-di-tert-butylphenol group significantly reduces toxicity compared to the corresponding initial substances; methyl derivatives are more toxic than their phenyl analogues. Compounds of GHS toxicity classes IV and V can be considered as leading candidates for promising preclinical studies in the field of experimental oncology. Conclusion. Substances of Me-3 and Me-5, which have the highest safety for intragastric use, were recommended for further study as antitumor drug agents.