Влияние комбинации цисплатина с брассиностероидами на рост раковых клеток

In this work, the effect of brassinosteroids on the antitumor activity of classical cytostatic cisplatin in tumor cell lines A549 (human lung carcinoma) and Hep G2 (human hepatocellular carcinoma) was evaluated. Natural brassinosteroids 24-epibrassinolide and 28-homocastasterone, as well as their synthetic analogues (22S,23S)-24-epibrassinolide and (22S,23S)-28-homocastasterone were used. All four compounds with cisplatin inhibited the growth of cancer cells more effectively than cisplatin alone. Combinations with low concentrations of synthetic brassinosteroids were more effecient, and at 1 µM decreased the IC50 of cisplatin by almost 2 times. The results suggest a possible benefit of combinations of classical antitumor drugs with brassinosteroids in overcoming the negative effects of chemotherapy by reducing their effective doses.Изучено влияние природных брассиностероидов 24-эпибрассинолида и 28-гомокастастерона, а также их синтетических аналогов (22S,23S)-24-эпибрассинолида и (22S,23S)-28-гомокастастерона на противоопухолевую активность классического цитостатика цисплатина на опухолевых линиях A549 (карцинома легких человека) и Hep G2 (карцинома печени человека). Все четыре соединения в сочетании с цисплатином ингибировали рост раковых клеток. Более эффективными были комбинации с низкими концентрациями синтетических брассиностероидов. При концентрации брассиностероидов в 1 мкМ IC50 цисплатина уменьшалась почти в 2 раза. Полученные результаты свидетельствуют о возможности снижения эффективных доз классических противоопухолевых препаратов путем их использования в комбинации с брассиностероидами, что способствовало бы смягчению негативных последствий химиотерапии

АНТИКАНЦЕРОГЕННАЯ АКТИВНОСТЬ БРАССИНОСТЕРОИДОВ В ОПУХОЛЕВЫХ КЛЕТКАХ КАРЦИНОМЫ ПЕЧЕНИ

In this study, we first characterized the effect of natural brassinosteroids, 24-epibrassinolide (EBl) and 28-homocastasterone (HCS), and synthetic analogs, (22S,23S)-24-epibrassinolide and (22S,23S)-28-homocastastone, on the growth of the cancer cell line Hep G2 (hepatocellular carcinoma), as well as on the catalytic activity of cytochrome P450, which participates in the metabolism of most procarcinogens. All four compounds at high concentrations suppressed the proliferation of the test cell line. It is also interesting that at low concentrations, 24-EBl, (22S,23S)-24-EBl and (22S,23S)28-HCS activated significantly the Hep G2 cell growth. All studied brassinosteroids, except for 28-HCS, inhibited the activity of CYP1A1 and CYP1B1. The effect depended on the structure of the side chain and was more pronounced in the case of the SS orientation of the hydroxyl groups at the positions C22 and C23 ((22S,23S)-28-homocastasterone). The results of this work suggest that the studied brassinosteroids (especially (22S,23S)-28-homocastasterone) can be used to create effective drugs for tumor prevention and treatment.Впервые охарактеризовано влияние природных брассиностероидов 24-эпибрассинолида (24-ЭБ) и 28-гомокастастерона (28-ГКС), а также синтетических аналогов (22S,23S)-24-эпибрассинолида и (22S,23S)-28-гомокастастерона на пролиферацию активности в раковой клеточной линии Hep G2 (карцинома печени), а также на каталитическую активность цитохрома P450, который участвует в метаболизме большинства проканцерогенов. Все четыре соединения при высоких концентрациях были активными в подавлении клеточной пролиферации исследуемой линии. Интересным является и тот факт, что при низких концентрациях 24-ЭБ, (22S,23S)-24-ЭБ и (22S,23S)-28-ГКС достоверно активировали рост клеток Hep G2. Все исследуемые брассиностероиды ингибировали активность CYP1A1 и CYP1B1, за исключением 28-ГКС. Оказываемый эффект зависел от структуры боковой цепи и был более выражен в случае SSориентации гидроксильных групп в положении C22 и С23 ((22S,23S)-28-гомокастастерон). Полученные результаты указывают на возможность использования исследуемых брассиностероидов (в наибольшей степени (22S,23S)-28-ГКС) для создания более эффективных препаратов для профилактики и лечения опухолевых заболеваний.

Relative and Absolute Configuration of Allohedycaryol. Enantiospecific Total Synthesis of Its Enantiomer

The enantiomer of (+)-allohedycaryol, a germacrane alcohol isolated from giant fennel (Ferula communis L.), has been synthesized, thereby elucidating the relative and absolute stereochemistry of the natural product. The synthesis of (-)-allohedycaryol started from (+)-α-cyperone (5) which was available in relatively large quantities via alkylation of imine 7 derived from (+)-dihydrocarvone and (R)-(+)-1-phenylethylamine. In a number of steps 5 was converted into the mesylate 4 with a regio- and stereoselective epoxidation as the key step. A Marshall fragmentation of 4 was used to prepare the trans,trans-cyclodeca-1,6-diene ring present in allohedycaryol. The conformation of synthetic (-)-allohedycaryol was elucidated via photochemical conversion into a bourbonane system. The synthesis of (-)-allohedycaryol also showed that natural (+)-allohedycaryol has the opposite absolute stereochemistry to that normally found in higher plants.

Synthesis of [7,7-2H2]epibrassinolide

Synthesis of labelled epibrassinolide containing two deuterium atoms in a position which is not subjected to isotopic exchange is reported. Key transformations include preparation of 6,7-seco steroidal diacid, its cyclization to a cyclic anhydride followed by a regioselective reduction with NaBD4. The obtained [7,7-2H2]epibrassinolide can be used in biochemical experiments when the loss of isotopic label should be avoide

Visible Light-Promoted Catalytic Ring-Opening Isomerization of 1,2-Disubstituted Cyclopropanols to Linear Ketones

In this article, we report a photocatalytic protocol for the isomerization of 1,2-disubstituted cyclopropanols to linear ketones. The reaction proceeds via radical intermediates and tolerates various functional groups

Palladium-Catalyzed 2-(Neopentylsulfinyl)aniline Directed C-H Acetoxylation and Alkenylation of the Arylacetamides

A directing group that promotes very fast diacetoxylation of the arylacetamides is reported. The auxiliary also promotes alkenylation with vinyl ketones, which were generated in one-pot from the cyclopropanols

Synthesis of ergostane-type brassinosteroids with modifications in ring A

Herein, we present a new strategy for the preparation of a broad range of brassinosteroid biosynthetic precursors/metabolites differing by the ring A fragment. The protocol is based on the use of readily available phytohormones of this class bearing a 2α,3α-diol moiety (epibrassinolide or epicastasterone) as starting materials. The required functionalities (Δ2-, 2α,3α- and 2β,3β-epoxy-, 2α,3β-, 2β,3α-, and 2β,3β-dihydroxy-, 3-keto-, 3α- and 3β-hydroxy-, 2α-hydroxy-3-keto-) were synthesized from 2α,3α-diols in a few simple steps (Corey–Winter reaction, epoxidation, oxidation, hydride reduction, etc.)

New synthesis of castasterone

An improved synthesis that could produce gram quantities of castasterone was proposed. The starting material was stigmasterol, the cyclic part of which was transformed in the first synthetic step into the 3α,5-cyclo-6-ketone. The side-chain carbon skeleton in the target compound was constructed with the required stereochemistry of the C-24 methyl via addition of methylacetylene, hydrogenation of the propargyl alcohol over Lindlar catalyst, and Claisen rearrangement. Diols were introduced using Sharpless asymmetric dihydroxylation of the intermediate ∆2,22-dienone in the presence of (DHQD)2AQN. A unique feature of the synthesis was the avoidance of chromatographic separations of propargyl alcohols with similar chromatographic mobilities because the C-22 diastereomers were enriched in subsequent redox reactions

New synthesis of castasterone

An improved synthesis that could produce gram quantities of castasterone was proposed. The starting material was stigmasterol, the cyclic part of which was transformed in the first synthetic step into the 3α,5-cyclo-6-ketone. The side-chain carbon skeleton in the target compound was constructed with the required stereochemistry of the C-24 methyl via addition of methylacetylene, hydrogenation of the propargyl alcohol over Lindlar catalyst, and Claisen rearrangement. Diols were introduced using Sharpless asymmetric dihydroxylation of the intermediate ∆2,22-dienone in the presence of (DHQD)2AQN. A unique feature of the synthesis was the avoidance of chromatographic separations of propargyl alcohols with similar chromatographic mobilities because the C-22 diastereomers were enriched in subsequent redox reactions