Synthesis and biological evaluation of a novel class of isatin analogs as dual inhibitors of tubulin polymerization and Akt pathway

Abstract

A novel series of 5,7-dibromoisatin analogs were synthesized and evaluated for their cytotoxicities against four human cancer cell lines including colon HT29, breast MCF-7, lung A549 and melanoma UACC903. Analogs 6, 11 and 13 displayed good in vitro anticancer activity on the HT29 human colon cancer cell line in the 1 µM range. Analogs 5, 9 and 12, containing a selenocyanate group in the alkyl chain were the most promising compounds on the breast cancer MCF-7 cell line. Biological assays relating to apoptosis were performed to understand the mechanism of action of these analogs. Compounds 5 and 6 were found to inhibit tubulin polymerization to the same extent as the anticancer drug vinblastine sulfate, but compounds 11 and 13 inhibited significantly better than vinblastine. Further western blot analysis suggested that compound 6 at 2 µM reduced both levels and phosphorylation state of Akt. Compounds 11 and 13 at 1 µM caused reduced Akt protein levels and strongly suppressed the phosphorylation of Akt. Therefore, 11 and 13 were demonstrated as efficient dual inhibitors of both tubulin polymerization and the Akt pathway and good candidates for further study. More importantly, the strategy of microtubule and Akt dual inhibitors might be a promising direction for developing novel drugs for cancer.

Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking

“…Decoy-set method An internal database was developed using 800 compounds containing 43 active structures collected from the reported literature [22][23][24][25][26][27][28][29][30][31][32] . The database was used to evaluate the discriminative ability of the best pharmacophore model when distinguishing the active compounds from the inactive compounds.…”

Comparative study of the cytotoxic properties of isatin-containing derivatives of 4-thiazolidinone with different structure toward human tumor cells in vitro

“…Вивчення взаємозв'язків між структурою та біологічною активністю ізатину показали, що заміщення атомів водню атомами галогену в молекулі ізатину (5-бромо-, 5-йодо-і 5-флуороізатин) призводить до 5-10-кратного зростання його токсичної дії щодо злоякісних клітин in vitro [8]. Зо-крема, цитотоксична активність 5,7-дибромоізатину щодо клітин лінії U937 гістіо-цитарної лімфоми людини є суттєво вищою порівняно з активністю батьківської сполуки -ізатину [6].…”

“…Після 24-х годин інкубації клітин лінії Jurkat з речовинами від-бирали 2×10 6 клітин, осаджували їх центрифугуванням при 1000 обертів/хв про-тягом 5 хв, ресуспендували в 1 мл охолодженого ЗФР. Клітини фіксували додаван-ням 4 мл абсолютного етанолу (-20 °C) і зберігали при -20 °С до використання (не більше 1 тижня).…”

Recent Highlights in the Development of Isatin-Based Anticancer Agents

“…Conversely, hybridisation of thiocyanate, isothiocyanate or selenocyanate moieties (potent inhibitors of the PI3K/Akt pathway) to 5,7-dibromoisatin (3h) afforded 12 novel 5,7-dibromo-Nalkylisatin derivatives that concomitantly inhibit tubulin polymerisation and phosphorylation of Akt [169]. Fig.…”