The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site

Abstract

Microtubule targeting agents (MTAs) that interfere with the dynamic state of the mitotic spindle are well-known and effective chemotherapeutic agents. These agents interrupt the microtubule network via polymerization or depolymerization, halting the cell cycle progression and leading to apoptosis. We report two novel pyrrole-based carboxamides (CAs) (CA-61 and -84) as the compounds exhibiting potent anti-cancer properties against a broad spectrum of epithelial cancer cell lines, including breast, lung, and prostate cancer. The anti-cancer activity of CAs is due to their ability to interfere with the microtubules network and inhibit tubulin polymerization. Molecular docking demonstrated an efficient binding between these ligands and the colchicine-binding site on the tubulin. CA-61 formed two hydrogen bond interactions with THR 179 (B) and THR 353 (B), whereas two hydrogen bonds with LYS 254 (B) and 1 with ASN 101 (A) were identified for CA-84. The binding energy for CA-84 and CA-61 was −9.910 kcal/mol and −9.390 kcal/mol. A tubulin polymerization assay revealed a strong inhibition of tubulin polymerization induced by CA-61 and -84. The immunofluorescence data revealed the disruption of the tubulin assembly in CA-treated cancer cells. As an outcome of the tubulin inhibition, these compounds halted the cell cycle progression in the G2/M phase, leading to the accumulation of the mitotic cells, and further induced apoptosis. Lastly, the in vivo study indicated that CAs significantly inhibited the HCC1806 breast cancer xenograft tumor growth in a nude mouse model. Collectively, we identified the novel CAs as potent MTAs, inhibiting tubulin polymerization via binding to the colchicine-binding site, disrupting the microtubule network, and exhibiting potent pro-apoptotic activities against the epithelial cancer cell lines both in vitro and in vivo.

Computational-Based Discovery of the Anti-Cancer Activities of Pyrrole-Based Compounds Targeting the Colchicine-Binding Site of Tubulin

“…To our knowledge, pyrrole and pyrrole-fused heterocycles are suitable to develop novel and effective scaffolds for drugs exhibiting anti-cancer activities due to the targeting of the CBS. Indeed, these scaffolds exhibit high capacities for expanding the chemical space of tubulin inhibitors due to the existence of the various ways to synthesize the derivatives with various functional groups, as well as a wide modification of existing candidate molecules [47][48][49][50][51][52][53].…”

Exploring Pyrrolo-Fused Heterocycles as Promising Anticancer Agents: An Integrated Synthetic, Biological, and Computational Approach

“…As such, it is increasingly evident that simple molecular docking approaches for ligand binding pose prediction by using X-ray structures of tubulin co-crystallized with structurally different molecular scaffolds can be challenging and have limited reliability. Although useful for medicinal chemistry, structural insights obtained from molecular docking studies alone regarding the interaction between pyrrole/pyrrole-fused heterocyclic derivatives and tubulin [ 6 , 25 , 26 ] can ultimately confuse novel design and development efforts in this class of tubulin inhibitors due to the possibility of questionable interpretation [ 27 ].…”

Study of Antioxidant Activity and Quantum-chemical Calculations of 2-aminopyrroles

“…При разработке нового метода определения антиоксидантной активности in vitro использовались результаты ДФПГ-теста антирадикальной активности для определения сходимости с результатами классических in vitro тестов антиоксидантной активности, а также квантово-химические расчеты, позволяющие оценить реакционную способность соединений в биологических системах за счет определения физико-химических параметров мо-лекулы. Исследование антиоксидантной и антирадикальной активности 2-аминопирролов дополняет актуальность исследования, поскольку позволяет раскрыть возможности перспективной группы веществ-цитостатиков, действие которых на опухолевую ткань может быть дополнено нарушением патологического баланса свободных форм кислорода [7][8][9][10].…”