Synthesis, biological evaluation and molecular docking studies of new amides of 4-bromothiocolchicine as anticancer agents. Issue 23 (1st December 2019)

• Record Type: Journal Article
• Authors: Klejborowska, Greta; Urbaniak, Alicja; Preto, Jordane; Maj, Ewa; Moshari, Mahshad; Wietrzyk, Joanna; Tuszynski, Jack A.; Chambers, Timothy C.; Huczyński, Adam
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 23(2019)
• Publication Date: 2019-12-01
• Subjects: IAKHMKGGTNLKSZ-INIZCTEOSA-N -- NUYSHVFRJHAPSA-HNNXBMFYSA-N -- LLFBPNMSLVUHNP-HNNXBMFYSA-N -- XJBAJLRTEDWFGL-ZDUSSCGKSA-N -- FXNVGRHOXRSZDE-HNNXBMFYSA-N -- RTQOPDUFPFFLPZ-INIZCTEOSA-N -- OSRZHSDXBKTPCP-IBGZPJMESA-N -- IZZHBIUGMGQIAK-HNNXBMFYSA-N -- WUYQDYOIAGOGFK-INIZCTEOSA-N -- CORKGTHLKVMUAN-QFIPXVFZSA-N -- ZMVUPVYOCPDGBL-KRWDZBQOSA-N; Anticancer activity -- Tubulin inhibitors -- Triple-modified colchicine -- Amides -- Mechanistic investigation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115144
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Novel triple-modified colchicine derivatives were designed and synthesized as anti-cancer agents. Some of compounds were active in the nanomolar range against several different cancer cell lines. The antiproliferative activity results were validated with molecular docking simulation study with the tubulin protein. Colchicine derivatives show favorable activity comparing to their parent molecule. Abstract: Colchicine is the major alkaloid isolated from the plant Colchicum autumnale, which shows strong therapeutic effects towards different types of cancer. However, due to the toxicity of colchicine towards normal cells its application is limited. To address this issue we synthesized a series of seven triple-modified 4-bromothiocolchicine analogues with amide moieties. These novel derivatives were active in the nanomolar range against several different cancer cell lines and primary acute lymphoblastic leukemia cells, specifically compounds: 5–9 against primary ALL-5 (IC50 = 5.3–14 nM), 5, 7–9 against A549 (IC50 = 10 nM), 5, 7–9 against MCF-7 (IC50 = 11 nM), 5–9 against LoVo (IC50 = 7–12 nM), and 5, 7–9 against LoVo/DX (IC50 = 48–87 nM). These IC50 values were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies revealed that colchicine and selected analogues induced characteristics of apoptotic cell death but manifested their effects in different phases of the cell cycle in MCF-7 versus ALL-5 cells. Specifically, while colchicine and the studied derivatives arrested MCF-7 cells in mitosis, very little mitotically arrested ALL-5 cells were observed, suggesting effects were manifest instead in interphase. We also developed an in silico model of the mode of binding of these compounds to their primary target, β-tubulin. We conducted a correlation analysis (linear regression) between the calculated binding energies of colchicine derivatives and their anti-proliferative activity, and determined that the obtained correlation coefficients strongly depend on the type of cells used.