synthesis biological evaluation and molecular docking studies of new amides of 4 chlorothiocolchicine as anticancer agents

Abstract Colchicine belongs to a large group of microtubule polymerization inhibitors. Although the anti-cancer activity of colchicine and its derivatives has been established, none of them has found commercial application in cancer treatment due to side effects. Therefore, we designed and synthesized a series of six triple-modified 4-chlorothiocolchicine analogues with amide moieties and one urea derivative. These novel derivatives were tested against several different cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and primary acute lymphoblastic leukemia (ALL) cells and they showed activity in the nanomolar range. The obtained IC50 values for novel derivatives were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies of colchicine and selected analogues were undertaken to indicate that they induced apoptotic cell death in ALL-5 cells. We also performed in silico studies to predict binding modes of the 4-chlorothiocolchicine derivatives to different β tubulin isotypes. The results indicate that select triple-modified 4-chlorothiocolchicine derivatives represent highly promising novel cancer chemotherapeutics

Synthesis, biological evaluation and molecular docking studies of new amides of 4-bromothiocolchicine as anticancer agents

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

Molecular Insights in Psychiatry

This Special Issue included articles discussing several important psychiatric phenomena whose elucidation can be provided by cellular and subcellular molecular mechanisms [...

Quantum Brain Dynamics and Holography

We describe non-equilibrium quantum brain dynamics (QBD) for the breakdown of symmetry and propose the possibility of hologram memory based on QBD. We begin with the Lagrangian density of QBD with water rotational dipole fields and photon fields in 3+1 dimensions, and derive time evolution equations of coherent fields. We show a solution for super-radiance derived from the Lagrangian of QBD and propose a scenario of holography by the interference of two incident super-radiant waves. We investigate the time evolution of coherent dipole fields and photon fields in the presence of quantum fluctuations in numerical simulations. We find that the breakdown of the rotational symmetry of dipoles occurs in inverted populations for incoherent dipoles. We show how the waveforms of holograms with interference patterns evolve over time in an inverted population for incoherent dipoles. The optical information of hologram memory can be transferred to the whole brain during information processing. The integration of holography and QBD will provide us with a prospective approach in memory formation

Computational Prediction and Experimental Validation of the Unique Molecular Mode of Action of Scoulerine

Scoulerine is a natural compound that is known to bind to tubulin and has anti-mitotic properties demonstrated in various cancer cells. Its molecular mode of action has not been precisely known. In this work, we perform computational prediction and experimental validation of the mode of action of scoulerine. Based on the existing data in the Protein Data Bank (PDB) and using homology modeling, we create human tubulin structures corresponding to both free tubulin dimers and tubulin in a microtubule. We then perform docking of the optimized structure of scoulerine and find the highest affinity binding sites located in both the free tubulin and in a microtubule. We conclude that binding in the vicinity of the colchicine binding site and near the laulimalide binding site are the most likely locations for scoulerine interacting with tubulin. Thermophoresis assays using scoulerine and tubulin in both free and polymerized form confirm these computational predictions. We conclude that scoulerine exhibits a unique property of a dual mode of action with both microtubule stabilization and tubulin polymerization inhibition, both of which have similar affinity values