2731-16-0Relevant articles and documents
Stereochemical variations on the colchicine motif. Part 2.1 Unexpected tetracyclic isoxazole derivatives
Berg, Ulf,Bladh, Hakan,Hoff, Maria,Svensson, Christer
, p. 1697 - 1704 (1997)
Attempts to expand the colchicine B-ring in 7-oxodeacetamidothiocolchicine 1 by a Beckmann-type rearrangement lead to unexpected tetracyclic isoxazole derivatives 2 and 3. The syntheses, crystal and solution structures, conformational interconversions and binding properties to tubulin are reported. The molecules exist as mixtures of two enantiomeric conformations due to hindered rotation around the A and C rings, which are twisted by dihedral angles of 62° (1) and 46° (2) in the crystal. Solid, solution and gas phase (according to MM2) structures are compared. Dynamic 1H NMR analyses give the following thermodynamic parameters for the rotation around the A-C pivot bond: (1) ΔG?381 K = 77.4; (2) ΔG?300 K = 60.7; ΔH? = 55.6 ± 1.6 kJ mol-1; ΔS? = -16.7 ± 15 J mol-1 K-1; (3) ΔG?298 K = 60.1, ΔH? = 59.9 ± 2.0 J mol-1 and ΔS? = -0.7 ± 15 J mol-1 K-1. The drugs 1 and 2 depolymerize microtubules by binding to tubulin according to both in vitro and in vivo studies, but 1 is considerably more active than 2. Compound 3 does not seem to bind notably to tubulin.
Synthesis, anticancer activity and molecular docking studies of N-deacetylthiocolchicine and 4-iodo-N-deacetylthiocolchicine derivatives
Klejborowska, Greta,Urbaniak, Alicja,Maj, Ewa,Wietrzyk, Joanna,Moshari, Mahshad,Preto, Jordane,Tuszynski, Jack A.,Chambers, Timothy C.,Huczyński, Adam
, (2021/02/05)
Colchicine is a plant alkaloid with a broad spectrum of biological and pharmacological properties. It has found application as an anti-inflammatory agent and also shows anticancer effects through its ability to destabilize microtubules by preventing tubulin dimers from polymerizing leading to mitotic death. However, adverse side effects have so far restricted its use in cancer therapy. This has led to renewed efforts to identify less toxic derivatives. In this article, we describe the synthesis of a set of novel double- and triple-modified colchicine derivatives. These derivatives were tested against primary acute lymphoblastic leukemia (ALL-5) cells and several established cancer cell lines including A549, MCF-7, LoVo and LoVo/DX. The novel derivatives were active in the low nanomolar range, with 7-deacetyl-10-thiocolchicine analogues more potent towards ALL-5 cells while 4-iodo-7-deacetyl-10-thiocolchicine analogues slightly more effective towards the LoVo cell line. Moreover, most of the synthesized compounds showed a favorable selectivity index (SI), particularly for ALL-5 and LoVo cell lines. Cell cycle analysis of the most potent molecules on ALL-5 and MCF-7 cell lines revealed contrasting effects, where M-phase arrest was observed in MCF-7 cells but not in ALL-5 cells. Molecular docking studies of all derivatives to the colchicine-binding site were performed and it was found that five of the derivatives showed strong β-tubulin binding energies, lower than ?8.70 kcal/mol, while the binding energy calculated for colchicine is ?8.09 kcal/mol. The present results indicate that 7-deacetyl-10-thiocolchicine and 4-iodo-7-deacetyl-10-thiocolchicine analogues constitute promising lead compounds as chemotherapy agents against several types of cancer.
Synthesis, antiproliferative activity and molecular docking of thiocolchicine urethanes
Majcher, Urszula,Urbaniak, Alicja,Maj, Ewa,Moshari, Mahshad,Delgado, Magdalena,Wietrzyk, Joanna,Bartl, Franz,Chambers, Timothy C.,Tuszynski, Jack A.,Huczyński, Adam
, p. 553 - 566 (2018/09/29)
A number of naturally occurring compounds such as paclitaxel, vinblastine, combretastatin, and colchicine exert their therapeutic effect by changing the dynamics of tubulin and its polymer form, microtubules. The identification of tubulin as a potential target for anticancer drugs has led to extensive research followed by clinical development of numerous compounds from several families. In this paper we report on the design, synthesis and in vitro evaluation of a group of thiocolchicine derivatives, modified at ring-B, labelled here compounds 4–14. These compounds have been obtained in a simple reaction of 7-deacetyl-10-thiocolchicine 3 with eleven different alcohols in the presence of triphosgene. These novel agents have been checked for anti-proliferative activity against four human cancer cell lines and their mode of action has been confirmed as colchicine binding site inhibition (CBSI) using molecular docking. Molecular simulations provided rational tubulin binding models for the tested compounds. On the basis of in vitro tests, derivatives 4–8 and 14 demonstrated the highest potency against MCF-7, LoVo and A549 tumor cell lines (IC50 values = 0.009–0.014 μM). They were more potent and characterized by a higher selectivity index than several standard chemotherapeutics including cisplatin and doxorubicin as well as unmodified colchicine. Further, studies revealed that colchicine and its several derivatives arrested MCF-7 cells in mitosis, while its selected derivatives caused microtubule depolymerization.