- Stereochemical variations on the colchicine motif. Part 2.1 Unexpected tetracyclic isoxazole derivatives
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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.
- Berg, Ulf,Bladh, Hakan,Hoff, Maria,Svensson, Christer
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- Synthesis of Thicolchicine-Based Conjugates: Investigation towards Bivalent Tubulin/Microtubules Binders
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Four different hybrid compounds have been efficiently synthesized by conjugation of deacetylthiocolchicine with pironetin-inspired derivatives. The modest bioactivity and the apparent absence of interaction with α-tubulin is explained by a posteriori in silico investigation, which suggests a relevant distance between the thiocolchicine binding site and the proper pocket on the α-tubulin. The modest activity on resistant cells suggested that the lipophilic nature of the linker used renders the resulting compounds better substrates for p-Gp efflux pumps. The study better clarifies the design of bivalent compounds that target hetero tubulin/microtubules.
- Bonandi, Elisa,Foschi, Francesca,Marucci, Cristina,Dapiaggi, Federico,Sironi, Maurizio,Pieraccini, Stefano,Christodoulou, Michael S.,de Asís Balaguer, Francisco,Díaz, J. Fernando,Zidar, Nace,Passarella, Daniele
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- Synthesis, anticancer activity and molecular docking studies of N-deacetylthiocolchicine and 4-iodo-N-deacetylthiocolchicine derivatives
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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.
- Klejborowska, Greta,Urbaniak, Alicja,Maj, Ewa,Wietrzyk, Joanna,Moshari, Mahshad,Preto, Jordane,Tuszynski, Jack A.,Chambers, Timothy C.,Huczyński, Adam
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- METHODS AND USES OF COLCHICINE DERIVATIVES
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Colchicine derivative(s), method(s) and use(s) thereof for treatment of inflammation. In certain embodiments, the colchicine derivative is a compound of Formula I: (I)
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- 7-Deacetyl-10-alkylthiocolchicine derivatives-new compounds with potent anticancer and fungicidal activity
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A series of new semi-synthetic 7-deacetyl-10-alkylthiocolchicne derivatives with ethyl, n-propyl, i-propyl and n-butyl substituents were synthesised and characterised by spectroscopic methods, elemental analysis, DFT calculations and molecular docking simulations. All the synthesized compounds have been tested for fungicidal and anticancer activities against SKOV-3, LoVo, MCF-7, MDA-MB-231 and the lung-derived fibroblast CCD39Lu. All the new colchicine derivatives exhibit significantly higher cytotoxicity towards the SKOV-3 tumour cell line than the natural product-colchicine. The most effective cytotoxic agents were 7-deacetyl-10-n-buthylthiocolchicine and 7-deacetyl-10-i-propylthiocolchicine. Among all the compounds tested, 7-deacetyl-10-n-buthylthiocolchicine exhibited the highest fungicidal activity. Molecular modeling indicated that several mutations found in the β-tubulin unit of the tested fungal strains are crucial for antifungal activity and selectivity of 7-deacetyl-10-n-buthylthiocolchicine. The obtained results may be useful for the development of selective colchicine derivatives as effective fungicidal and/or anticancer drugs.
- Kurek, Joanna,Kwa?niewska-Sip, Patrycja,Myszkowski, Krzysztof,Cofta, Grzegorz,Murias, Marek,Barczyński, Piotr,Jasiewicz, Beata,Kurczab, Rafa?
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supporting information
p. 1708 - 1714
(2018/10/26)
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- Synthesis, antiproliferative activity and molecular docking of thiocolchicine urethanes
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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.
- Majcher, Urszula,Urbaniak, Alicja,Maj, Ewa,Moshari, Mahshad,Delgado, Magdalena,Wietrzyk, Joanna,Bartl, Franz,Chambers, Timothy C.,Tuszynski, Jack A.,Huczyński, Adam
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p. 553 - 566
(2018/09/29)
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- Synthesis and antitumour activity of novel colchicine C-10 derivatives
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A series of new colchicine C-10 derivatives (2a-i, 3a-h) were synthesized by replacement of the 10-methoxy with NR2 and SCH3 in order to determine their cytotoxic activity. The compounds were synthesized in good yield and the structures of all newly synthesized compounds were established on the basis of their IR, 1H NMR and elemental analysis. The synthesized compounds were tested in vitro antitumor activity against four human cancer cell lines by MTT assay. It was found that many of the derivatives displayed significant activity, particularly, compound 2a and 2b showed more potent cytotoxic activities than colchicine.
- Shen, Li Hong,Zhang, Le,Wang, Hai Xian,Wang, Xin,Zhang, Gai Jiao
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p. 7475 - 7476
(2015/04/22)
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- Discovery of structurally simplified analogs of colchicine as an immunosuppressant
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We have discovered a new class of colchicine-derived therapeutic agents for immune diseases including rejection of organ-transplantation and autoimmune disease. Compound 2, which had been developed to overcome poor pharmacokinetic properties of compound 1, a first-generation colchicine analog, turned out to show toxicity such as intestinal toxicity and loss of weight during in vivo tests. The deletion of 7-carboxamide group and middle ring-truncation in colchicine allowed us to have structurally simplified analogs with strong immunosuppressive activity. Herein, we report non-alkaloid tricyclic compound 7 and 12 as immunosuppressants which exhibited a strong immunosuppressive in vivo efficacy on the T-dependent antibody response, the Zymosan A-induced arthritis model and the Carrageenan-induced edema model. Compound 7 and 12 revealed less toxicity than the previous lead compound 2, and their minimum lethal doses (MLD) were proved to exceed 100 mg/kg.
- Chang, Dong-Jo,Kim, Wan-Joo
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p. 3121 - 3125
(2014/06/24)
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- New synthetic thiocolchicine derivatives as low-toxic anticancer agents
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New thiocolchicine derivatives (1-8) were designed as less toxic anticancer agents possessing the powerful anticancer activity of colchicine. The synthesis and biological evaluation of these compounds were described. As a preliminary result of biological in vitro investigation, compounds 1, 6, and 7 showed lower toxicities than that of colchicine in combination with potent anticancer activities.
- Lee, Sun-Hee,Park, Sun-Kyoung,Kim, Jeong-Mi,Kim, Myung-Hwa,Kim, Kwang-Hee,Chun, Kwang-Woo,Cho, Kyung-Hea,Youn, Ji-Youn,Namgoong, Sung Keon
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p. 582 - 589
(2007/10/03)
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- Diagnostic or therapeutic somatostatin or bombesin analog conjugates and uses thereof
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Disclosed are peptide agents and uses thereof that are analogs of biologically active peptides such as somatostatin and bombesin. The compounds of the invention have the general formula X-Y-Z-Q, where X is a cytotoxic agent, therapeutic agent, detectable label or chelating group, and Q is a biologically active peptide. In peptide agents of the invention Y is optionally a hydrophilic polymer or peptide, and Z is a linking peptide bonded to Q at the amino terminus of Q, having two, three, four, or five, amino acid residues selected to link X to Q, while retaining the biological activity of Q. Methods of using these peptide agents in the diagnosis and treatment of diseases are also disclosed.
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(2008/06/13)
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- COLCHICINE DERIVATIVES
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Certain N-deacetylcolchicine and N-deacetylthiocolchine derivatives are described wherein the 7-N position on the B ring is substituted with the group —C(O)—(CHR4)m-AR, wherein m is an integer of 0-10, A is S, O, N or a covalent bond
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- TRICYCLIC DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, THEIR PREPARATIONS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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The present invention relates to tricyclic derivatives or pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them. More precisely, the present invention relates to tricyclic derivatives as colchicine derivatives, pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them. Tricyclic derivatives of the present invention show very powerful cytotoxicity to cancer cell lines but were much less toxic than colchicine or taxol, confirmed through animal toxicity test. Tricyclic derivatives of the invention also decrease the volume and weight of a tumor and have a strong angiogenesis inhibiting activity in HUVEC cells. Thus, tricyclic derivatives of the present invention can effectively be used as an anticancer agent, anti-proliferation agent and an angiogenesis inhibitor.
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- Antitumor Agents-CLXXV. Anti-tubulin action of (+)-thiocolchicine prepared by partial synthesis
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(+)-Thiocolchicine (2b) was prepared from (±)-colchicine (1) in a five-step reaction sequence that included chromatographic separation of appropriate camphanylated diastereomers. Acid hydrolysis of the (+)-diastereomer, followed by acetylation, yielded the desired product 2b. (+)-Thiocolchicine has 15-fold lower inhibitory activity against tubulin polymerization than (-)-thiocolchicine, and is 29-fold less potent for inhibiting growth of human Burkitt lymphoma cells. The enantiomer 2a, prepared from the (-)-camphanylated diastereomer, had potent activity in all assays comparable to that of (-)-thiocolchicine prepared by other methods. These results support the hypothesis that the proper configuration of colchicine-related compounds is an important requirement for their anti-tubulin action.
- Shi, Qian,Verdier-Pinard, Pascal,Brossi, Arnold,Hamel, Ernest,Lee, Kuo-Hsiung
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p. 2277 - 2282
(2007/10/03)
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- Antitumor Agents. 141. Synthesis and Biological Evaluation of Novel Thiocolchicine Analogs: N-Acyl-, N-Aroyl-, and N-(Substituted benzyl)deacetylthiocolchicines as Potent Cytotoxic and Antimitotic Compounds
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Three series of novel thiocolchicine analogs, N-acyl-, N-aroyl-, and N-(substituted benzyl)deacetylthiocolchicinoids, have been synthesized and evaluated for their cytotoxicity against various tumor cell lines, especially solid tumor cell lines, and for their inhibitory effects on tubulin polymerization in vitro. Most of these compounds showed strong inhibitory effects on tubulin polymerization comparable to that obtained with thiocolchicine and greater than that obtained with colchicine. Only compounds with a long side chain at C(7) position, such as 22-24, did not inhibit tubulin polymerization. Several of the active N-aroyldeacetylthiocolchicine analogs had positive optical rotations, in contrast to the negative optical rotation observed with most colchicinoids. This property might be attributed to a reversal of biaryl configuration from the normal aS to aR. Therefore, the N-aroyl analogs were further evaluated by circular dichroism, which readily distinguishes between the aS and aR biaryl configurations. This latter technique demonstrated that the active N-aroyl analogs do have an aS configuration despite their positive optical rotations. However, comparison of 1H NMR and UV spectral data of N-(substituted benzyl)deacetylthiocolchicines with those of corresponding N-aroyldeacetylthiocolchicines suggested a different biaryl dihedral angle . The similar tubulin binding properties of these compounds suggest that a biaryl dihedral angle of 53 deg is not essential for colchicinoid-tubulin interaction. The increased cytotoxicity of N-(substituted benzyl)deacetylthiocolchicines compared to the N-aroyldeacetylthiocolchicines may be attributed to different lipophilicity, drug uptake, or drug metabolism in the tumor cells. The side chain at the C(7) position affects inhibition of tubulin polymerization and the cytotoxic activity of colchicinoids as a function of its size and its contribution to lipophilicity.
- Sun, Li,Hamel, Ernest,Lin, Chii M.,Hastie, Susan B.,Pyluck, Amy,Lee, Kuo-Hsiung
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p. 1474 - 1479
(2007/10/02)
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- Thiocolchicinethiones: Acid Hydrolysis of Natural and iso-Isomers
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Thioketone 6 was prepared by thiation of isothiocolchicine (3) with Lawesson's reagent.Acid hydrolysis of 9-thiodeoxothiocolchicine (5) and the iso-isomer 6 afforded, in both cases, a similar mixture of deacetylthiocolchicine 2 and deacetylisothiocolchicine 4.Acetylation of 4 afforded isothiocolchicine 3.
- Muzaffar, Anjum,Brossi, Arnold
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p. 713 - 717
(2007/10/02)
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- Alkylthiocolchicines and N deacetyl alkylthiocolchicines and their antileukemic activity
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A series of alkylthiocolchicines (methyl, ethyl, n butyl, n hexyl, n octyl and pinanyl) was prepared from cholchicine by treatment with the appropriate alkyl mercaptan and p toluene sulfonic acid. Some of these compounds (methyl, ethyl, and n butylthiocolchicines) were deacetylated in good yields with 2 N hydrochloric acid in methanol. These compounds were tested for their antileukemic activity in an in vitro assay against L 1210 (mouse leukemia). Preliminary results showed that methylthiocolchicine is more active and the other alkylthiocolchicines are much less active than colchicine. N deacetyl methylthiocolchicine is as active as colchicine.
- Shiau,De,Harmon
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p. 646 - 648
(2007/10/06)
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