- 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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- 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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- 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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- 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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- Photochemical Isomerization of Colchicine and Thiocolchicine
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The photochemical reactivity of colchicine and thiocolchicine is described. Although the irradiation of colchicine gave a well-known transposition reaction to β- and γ-lumicolchicines, thiocolchicine did not react. Femtosecond transient spectroscopy of colchicine showed a strong band with maximum at 510 nm appearing at τ = 0. It disappeared within few hundred femtoseconds, leaving a broad structureless band with a maximum around 470 nm. A second band is observed around 410 nm. The analysis in time showed that the 510-nm component appeared instantaneously and decayed following a biexponential low with time constants of 300 ± 100 fs and 40 ps. The kinetics at 420 nm has a measurable rise time of 300 ± 150 fs. Quantum mechanical calculations on colchicine showed that this absorption is due to a S 1 → S11 transition. In thiocolchicine, the instantaneous formation of a structure with maxima out of the investigated spectral region was observed. A strong absorption around 650 nm indicated the presence of a band with a maximum at longer wavelengths (> 700 nm) and a peak around 380 nm, which partially coincides with the ground-state absorption and therefore strongly affected by its bleaching. The instantaneous formation of an absorption around 650 nm and its rapid (～500 fs) decay was observed. At shorter wavelengths (400 nm), the decay was fitted with a biexponential curve with the first time constant of about 80 ps. The second part of the decay had a very long tail up to 500 ps. Transient spectroscopy and configuration interaction calculations are in agreement with a mechanism involving a disrotatory cyclization of colchicine in its first excited singlet state. The lack of reactivity observed in thiocolchicine was explained by considering the presence of efficient ISC to the triplet state.
- Bussotti, Laura,Cacelli, Ivo,D'Auria, Maurizio,Foggi, Paolo,Lesma, Giordano,Silvani, Alessandra,Villani, Vincenzo
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- Derivatives of thiocolchicine and its applications to CEM cells treatment using 19F Magnetic Resonance ex vivo
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It was shown, that cultured ex vivo human T-Lymphoblastoid (CEM) cells respond to synthesized thiocolchicine and fluorine thiocolchicine derivatives. The preparation of derivatives with substitution at C-3 and C-7 is described. All compounds were used at concentration from 1 nM to 1000 nM. Inhibitory effects of these compounds were examined in the three-dimensional (3-D) culture and cells morphology during treatment was monitored using 9.4 T MRI system. We performed studies of these compounds in CEM cells ex vivo using 1H and 19F Magnetic Resonance Imaging (MRI), 19F Magnetic Resonance Spectroscopy (MRS), High Performance Liquid Chromatography coupled with Ultra Violet (HPLC-UV) and Electron Impact Mass Spectrometry (EIMS). The results of the multi-technique approach are consistent with the fact that the new derivatives are more efficient than colchicine and thiocolchicine ex vivo. Crown Copyright
- Bartusik, Dorota,Tomanek, Boguslaw,Lattova, Erika,Perreault, Helene,Tuszynski, Jack,Fallone, Gino
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- Antiproliferative activity and molecular docking of novel double-modified colchicine derivatives
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Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticancer agent with a known antimitotic effect on cells. However, the use of colchicine as well as many of its derivatives in long-term treatment is hampered by their high toxicity. To create more potent anticancer agents, three novel double-modified colchicine derivatives have been obtained by structural modifications in C-4 and C-10 positions. The binding affinities of these derivatives of colchicine with respect to eight different isotypes of human β-tubulin have been calculated using docking methods. In vitro cytotoxicity has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo and LoVo/DX). Computer simulations predicted the binding modes of these compounds and hence the key residues involved in the interactions between tubulin and the colchicine derivatives. Two of the obtained derivatives, 4-bromothiocolchicine and 4-iodothiocolchicine, were shown to be active against three of the investigated cancer cell lines (A549, MCF-7, LoVo) with potency at nanomolar concentrations and a higher relative affinity to tumor cells over normal cells.
- Majcher, Urszula,Klejborowska, Greta,Moshari, Mahshad,Maj, Ewa,Wietrzyk, Joanna,Bartl, Franz,Tuszynski, Jack A.,Huczyński, Adam
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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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- 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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(2020/01/24)
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- Synthesis and antiproliferative screening of novel analogs of regioselectively demethylated colchicine and thiocolchicine
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Colchicine, a pseudoalkaloid isolated from Colchicum autumnale, has been identified as a potent anticancer agent because of its strong antimitotic activity. It was shown that colchicine modifications by regioselective demethylation affected its biological properties. For demethylated colchicine analogs, 10-demethylcolchicine (colchiceine, 1) and 1-demethylthiocolchicine (3), a series of 12 colchicine derivatives including 5 novel esters (2b-c and 4b-d) and 4 carbonates (2e-f and 4e- f) were synthesized. The antiproliferative activity assay, together with in silico evaluation of physicochemical properties, confirmed attractive biological profiles for all obtained compounds. The substitutions of H-donor and H-acceptor sites at C1 in thiocolchicine position provide an efficient control of the hydration affinity and solubility, as demonstrated for anhydrate 3, hemihydrate 4e and monohydrate 4a.
- Czerwonka, Dominika,Huczyński, Adam,Katrusiak, Andrzej,Maj, Ewa,Sobczak, Szymon,Wietrzyk, Joanna
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supporting information
(2020/03/17)
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- Synthesis of sulfur containing colchicine derivatives and their biological evaluation as cytotoxic agents
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Semi-synthetic C-10 alkyl thio analogues of the cytotoxic natural alkaloid colchicine have been found to exhibit cytotoxicity towards tumour cell lines at levels comparable to that of the natural product. An efficient synthesis of 10-alkyl thiocolchicines in mild conditions is proposed and the products are studied by 1H and 13C NMR, FT-IR, MS-EI methods and elementary analysis. The crystal structure of 10-ethylthiocolchicine is characterised using X-ray diffraction methods. Cytotoxic activity against selected cancer cell lines for all obtained 10-alkylthio analogues of colchicine is also reported.
- Kurek, Joanna,Boczon, Wladyslaw,Myszkowski, Krzysztof,Murias, Marek,Borowiak, Teresa,Wolska, Irena
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p. 279 - 289
(2014/03/21)
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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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- NOVEL COLCHICINE DERIVATIVES, METHODS AND USES THEREOF
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The invention relates to colchicine derivatives, methods and uses thereof for treatment of cancer. In certain embodiments, the colchicine derivative comprises a compound of formula (I), wherein Z is O or S; R1 is selected fro H, a halo group, a substituted or unsubstituted hydrocarbon group, or a substituted or unsubstituted heterogeneous group; R2 and R3 are each independently selected from H, a halo group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic; R is selected from H or a substituted or unsubstituted hydrocarbon group, with the proviso that when R, R2 and R3 are methyl groups, R1 is not -COCH3.
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(2011/04/14)
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- Design, synthesis and identification of novel colchicine-derived immunosuppressant
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Synthesis and biological evaluation of various colchicine analogues through the mixed-lymphocyte reaction (MLR), lymphoproliferation, and inhibitory effects on the inflammatory genes are described. In addition, a new series of immunosuppressive agents developed on the structural basis of colchicine, as well as their structure-activity relationships is reported. The most potent analogue 20a exhibited an excellent immunosuppressive activity on in vivo skin-allograft model, which is comparable to that of cyclosporin A.
- Chang, Dong-Jo,Yoon, Eun-Young,Lee, Geon-Bong,Kim, Soon-Ok,Kim, Wan-Joo,Kim, Young-Myeong,Jung, Jong-Wha,An, Hongchan,Suh, Young-Ger
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p. 4416 - 4420
(2010/04/05)
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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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- Mammalian DNA topoisomerase II inhibitor and method
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A novel antiproliferative drug and methods are disclosed. The drug has the general structural formula: STR1 where R1=OR1 ', SR1 ', or N(R1 'R1 ")2, where R1 ' and R1 " are H or lower alkyl groups, and R2 is an acylamino, or aroylamino group. The compound is useful for inhibiting cell proliferation in drug-resistant tumor cells. Also disclosed is a method of chemical converting a colchicine derivative to form an active inhibitor of DNA topisomerase II.
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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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