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Plants produce and store many organic compounds like amino acids, proteins, carbohydrates, fats, and alkaloids, which are usually treated as secondary metabolites. Many alkaloids are biologically active for humans. For thousand years, extracts from plants containing alkaloids had medicinal use as drugs and they owe their powerful effects thanks to presence of alkaloids. Alkaloids have anti-inflammatory, antibacterial, analgesic, local anesthetic, hypnotic, psychotropic, antimitotic, and antitumor activity. Nowadays, alkaloids from plants are still of great interest to organic chemists, pharmacologists, biologists, biochemists, and pharmacists. Plants of Liliaceae family contain colchicine as the main alkaloid, which has cytotoxic activity. Colchicine has limited pharmacological application because of its toxicity, but many derivatives have been synthesized and their cytotoxic activity and tubulin-binding properties have been tested. Many of the synthetic derivatives showed good cytotoxic activity.
Chemistry Department, Adam Mickiewicz University, Poznań, Poland
*Address all correspondence to: joankur@amu.edu.pl
1. Introduction
One of the best known biologically active compounds from ancient times is colchicine (Figure 1), an alkaloid naturally occurring in Colchicum autumnale a plant of Liliaceae family and also in Gloriosa superba. In the past, extracts from these plants containing colchicine were useful in gout therapy and still are [1]. The anti-gout action of colchicine could be explained by its powerful spindle toxicity [2, 3]. Moreover, colchicine is a useful medicine in the treatment of familial Mediterranean fever (FMF), liver cirrhosis, chronic myelocytic leukemia, Behçet disease, chondrocalcinosis and other microcrystalline arthritis also more recently in cardiovascular diseases, Sweet’s syndrome, and hepatic disorders (HCC hepatocellular carcinoma) [4, 5, 6, 7, 8, 9, 10, 11, 12].
Figure 1.
Colchicine molecule (color version available on the online version).
In 2009, the FDA approved colchicine for the treatment of gout and familial Mediterranean fever (FMF) [1]. Recent investigations utilizing large cohorts of gout patients who have been taking colchicine for years have demonstrated novel applications within oncology, immunology, cardiology, and dermatology [4, 13, 14, 15, 16]. Some emerging dermatologic uses include the treatment of epidermolysis bullosa acquisita, leukocytoclastic vasculitis, and aphthous stomatitis. Colchicine has also anti-inflammatory and anticancer properties. Colchicine has been proven to have a fairly narrow range of effectiveness as a chemotherapy agent though it is also occasionally used in veterinary medicine to treat cancers in some animals. Nowadays, colchicine is very useful as an antimitotic agent in cancer research involving cell culture [17]. Colchicine has limited medical usage because of its high toxicity [18]. Because of this reason, many attempts have been made to design, synthesize new colchicine derivative and to screen them as cytotoxic agents to search more biologically active/effective compounds with lower toxicity.
Colchicine 1 and related alkaloids were isolated from many plants of Liliaceae family. The Colchicum species are most known plants in which colchicine exists in majority and other colchicine-like derivatives are in minority. Unripe seeds of Colchicum plants were found to contain 40% less colchicine 1 than fully ripe one [19]. Colchicine occurs in all parts of Colchicum plants but especially in seeds and bulbs. One of the most known plants which contain colchicine 1 is meadow saffron (C. autumnale,Figure 2). The other plants of Colchicum sp. are: C. crocifolium, C. turicum, C. kesselvingii, C. luteum, C. byzantinum, C. crocifolium, C. szovitsii, C. soboliferum, and many more [20]. Beside 1 in these plants of Colchicum species also are present: 2-demethylcolchicine 2, 3-demethylcolchicine 3, demecolcine 4, 2-demethylcolchiceine 5, 3-demethylcolchiceine 6, N-methyl-demecolcine 7, 3-demethyl-N-methyl-demecolcine 8, N-formyl-N-deacetylcolchicine 9 [19], N-deacetylcolchicine 10, N-deacetylcolchiceine 11, and colchiceine 12. Many of colchicine alkaloids exist in plants in glycoside form [21, 22]. Colchicine and its derivatives are also present in other plants like: Gloriosa superba, Merendera species (M. kurdica, M. sobolifera, M. vaddeana, M. robusta, and many more), Bulbocodium vernum, Androcymbium palaestinum, and Kreysigia multiflora [20, 23]. In Gloriosa superba plants were found alkaloids: 1, 2, 5, 6, 2,3-O-didemethylcolchicine 13, 2,3-O-didemethyl-N-deacetylcolchicine 14, and 2,3-O-didemethyl-N-formyl-N-deacetylcolchicine 15 [22]. More recently, a new colchicine glycoside, 3-O-demethylcolchicine-3-O-α-d-glucopyranoside 41 has been isolated from Gloriosa superba seeds [22]. Moreover, in plants extracts were also isolated photolysis products of colchicine like α-lumicolchicine, β-lumicolchicine, γ-lumicolchicine, and their 3-O-demethyl derivatives [24, 25].
Figure 2.
Meadow saffron Colchicum autumnale: bulb, flowers, and leaves (color version available on the online version). (*author’s own photos).
Colchicine (1) is an alkaloid with unusual structure and has the whole family of structural relations. This alkaloid was isolated in 1820 by Pelletier and Caventou [26]. Although listed at this point, colchicines are biogenetically very close to the isoquinoline alkaloids. Colchicines posses exocyclic N-atoms [15]. Corrected structure of colchicine molecule with seven-membered C ring proposed Dewar in 1945 [27]. Colchicine possesses both one stereogenic center at C7 and chirality axis, since the two rings A and C are not positioned in coplanar fashion (atropisomerism). In naturally occurring (−)-aR,7S-colchicine, the two rings (A and C) are oriented in a clockwise manner [15].
4. Natural, semi-synthetic, and synthetic colchicines
Many naturally occurring colchicine alkaloids (some of them are listed in Figures 3 and 4) have been converted into semi-synthetic compounds and have been prepared as potential antitumor agents. Usually starting with colchicine 1 hundreds of semi-synthetic and synthetic colchicine derivatives have been synthesized [28, 29, 30].
Figure 3.
Naturally occurring colchicine derivatives (color version available on the online version).
Figure 4.
Natural, seminatural and synthetic colchicines (chosen examples).
Starting compound was 1,2-O-didemethylcolchicine 16 converted into 1,2,3-O-tridemethylcolchiceine 17 [28, 29, 30], 1,2,3-O-tridemethyl-N-deacetylcolchiceine 18 [28, 29, 30], 1,2,3-O-tridemethyl-N-deacetyl-N-trifluoroacetylcolchiceine 19 [28, 29, 30], and 1,2,3-O-tridemethyl-N-deacetyl-N-formyl(2,4,6-trihydroxyphenyl)colchiceine 20 [28, 29, 30]. 1,2-didemethyl-N-deacetylcolchicine 21 was converted into: 1,2-didemethyl-N-deacetyl-N-(propane-2,3-diol)colchicine 22 [31] and 1,2-didemethyl-N-deacetyl-N-(propane-2,3-diacetyl)colchicine 23 [31]. Derivatives 24 with halogene substituent and with alkyl, aryl, or hydrogen 25 at C-10 position have also been obtained [32]. 10-demetoxy-10-azido-colchicine 26 [33] and 10-demetoxy-10-amino-colchicine = colchiceinamide 27 [34]. 2-Demethyl-N-benzyldemecolcine = speciocolchine 28 [35] has been prepared from 2-demethyldemecolcine. 10-O-p-tosylsulfonylcolchiceine 29 can be converted into compound 24 [36]. One of the interesting derivatives modified at C-7 position by –sulfur-containing substituent is N-deacetyl-N-(2merkaptoacetyl)-colchicine 30 (DAMA-colchicine) [37]. Glycopeptide dendrimer conjugates of colchicine modified at C-7 have been synthesized and tested as mitosis inhibitors [38]. N-substituted derivatives colchicine-lipids with different length of alkyl chain of olenyl and stearyl groups have been obtained and their interaction with lipid membrane has been studied [39]. Ring-C-modified colchicine analogs with different nitroso substituents in Diels-Alder reaction have been obtained [40]. 3-Demethyl derivative of colchicine and 10-metylthiocolchicine have been obtained also by regioselective bioconversion of 1 and 31 by microorganisms Bacillus IND-B 375 and stain of Bacillus megaterium ACBT03 [41, 42].
4.1. C-10 sulfur-containing derivatives
After many years of searching colchicine derivatives as good cytotoxic agents, it was established that exchange of methoxyl substituent ─OCH3 at C-10 position to amino group (NH2, NHR1, or NR1R2) and especially to methylthio (CH3S─) or alkylthio increases cytotoxic activity. Thiocolchicine 31 is a colchicine 1 derivative used in the therapy of some diseases [43] and extensively studied in the field of oncological research as antimitotic agent [44, 45, 46]. There were mentioned some of wide range of synthesized colchicine compounds with thio substituent at C-10 position during last 60 years. Derivatives with alkylthio substituent at C-10 position have been synthesized from colchicine 31–35 (Figure 5) [47]. N-deacetyl-10-methylthiocolchicine 36 was converted into compounds: 37 [44], 38 and 39 [44]. 10-Methylthiocolchine was modified at C-3 position to compound 3-demethoxy-3-amino-10-methylthiocolchicine 40 and then to 3-demethoxy-3-glycosylaminothiocolchicines 41–47 (Figure 5) [48]. From derivatives 48–52esters of 1-O-demethyl, 2-O-demethyl and 3-O-demethylthiocolchicine were also obtained 53–57 (Figure 5) [49]. 10-methylthiocolchicine has been demethylated to 1-demethyl-10-methylthiocolchicine 58, 2-demethyl-10-methylthiocolchicine 59, and 1,2-O-didemethylthiocolchicine 52 then 58 and 59 have been oxidized to quinine (Figure 6) [50]. Complex ethers of 3-demethyl-10-methylthiocolchicine 62–65 have been prepared as potential pharmaceuticals [51]. The C-7 amide group of ring B with (R)-configuration [15] is also one of the crucial factors which decide of molecule’s anticancer activity. Eight synthetic derivatives of N-deacetylthiocolchicine have been obtained and tested against cancer cell lines and 3 of them showed good activity 66, 67, 68 [52]. Thiocolchicine derivative 69 has been modified at C-2 carbon atom and then converted into salt 70 [53]. Among 37 thiocolchicine derivatives tested, compound 71 showed good activity as inhibitor of topoisomerases in vitro [54]. N-substituted thiocolchicine derivatives and their water-soluble phosphate salts 72–78 (and 5 others) have been obtained and their activity have been tested against cancer cell lines [55] (Figure 7).
Figure 5.
Seminatural and synthetic thiocolchicines (chosen examples).
Figure 6.
Thiocolchicines with modified ring A: 60 1,4-quinone and 61 quinomethane.
Figure 7.
Thiocolchicines modified on ring B.
From compound 79 acetamido ─NHCOCH3 substituent from C-7 has been removed and replaced by ═CH2 group [56]. Hybrids of vindoline, anhydrovinblastine, and vinorelbine with thiocolchicine 31 podophyllotoxin and baccatinIII have been tested in arresting cell cycle and cytotoxic activity [57]. Series of thiocolchicine-podophyllotoxin conjugates have been obtained and their tubulin activity has been tested [58].
Compounds 80, 81, 82, 83, 84, and 85 have been synthesized by four synthesis steps from colchicine 1 to thiocolchicine 31 then to 7-deacetylthiocolcicine 36 which has been converted into 80 and then to 81, 82, 83, 84, 85 and eight others which possess six-membered ring B [59].
Colchicine 1 has been known and used from ancient times, despite its toxicity to cure acute gout attacks because of its anti-inflammatory properties. After administration of colchicine 1, it is mainly metabolized in liver via demethylation by cytochrome P450 system (isoform CYP 3A4) to 2-demethylcolchicine 2 and 3-demethylcolchicine 3 [11]. Colchiceine 12 was described as a metabolite in rats produced by cytochrome P450 3A4 isoform [60], but it does not occur in humans in vivo [61]. Colchicine’s most common toxicity is gastrointestinal (nausea, vomiting, diarrhea, abdominal pain) which occurs during first 24 hours after overdose. Toxic effect of colchicine appears after oral administration of 7–60 mg of colchicine and is fatal, symptoms occur in about 4 h and death in about 4 days. Severe colchicine overdose may be treated with a colchicine-specific antigen-binding immunoglobulin [11].
Beside colchicine 1 has many naturally occurring derivatives many attempts have been made to discover more effective and less toxic analogs by modifying the substituents of its basic structure.
Colchicine blocks mitosis metaphase due to different anti-mitotic effects: disruption of mitotic spindle formation and second disruption of the sol-gel formation. Colchicine can also interact with lipid membranes. The interaction between colchicine and membrane results with significant alternations of both the properties of the lipid membrane and alkaloid [39]. Tubulin is an α and β heterodimer initially identified as the cellular colchicine-tubulin protein [10, 62]. Colchicine can interact with human serum albumin, which has been studied by spectroscopic method [63, 64]. Study of colchicine-tubulin complex showed that colchicine binds at the location where it prevents curved tubulin from adopting a straight structure, which inhibits assembly. Microtubules are cytoskeletal polymers of tubulin involved in many cellular functions [65]. Their dynamic instability is controlled by many proteins and compounds such as colchicine.
Colchicine and its biologically active derivatives, especially thiocolchicine and its derivatives, have been extensively tested on cancer cell lines for in vitro cytotoxicity, in mice, evaluated for inhibition of tubulin polymerization [66], on axonal cytoskeleton of rat peroneus nerve [67]. Thiocolchicine has been studied as a potent compound to treat Peyronie’s disease [68]. Derivatives of thiocolchicine have been tested ex vivo to human T-lymphoblastoid (CEM) cells [69].
6. Cytotoxic activity of colchicine and its derivatives
Cytotoxic activity of colchicine has been known for many decades. In 1968, it was known that colchicine can efficiently bind to tubulin. Its antitumor activity derives from its tubulin binding activity [39]. Nowadays, it is known that colchicine can act with α and β tubulin in microtubules and disrupt the formation of microtubules. In past decades, many attempts have been made to design and synthesize new colchicine derivatives which could be less toxic and more effective compounds than colchicine as cytotoxic agents. On the basis of years of screening colchicine derivatives, their activity against human cancer cell lines structure: activity relationship has been established. It was found out that derivatives with alkylthio substituents at C-10 position and modified at C-7 usually are more active and less toxic than colchicine. One of the most known active semi-synthetic colchicine derivatives is thiocolchicine (10-methylthiocolchicine) 31. Some of the obtained derivatives seem to be effective and promising agents against selected human cancer cell lines and possibly in the future could be used as anticancer drugs. Cytotoxic activity of colchicine derivatives has been tested in in vitro experiments on mice (KLN205, A2C12, yB8, yD12, βD10, yA7, yA3, B3, βD5, A2B1, yD1) [70] or hamster (CHO-K1) [45] cancer cell lines and human cancer cell lines such as: MFC-7 human breast adenocarcinoma [40, 45, 47, 54, 71, 72] and MDA-MB-231 [47, 72] human Caucasian breast adenocarcinoma, SK-Br-3 human breast cancer cell line [46], DLD-1 [47] and LOVO [47] human colon adenocarcinoma, HCT-5 colon cancer, HCT-15 colon carcinoma [44, 45], A549 human lung adenocarcinoma [44, 52, 53, 54, 55, 57, 58, 70], DMS-114 small lung cell cancer [44], SKOV-3 ovarian cancer [46], OVCAR-3 ovarian carcinoma [44], A2780 human ovarian carcinoma cell line [73], 1A9 human ovarian carcinoma [53], KB human epidermoid carcinoma [46, 53, 57], PC-3 prostate cancer [40], H460 human large cell lung carcinoma [71], SF268 human astrocytoma [71], HTC-8 human ileocecal carcinoma cell [46, 57], DU-145 human prostate carcinoma [46], SKMEL-2 human skin malignant melanoma [46, 54], SKMEL-5 human skin malignant melanoma [44], RXF-631 renal carcinoma [44], SNB-19 CNS carcinoma [44], RPMI-7951 malignant melanoma [56], TE671 human medulloblastoma [56], HepG2 human hepatocyte carcinoma [70], CaCo-2 human colon carcinoma [70], and CAKI-1 kidney carcinoma [54]. As a positive control in cytotoxic tests were used: colchicine, doxorobucin or camptothecin and MTT tests [39, 57] or SRB tests MTS assay [70]. Values of IC50 for compounds 1, 4, 7, 8, 31, 32, 33, 34, and 35 are given in Table 1. Naturally occurring colchicine and other colchicine-like alkaloids were tested against human cancer cell lines and usually showed much better activity than parent compound.
The IC50 values (nM) of compounds tested against cancer cell lines: MCF-7 [47], MDA-MB-231 [47], DLD-1 [47], LoVo [47], H460 [71] and SF268 [71]. Data were obtained from triplicate experiments. Doxorubicin was used as positive control (MTT test) [47].
Thiocolchicine 31 showed good activity against A2780 human ovarian carcinoma cell line with value of IC50 1.6 nM [73]. The water-soluble compound 69 (salt of succinic acid of N,N-dimethyl-N-deacetylthiocolchicine) showed selective activity against HTC-8 0.022 μg/mL and SK-BR-3 0.012 0.022 μg/mL cancer cells [46]. The second salt of succinic acid of N-deacetylthiocolchicine 72 showed activity against five of tested cancer cell lines 0.001–0.005 μg/mL (HTC-8, SK-BR-3, A549, DU145, KB) [46].
Thiocolchicine derivative 83 modified at C-7 position showed good cytotoxic activity against A549, RPMI-7951, and TE671 cancer cell lines 0.001 nM/mL [56]. Derivatives 66, 67, and 68 showed good cytotoxic activity against A549, SKOV-3, SKMEL-2, HCT-15, and MCF-7 cancer cell lines with IC50 values 5.2–29.8 nM [52]. 69 and 70 showed significant activity against tumor cell lines: A549, 1A9, and KB with values of IC50 0.02–0.06 μg/mL [53]. Hybrids of vindoline, anhydrovinblastine, and vinorelbine with thiocolchicine have been tested in arresting cell cycle and against A549 cell lines [57].
Many of tested colchicine derivatives and thiocolchicine derivatives obtained by partial synthesis were assayed measuring mitotic arrest in L1210 murine leukemia cell cultures [70], their binding to tubulin in vitro, their antitumor activity against the P388 lymphocytic leukemia screen in mice, and their inhibition of swelling produced in rat paws by injection with uric acid. To measure inhibition in binding different colchicine derivatives to tubulin, many tests have been used in vitro and in vivo: CD spectra [74], radiolabeled compounds, and cancer cell lines.
The effect on tubulin can be assessed in vitro by measuring inhibition of tubulin polymerization [53, 66, 70] and binding of radiolabeled colchicine to tubulin [75]. Significant inhibition in binding to tubulin greater than colchicine 1 was observed with 3-demethylcolchicine (3), 10-methylthiocolchicine 31, and 3-demethyl-10-methylthiocolchicine 48 [76]. Significant inhibition of binding radiolabeled colchicine to purified tubulin was observed with thiocolchicine and 3-demethylthiocolchicine (Table 2).
Inhibitor added
Inhibitor:radiolabeled colchicine (%)
1:1
10:1
Non-radiolabeled 1
25
83
2
14
60
3
25
77
31
55
94
48
41
89
Table 2.
Inhibition [%] of binding radiolabeled colchicine to purified tubulin [76].
Colchicine showed to be too much toxic to be used as a drug candidate for cancer diseases. Colchicine is much more less toxic than colchicine [77]. Through past decades many derivatives were tested against cancer cell lines to checked their cytotoxic activity and activity in vitro to disrupt microtubule network and spindle formation. Binding of colchicine analogs to tubulin measured by competition for labeled colchicine is for 1 5 × 10−6, 31 4 × 10−6, and 41 2–3 × 10−5 [76]. Inhibition of tubulin assembly by thiocolchicine derivatives 69 and 70 is IC50 8.7 μM and IC50 3.8 μM, respectively [53]. The compounds 72, 76, and 77 showed potent inhibition of tubulin assembly IC50 = 0.8–1.1 μM, for comparison for 1 is 1,5 μM [54]. Compound 83 showed good inhibition of tubulin polymerization and inhibition of colchicine binding (%), IC50 3.4 μM and 60% and 79 IC50 2.4 μM and 91%; 82 IC50 6.6 μM and 78% [56]. Hybrid thiocolchicine-vindoline causes cell cycle arrest in the G2/M phase [57]. Inhibition of tubulin polymerization has been studied with thiocolchicine-podophyllotoxin conjugates, where 31 was modified at C-7 substituent [63].
In vivo P388 mouse leukemia test data P388 for colchicine 1 is 0.5, 31 is 0.18, and 48 is 5 [mg/kg] [76].
Some of colchicines have been tested as prodrugs. Zyn-linked™ colchicines which are conjugates of colchicine derivatives with proprietary lipophylic molecules (ZYN-160 4-formylthiocolchicine, PKH139, PKH153, PKH147) via acid cleavable linkages (PKH155, PKH159, ZYN-217) produced prodrugs (PKH140, PKH154, PKH156, PKH158, ZYN-162) with enhanced antitumor activity (A2780 human ovarian carcinoma cell line) [73]. Conjugates have blocked cell in the G2/M phase of the cell cycle and were up to 100-fold less active in vitro than unlinked drug [73]. Ring B-modified colchicine derivative CT20126 showed immunosuppressive and cytotoxic activity [78]. N-acetylcolchinol phosphate is a prodrug (ZD6126) derived from colchicine [79]. Thiocolchicine dimers IDN5404 and IDN5676 have been tested as prodrugs active as inhibitor of Topo-I and without loss of the spindle poison properties [80]. Colchitaxel is another active compound with cytotoxic activity which combines colchicine and paclitaxel [81].
7.2. Drugs with colchicine
Besides antitumor activity, colchicine has anti-inflammatory properties. Colchicine reduces the formation of uric acid crystals in the affected joint and thereby reduces the amount of acute inflammation and pain. It also decreases the levels of uric acid in the blood or the amount that is excreted in the urine. More recently colchicine has been proposed as a potential drug in treatment for various conditions (except gout), what can open new way of its possible future application. Nowadays, colchicine is the useful drug in illnesses: familial Mediterranean fever (FMF), liver cirrhosis, disk problems, Behçet syndrome, prevention of post-pericardial syndrome, primary biliary cirrhosis, hepatic cirrhosis, dermatitis herpetiformis, Paget’s disease of bone, pseudogout, and idiopathic pulmonary fibrosis.
Colchicine can be used to treat familial Mediterranean fever in children 4 years of age and older.
Colchicine is available as a tablet, capsule, and a gel. In tablet form, it is available in a generic 0.6 mg tablet and as Colcrys 0.6 mg tablet. It is available as a capsule in a generic form of 0.6 mg and as Mitigare 0.6 mg capsule. There is a topical gel form of Colchicum autumnale, available as ColciGel. Colchicine is commonly administered orally, and use of the topical gel is rare. Due to toxicity of colchicine from 2009, the injectable form is not available. Dosing is dependent on age of patient and kind of illness.
Usually, colchicine is a major component of tablets or capsules in which in a single tablet or capsule its amount is in range of 0.5 or 0.6 mg, sometimes is used as an injection (disk problems). Usually a man/woman of 60 kg takes a dose of 0.5–4.8 mg/day [82, 83]. Since 2008, only oral use of colchicine for patients is possible because of 50 cases of serious adverse events [84]. The known medicines with colchicine are: Colchicum Dispert®, Colcrys, Mitigare, and Colchimax. Col-Benemid or Proben-C is a drug where next to colchicine probenecid is added as uricosuric agent.
7.3. Drugs with colchicine derivatives
One of the known colchicine derivatives that has been used for the treatment of Hodgkin’s lymphoma and chronic granulocytic leukemia is N-deacetyl-N-methylcolchicine, brand name is Colcemid [72]. Moreover, its efficacy against melanoma and prostatic cancer has been established.
Thiocolchicoside (=glucopyranosyl derivative of the semi-synthetic 3-O-demethylthiocolchicine 41), is well-known as a muscle relaxing agent and as an anti-inflammatory drug substance [85]. This compound is registered in different countries under the trade names of Colcamyl, Coltramyl, Coltrax, Miorel, and Musco-Ril. Muscle spasm is one of the main factors responsible for chronic pain, and because this particular drug reduces muscle tone, it is used in therapy for the treatment of contractures and inflammatory conditions that affect the muscular system [48].
A new tool for searching new potent anticancer agents is docking studies. Some years ago it became possible to study new compounds of possible biological activity by new technical methods like molecular modeling and docking studies [37, 86, 87, 88, 89, 90].
The way to search new colchicine derivatives especially thiocolchicine derivatives seems to be worth trying because of its promising cytotoxicity. Many new derivatives have been obtained, have been tested for many different cancer cell lines, and many of them seem to be promising anticancer agents in the future.
Scientists still keep designing and synthesizing more and more colchicine derivatives for searching almost ideal anticancer agent. New methods, such as molecular modeling and docking studies, seem to be useful tool in searching for new colchicine derivatives as effective cytotoxic agents.
1.Roubille F, Kritikou E, Busseuil D, Barrère-Lemaire S, Tardif J-C. Colchicine: An old wine in a new bottle? Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry. 2013;12:1-23. DOI: 10.2174/187152313804998623
2.Cook JW, Loudon JD. In: Manske RH. editor. The Alkaloids. Vol. 2. New York: Academic Press; 1952. p. 261
3.Wildman WC, Pursey BA. In: Manske RH. editor. The Alkaloids. Vol. 11. New York: Academic Press; 1962. pp. 41-413
4.Papageorgiou N, Briasoulis A, Lazaros G, Imazio M, Tousoulis D. Colchicine for prevention and treatment of cardiac diseases: A meta-analysis. Cardiovascular Therapeutics. 2017;35(1):10-18. DOI: 10.1111/1755-5922.12226
5.Indraratna PL, Virk S, Gurram D, Day RO. Use of colchicine in pregnancy: A systematic review and meta-analysis. Rheumatology (Oxford, England). 2017;23. DOI: 10.10093/rheumatology/kex353
6.Wang MX, Deng XL, Mu BY, Cheng YJ, Chen YJ, Wang Q, Huang J, Zhou RW, Huang CB. Effect of colchicine in prevention of pericardial effusion and atrial fibrillation: A meta-analysis. Internal and Emergency Medicine. 2016;11(6):867-876. DOI: 10.1007/s11739-016-1496-5
7.Hemkens LG, Ewald H, Gloy VL, Arpagaus A, Olu KK, Nidorf M, Glinz D, Nordmann AJ, Briel M. Cardiovascular effects and safety of long-term colchicine treatment: Cochrane review and meta-analysis. Heart. 2016;102(8):590-596. DOI: 10.1136/heartjnl-2015-308542
8.Agarwal SK, Vallurupalli S, Uretsky BF, Hakeem A. Effectiveness of colchicine for the prevention of recurrent pericarditis and post-pericardiotomy syndrome: An updated meta-analysis of randomized clinical data. European Heart Journal—Cardiovascular Pharmacotherapy. 2015;1(2):117-125. DOI: 10.1093/ehjcvp/pvv001
9.Imazio M, Brucato A, Forno D, Ferro S, Belli R, Trinchero R, Adler Y. Efficacy and safety of colchicine for pericarditis prevention. Systematic review and meta-analysis. Heart. 2012;98(14):1078-1082. DOI: 10.1136/heartjnl-2011-301306
10.Terkeltaub RA. Colchicine update: 2008. Seminars in Arthritis and Rheumatism. 2008;38:411-419. DOI: 10.1016/j.semarthrit.2008.08.006
11.Bhat A, Naguwa SM, Cheema GS, Gershwin ME. Colchicine revisited. Annals of the New York Academy of Sciences. 2009;1173:766-773. DOI: 10.1111/j.1749-6632.2009.04674.x
12.Smilde BJ, Woudstra L, Fong Hing G, Wouters D, Zeerleder S, Murk JL, van Ham M, Heymans S, Juffermans LJ, van Rossum AC, Niessen HWM, Krijnem PAJ, Emmens RW. Colchicine aggravates coxsackievirus B3 infection in mice. International Journal of Cardiology. 2016;216:58-65. DOI: 10.1016./j.ijcard.2016.04.144
13.Lennerz C, Barman M, Tantawy M, Sopher M, Whittaker P. Colchicine for primary prevention of atrial fibrillation after open-heart surgery: Systematic review and meta-analysis. International Journal of Cardiology. 2017;S0167-5273(17):32407-32415. DOI: 10.1016/j.ijcard.2017.08.039
14.Salih M, Smer A, Charnigo R, Ayan M, Darrat YH, Traina M, Morales GX, DiBiase L, Natale A, Elayi CS. Colchicine for prevention of post-cardiac procedure atrial fibrillation: Meta-analysis of randomized controlled trials. International Journal of Cardiology. 2017;15(243):258-262. DOI: 10.1016/j.ijcard.2017.04.022
15.Dasgeb B, Kornreich D, McGuinn K, Okon L, Brownell I, Sackett DL. Colchicine: An ancient drug with novel applications. The British Journal of Dermatology. 2017. DOI: 10.1111/bjd.15896
16.Puzas IÁ, Álvarez ML, Menendez FÁ, Yuste Romero S, Gómez Prieto O. Wells’ syndrome successfully treated with colchicine. Case Reports in Dermatology. 2017;9:65-69. DOI: 10.1159/000477756
17.Cutler SJ, Cutler HG, editors. Biologically Active Natural Products, Pharmaceuticals. 2000. p. 84
18.Budavari S. The Merck Index: An Encyclopedia of Chemicals, Drug and Biologicals. Rahway, New York: Merck&Co.; 1989
19.Saxton JE. The Alkaloids, A Specialist Periodical Report. vol. 2. London W1V0BN: The Chemical Society Burlington House; 1972. p. 144
20.Herbert RB. The biosynthesis of plant alkaloids and nitrogenous microbal metabolites. 2.2. Colchicine. Natural Product Reports. 1999;16:199-208; Bentley KW. β-Phenylethylamines and the isoquinoline alkaloids. 17. Colchicine and related alkaloids. Natural Product Reports. 2002;19:332-356; Herbert RB. β-Phenylethylamines and the isoquinoline alkaloids. 3.2. Colchicine. Natural Product Reports. 2001;18:148-170; Bentley KW. β-Phenylethylamines and the isoquinoline alkaloids. 21. Colchicine. Natural Product Reports. 1991;7:358-366; Herbert RB. The biosynthesis of plant alkaloids and nitrogenous microbal metabolites. 2.2. Colchicine. Natural Product Reports. 1992;9:507-519; Bentley KW. The biosynthesis of plant alkaloids and nitrogenous microbal metabolites. 21. Colchicine and its analogues. Natural Product Reports. 1992;9:365-396; Bentley KW. The biosynthesis of plant alkaloids and nitrogenous microbal metabolites. 21. Colchicine and related alkaloids. Natural Product Reports. 1994;11:555-576; Bentley KW. The biosynthesis of plant alkaloids and nitrogenous microbal metabolites. 18. Colchicine and related alkaloids. Natural Product Reports. 1995;12:419-441
21.Saxton JE. The Alkaloids, A Specialist Periodical Report. Vol. 3. London W1V0BN: The Chemical Society Burlington House; 1973. p. 300
22.Suri OP, Gupta BD, Suri KA, Sharma AK, Satti NK. A new glycoside, 3-O-demethylcolchicine-3-O-α-d-glucopyranoside, from Gloriosa Superba seeds. Natural Product Letters. 2001;15(4):217-219. DOI: 10.1080/10575630108041284
23.Korner A, Kohn S. Development and optimization of a stability indicating method on a monolithic reversed-phase column for colchicum dry extract. Journal of Chromatography A. 2005;1089(1-2):148-157. DOI: 10.1016/j.chroma.2005.06.084
24.Chaudhuri PK, Thakur RS. 1,2-Didemethylcolchicine: A new alkaloid from Gloriosa superba. Journal of Natural Products. 1993;56(7):1174-1176. DOI: 10.1021/np50097a025
25.Saxton JE. editor. The alkaloids, A Specialist Periodical Report. Vol. 1. London, W1V0BN : The Chemical Society Burlington House; 1971. p. 457
26.Pelletier PJ, Caventou JB. Examen chimique de plusieus vègètaux de la famile des colchicènes, et du principle actif qu’ ils renferment. Annales de Chimie Physique. 1820;14:69-81
27.Dewar MJS. Structure of colchicine. Nature. 1945;155:141. DOI: 10.1038/155141d0
28.Kashiwara YM, Sun L, Tatematsu H, Bastow KF, Lee KH. Structures of tetra-O-demethylcolchicine, -isocolchicine, and 10-O-demethylcolchicine derivatives. Heterocycles. 1993;36:2531-2540. DOI: 10.3987/COM-93-6478
29.Bastow KF, Tatematsu H, Sun L, Fukushima Y, Lee KH. Synthesis and biological evaluation of tetrademethyl isocolchicine derivatives as inhibitors of DNA topoisomerase action in vitro. Bioorganic & Medicinal Chemistry Letters. 1993;(3):227-234. DOI: 10.1016/S0968-0896(00)82125-2
30.Bastow KF, Tatematsu H, Bori ID, Fukushima Y, Lee K-H. Induction of reversible protein-linked DNA breaks in human osteogenic sarcoma cells by novel cytocidal colchicine derivatives which inhibit DNA topoisomerase II in vitro: Absence of cross-resistance in a colchicine-resistant sub-clone. Bioorganic & Medicinal Chemistry Letters. 1993;3:1045-1050. DOI: 10.1016/S0960-894X(00)80284-X
32.Boye O, Hamel E, Brossi A. Medicinal Chemistry Research. 1991;1:149-159
33.Muzaffar A, Hamel E, Brossi A. Reaction of Colchiceinamide with phosgene and with thiophosgene: Structures and antitubulin activity of tetracyclic oxazolones, oxazolethiones and thiazolones of the colchicine series. Heterocycles. 1990;31(11):2037. DOI: 10.3987/COM-90-5558
34.Muzaffar A, Brossi A. Thiocolchicinethiones: Acid hydrolysis of natural and iso-isomers. Synthetic Communications. 1990;6:713. DOI: 10.1080/00397919008052314
35.Muzaffar A, Brossi A, Hamel E. Partial synthesis and antitubulin activity of minor colchicum alkaloids: N-acetoacetyl-deacetylcolchicine and 2-demethylspeciosine (Speciocolchine). Journal of Natural Products. 1990;53(1):1021-1024. DOI: 10.1021/np50070a044
36.Cazzava M, Pietra F. A general entry to 10-halocolchicides and 9-haloisocolchicides. Synthetic Communications. 1997;27(19):3405. DOI: 10.1080/00397919708005641
37.Ravelli RBG, Gigant B, Curmi PA, Jourdain I, Lachkar S, Sobel A, Knossow M. Insight into tubulin regulation from a complex with colchicine and stathmine-like domain. Nature. 2004;428:198-202. DOI: 10.1038/nature02393
38.Lagnoux D, Darbre T, Lienhard Schmitz M, Reymond J-L. Inhibition of mithosis by glycopeptide dendrimer conjugates of colchicine. Chemistry—A European Journal. 2005;11(13):3941-3950. DOI: 10.1002/chem.200401294
39.Mons S, Veretout F, Carlier M-F, Erk I, Lepault J, Trudel E, Salesse C, Ducray P, Mioskowski C, Lebeau L. The interaction between lipid derivatives of colchicine and tubulin: Consequence of the interaction of the alkaloid with lipid membrane. Biochimical Biophysica Acta. 2000;1468:381-396. DOI: 10.1016/S0005-2736(00)00279-0
40.Yang B, Zhu ZC, Goodson HV, Miller MJ. Synthesis and biological evaluation of ring-C modified colchicine analogs. Bioorganic & Medicinal Chemistry Letters. 2010;20:3831-3833. DOI: 10.1016/j.bmcl.1010.03.065
41.Poulev A, Bombardelli E, Ponzone C, Zenk M. Regioselective bioconversion of colchicine and thiocolchicine into their corresponding 3-demethyl derivatives. Journal of Fermentation and Bioengineering. 1995;79(1):33-38. DOI: 10.1016/0922-338X(95)92740-4
42.Dubey KK, Ray AR, Behera BK. Production of demethylated colchicine through microlab transformation and scale-up process development. Process Biochemistry. 2008;43:252-257. DOI: 10.1016/j.procbio.2007.12.002
43.Wolach B, Gotfried M, Jedeikin A. Colchicine analogues: Effect on amyloidogenesis in a murine model in vitro, on polymorphonuclear leukocytes. European Journal of Clinical Investigation. 1992;22(9):630-634. DOI: 10.1111/j.1365-2362.1992.tb01516.x
44.Sun L, Hamel E, Lin CM, Hastie SB, Pyluck A, Lee K-H. Antitumor agent. 141. Synthesis and biological evaluation of novel thiocolchicine analogs: N-acyl-, N-aroyl- and N-(substituted benzyl) deacetylthiocolchicines as a potent cytotoxic and antimitotic compounds. Journal of Medicinal Chemistry. 1993;36(10):1474-1479. DOI: 10.1021/jm00062a021
45.De Vincenzo R, Scambia G, Ferlini C. Antiproliferative activity of colchicine analogues on MDR-positive and MDR negative human cancer cell lines. Anti-Cancer Drug Design. 1998;13(1):19-33
46.De Vincezo R, Ferlini C, Distefano M. Biological evaluation on different human cancer cell lines of novel colchicine analogues. Oncology Research. 1999;11(3):145-152
47.Kurek J, Boczoń W, Murias M, Myszkowski K, Borowiak T, Wolska I. Synthesis of sulfur containing colchicine derivatives and their biological evaluation as cytotoxic agents. Letters in Drug Design & Discovery. 2014;11(3):279-289. DOI: 10.2174/15701808113106660086
48.Gelmi ML, Pocar D, Pontremoli G, Pellegrino S, Bombardelli E, Fontana G, Riva A, Balduini W, Carloni S, Cimino M, Johnson F. Demethoxy-3-glycosylaminothiocolchicines: Synthesis of a new class of putative muscle, relaxant compounds. Journal of Medicinal Chemistry. 2006;49(18):5571-5577. DOI: 10.1021/jm060585t
49.Kerekes P, Brossi A. Esters of 1-O-demethylthiocolchicne s: Formation of isomers in chloroform solution. Helvetica Chimica Acta. 1985;68(3):571-579. DOI: 10.1002/hlca.19850680306
50.Guan J, Brossi A, Zhu XK, Wang HK, Lee KH. Oxidation products of phenolic thiocolchicines: Ring a quinones and dienones. Synthetic Communications. 1998;28:1585-1590. DOI: 10.1080/00397919808006862
52.Lee SH, Park S-K, Kim J-M, Kim M-H, Kim KH, Chum KW, Cho KH, Youn J-Y, Namgoong SK. New synthetic thiocolchicine derivatives as low-toxic anticancer agents. Archiv der Pharmazie—Chemistry in Life Sciences. 2005;388:582-589. DOI: 10.1002/ardp.200500148
53.Nakagava-Gotto K, Chen C, Hamel E, Wu C-C, Bastow KF, Brossi A, Lee KH. Antitumor agents. Part 236: Synthesis of water-soluble colchicine derivatives. Bioorganic & Medicinal Chemistry Letters. 2005;15:235-238. DOI: 10.1016/j.bmcl.2004.07.098
54.Guan J, Zhu X-K, Tachibana Y, Bastow KF, Brossi A, Hamel E, Lee KH. Antitumor agents. 185. Synthesis and biological evaluation of tridemetoxylthiocolchicine analogues as novel topoisomerase II inhibitors. Journal of Medicinal Chemistry. 1998;41:1956-1961. DOI: 10.1021/jm980007f
55.Kozaka T, Nakagawa-Goto K, Shi Q, Lai CY, Hamel E, Bastow KF, Brossi A, Lee K-H. Antitumor agents 273. Design and synthesis of N-alkyl-thiocolchicinoids as potential antitumor agent. Bioorganic & Medicinal Chemistry Letters. 2010;20:4091-4094. DOI: 10.1016/j.bmcl.2010.05.081
56.Banwell M, Peters SC, Greenwood RJ, Mackay MF, Hamel E, Lin CM. Semisyntheses, X-ray crystal structures and tubulin-binding properties of 7-oxodeacetamidocolchicine and 7-oxodeacetamidoisocolchicine. Australian Journal of Chemistry. 1992;45(10):1577-1588. DOI: 10.1071/CH9921577
57.Passarella D, Giardini A, Peretto B, Fontana G, Sacchetti A, Silvani A, Ronchi C, Cappelletti G, Cartelli D, Borlak J, Danielli B. Inhibitors of tubulin polymerization: Synthesis and biological evaluation of hybrids of vindofine, anhydrovinblastine and vinorelbine with thiocolchicine, podophylotoxin and baccatin III. Bioorganic & Medicinal Chemistry. 2008;16:6269-6285. DOI: 10.1016/j/bmc.2008.04.025
58.Capelletti G, Cartelli D, Peretto B, Ventura M, Riccioli M, Colombo F, Snaith JS, Borrelli S, Passarella D. Tubulin-guided dynamic combinatorial library of thiocolchicine-podophyllotoxin conjugates. Tetrahedron. 2011;67:7354-7357. DOI: 10.1016/j/tet.2011.07.038
59.Sun L, McPhail AT, Hamel E, Lin CM, Hastie S, Chang JJ, Lee K-H. Antitumor agents. 139. Synthesis and biological evaluation of thiocolchicine analogues 5,6-dihydro-6-(S)-(acyloxy)- and 5,6-dihydro-6-(S)[(aroyloxy)methyl]-1,2,3-trimethoxy-9-(methylthio)8H-cyclohepta[a]naphthalen-8-ones as novel cytotoxic and antimitotic agents. Journal of Medicinal Chemistry. 1993;36:544-551. DOI: 10.1021/jm00057a004
60.Schonharting M, Mende G, Siebert G. Hoppe-Seyler’s. Zeitschrift für Physiologische Chemie. 1974;355:1991
61.Tateischi T, Soucek P, Caraco Y, Guengerich FP, Wood AJJ. Colchicine biotransformation by human liver microsomes: Identification of cyp3a4 as the major isoform responsible for colchicine demethylation. Biochemical Pharmacology. 1997;53(1):111-116. DOI: 10.1016/S0006-2952(96)00693-4
62.Pal D, Mahapatra P, Manna T, Chakrabati P, Bhattacharyya B, Banerje A, Basu G, Roy S. Conformational properties of α-tubulin tali peptidde: Implication for tail-body interaction. Biochemistry. 2001;40:15512-15519. DOI: 10.1021/bi015677t
63.Sułowska A, Maciążek-Jurczyk M, Bojko B, Równicka J, Zubik-Skupień I, Temba E, Pentak D, Sułkowski WW. Competitive binding of phenylbutazone and colchicine to serum albumin in multidrug therapy: A spectroscopic study. Journal of Molecular Structure. 2008;881:97-106. DOI: 10.1016/j.molstruc.2007.09.001
64.Hu YJ, Liu Y, Zhao RM, Qu SS. Interaction of colchicine with human serum albumin investigated by spectroscopic methods. International Journal of Biological Macromolecules. 2005;37:122-126. DOI: 10.1016./j.ijbiomac.2005.09.007
65.Sharma S, Poliks B, Chiauzzi C, Ravindra R, Blanden AR, Bane S. Characterization of the colchicine binding site on avian tubulin isotype βVI. Biochemistry. 2010;49:2932-2942. DOI: 10.1021/bi100159p
66.Shi Q, Verdier-Pinard P, Brossi A, Hamel E, Lee KH. Antitumor agents-CLXXV. Antitubulin action of (+)-thiocolchicine prepared by partial synthesis. Bioorganic & Medicinal Chemistry. 1997;5(12):2277-2282. DOI: 10.1016/S0968-0896(97)00171-5
67.Ferri P, Bruno C, Cecchini T, Ciaroni S, Ambrogini P, Guidi L, Cuppini R, Bombardelli E, Morazzoni P, Riva A, Del Grande P. Effects of thiocolchicine on axonal cytoskeleton of rat peroneus nerve. Experimental and Toxicologic Pathology. 2002;54:211-216. DOI: 10.1078/0940-2993-00249
68.Toscano IL, Rezende MV, Mello LF, Pires L, Paulillo D, Glina S. A prospective, randomized, single-blind study comparing intraplaque injection of thiocolchicine and verapamil in Peyronie’s disease: A pilot study. International Brazilian Journal of Urology. 2016;42(5):1005-1009. DOI: 10.1590/S1677-5538.IBJU.2015.0598
69.Batrusik D, Tomanek B, Lattová E, Perreault H, Tuszyński J, Fallone G. Derivatives of thiocolchicine and its applications to CEM cells treatment using 19F magnetic resonance ex vivo. Bioorganic Chemistry. 2010;38:1-6. DOI: 10.1016/j.bioorg.2009.10.002
70.Passarella D, Peretto B, Blasco y Yepes R, Cappelletti G, Cartelli D, Ronchi C, Snaith J, Fontana G, Danieli B, Borlak J. Synthesis and biological evaluation of novel thiocolchicine–podophyllotoxin conjugates. European Journal of Medicinal Chemistry. 2010;45:219-226. DOI: 10.1016/j.ejmech.2009.09.047
71.Alali FQ, Gharaibeh AA, Ghawanmeh A, Tawaha K, Qandil A, Burgess JP, Sy A, Nakanishi Y, Kroll DJ, Oberlies NH. Colchicinoids from Colchicum crocifolium Boiss. (Colchicaceae). Natural Product Research. 2010;24(2):152-159. DOI: 10.1080/14786410902941097
72.Gelmi ML, Motadelli S, Pocar D, Riva A, Bombardelli E, de Vincenzo R, Scambia G. N-deacetyl-N-aminoacetylthiocolchicine derivatives: Synthesis and biological evaluation on MDR-positive and MDR-negative human cancer cell lines. Journal of Medicinal Chemistry. 1999;42:5272-5276. DOI: 10.1021/jm981134e
73.Baker MA, Gray BD, Ohlsson-Wilhelm BM, Varpenter DC, Muirhead KA. Zyn-linked colchicines: controlled-release lipophilic prodrugs with enhanced antitumor activity. Journal of Controlled Release. 1996;40(1-2):89-100. DOI: 10.1016/0168-3659(95)00177-8
74.Chabin RM, Feliciano F, Hastie SB. Effects of tubulin binding and self-association on the near-ultraviolet circular dichroic spectra of colchicine and analogues. Biochemistry. 1990;29(7):1869-1875. DOI: 10.1021/bi00459a029
75.Brossi A. Bioactive alkaloids. 4. Results of recent investigation with colchicine and physostigmine. Journal of Medicinal Chemistry. 1990;33:2311-2319. DOI: 10.1021/jm00171a001
76.Brossi A, Herman JC, Chrzanowska M, Wolff J, Hamel E, Lin CM, Quin F, Suffness M, Silverton J. Colchicine and its analogues: Recent findings. Medicinal Research Reviews. 1988;8(1):77-94. DOI: 10.1002/med.2610080105
77.Gohar MA, Makkawi M. The antibacterial action of colchicine and colchiceine. The Journal of Pharmacy and Pharmacology. 1951;3(1):415-419. DOI: 10.1111/j.2042-7158.1951.tb13083.x
78.Kim SK, Cho SM, Kim H, Seok H, Kim SO, Kwon TK, Chang JS. The colchicine derivative CT20126 shows a novel microtubule-modulating activity with apoptosis. Experimental & Molecular Medicine. 2013;45:e19. DOI: 10.1038/emm.2013.38
79.Davis PD, Dougherty GJ, Blakey DC, Galbraith SM, Tozer GM, Holder AL, Naylor MA, Nolan J, Stratford MRL, Chaplin DJ, Hill SA. ZD6126: A novel vascular-targeting agent that causes selective destruction of tumor vasculature. Cancer Research. 2002;62(15):7247-7253
80.Raspaglio G, Ferlini C, Mozzetti S, Prislei S, Gallo D, Das N, Scambia G. Thiocolchicine dimers: A novel class of topoisomerase-I inhibitors. Biochemical Pharmacology. 2005;69:113-121. DOI: 10.1016/j.bcp.2004.09.004
81.Bombuwala K, Kinstle T, Popik V, O Uppal S, Olesen JB, Viña J, Heckman CA. Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxel. Beilstein Journal of Organic Chemistry. 2006;2:13-21. DOI: 10.1186/1860-5397-2-13
82.Imazio M, Brucato A, Cemin R. A randomized trial for acute pericarditis. New England Journal of Medicine. 2013;369:1522-1528. DOI: 10.1056/NEJMoa1208536
83.Terkeltaub RA, Furst DE, Bennet K, kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome oft he first multicenter, randomized, double-blind, placebo-controlled parallel-group, dose-comparison colchicine study. Arthritis and Rheumatism. 2010;62:1060-1068. DOI: 10.1002/art.27327
84.Cocco G, Chu DCC, Pandolfi S. Colchicine in clinical medicine. A guide for internists. European Journal of Internal Medicine. 2010;21:503-508. DOI: 10.1016/j.ejim.2010.09.010
85.Gervasi M, Sisti D, Benelli P, Fermández-Peña E, Calcabini C, Rocchi MBL, Lanata L, Bagnasco M, Tonti A, Viberto S, Sestili P. The effect of topical thiocolchicoside in preventing and reducing the increase of muscle tone, stiffness and soreness. Medicine. 2017;96(30):1-8. DOI: 10.1097/MD.0000000000007659
86.Abolhasani H, Zarghi A, Hamzeh-Mivehroud M, Alizadeh AA, Shahbazi J, Mojarrad SD. In-silico investigation of tubulin binding modes of a series of novel antiproliferative spiroisoxazoline compounds using docking studies. Iranian Journal of Pharmaceutical Research. 2015;14(1):141-147
87.Hu MJ, Zhang B, Yang HK, Liu Y, Chen YR, Ma TZ, Lu L, You WW, Zhao PL. Design, synthesis and molecular docking studies of novel indole-pyrimidine hybrids as tubulin polymerization inhibitors. Chemical Biology & Drug Design. 2015;86(6):1491-1500. DOI: 10.1111/cbdd.12616
88.Kumbhar BV, Borogaon A, Panda D, Kunwar A. Exploring the origin of differential binding affinities of human tubulin isotypes αβII, αβIII and αβIV for DAMA-colchicine using homology modelling, molecular docking and molecular dynamics simulations. PLoS One. 2016;11(5):e0156048. DOI: 10.1371/journal.pone.0156048
89.Li H, Liu T, Xuan H, Fang S, Zhao C. A combination of pharmacophore modeling, virtual screening, and molecular docking studies for a diverse set of colchicine site inhibitors. Medicinal Chemistry Research. 2014;23(11):4713-4723. DOI: 10.1007/s00044-014-1028-7
90.Nguyen TL, McGrath C, Hermone AR, Burnett JC, Zaharevitz DW, Day BW, Wipf P, Hamel E, Gussio R. A common pharmacophore for a diverse set of colchicine site inhibitors using a structure-based approach. Journal of Medicinal Chemistry. 2005;48(19):6107-6116. DOI: 10.1021/jm050502t
Written By
Joanna Kurek
Submitted: 17 June 2017Reviewed: 21 November 2017Published: 06 February 2018
Open access peer-reviewed chapter
