**Cytotoxic Colchicine Alkaloids: From Plants to Drugs**

**Cytotoxic Colchicine Alkaloids: From Plants to Drugs**

DOI: 10.5772/intechopen.72622

## Joanna Kurek Joanna Kurek Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72622

#### **Abstract**

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.

**Keywords:** colchicine, colchinoids, plants containing colchicine alkaloids, cytotoxic compounds, cancer cell lines, cytotoxic activity

## **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) [4–12].

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

**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, 13–16]. 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.

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

**Figure 2.** Meadow saffron *Colchicum autumnale*: bulb, flowers, and leaves (color version available on the online version).

Cytotoxic Colchicine Alkaloids: From Plants to Drugs http://dx.doi.org/10.5772/intechopen.72622 47

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 (−)-a*R*,7*S*-colchicine, the two rings (A and C) are

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

Starting compound was 1,2-*O*-didemethylcolchicine **16** converted into 1,2,3-*O*-tridemethyl colchiceine **17** [28–30], 1,2,3-*O*-tridemethyl-*N*-deacetylcolchiceine **18** [28–30], 1,2,3-*O*-tride methyl-*N*-deacetyl-*N*-trifluoroacetylcolchiceine **19** [28–30], and 1,2,3-*O*-tridemethyl-*N*-deace

derivatives [24, 25].

(\*author's own photos).

**3. Unusual chemical structure of colchinoids**

**4. Natural, semi-synthetic, and synthetic colchicines**

colchicine derivatives have been synthesized [28–30].

oriented in a clockwise manner [15].

### **2. Cytotoxic colchinoids in plants**

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

**Figure 2.** Meadow saffron *Colchicum autumnale*: bulb, flowers, and leaves (color version available on the online version). (\*author's own photos).

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].
