**3. Unusual chemical structure of colchinoids**

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

**Figure 1.** Colchicine molecule (color version available on the online version).

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

toxicity.

46 Cytotoxicity

**2. Cytotoxic colchinoids in plants**

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 oriented in a clockwise manner [15].
