**7. Pharmacological use of colchinoids**

#### **7.1. Colchicine prodrugs**

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**

bition 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**

**1:1 10:1**

*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].

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),

was modified at C-7 substituent [63].

**7.1. Colchicine prodrugs**

54 Cytotoxicity

**7.2. Drugs with colchicine**

**7. Pharmacological use of colchinoids**

**Inhibitor added Inhibitor:radiolabeled colchicine (%)**

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].

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].
