Colchicine analogues: Effect on amyloidogenesis in a murine model and, in vitro, on polymorphonuclear leukocytes

Abstract

Colchicine has been used in diverse clinical settings such as gout, familial Mediterranean fever, liver cirrhosis, Behcet's disease and pericarditis. It also has an antimitotic potential hitherto unexplored due to its narrow therapeutic toxic ratio. The aim of the present study was to compare the effectiveness and the toxicity of colchicine and three analogues: thiocolchicine, 2,3 dimethyl-colchicine and 3-dimethylthiocolchicine in the blockage of amyloid synthesis in a murine model. 3-demethylthiocolchicine was equipotent to colchicine in the blockage of casein induced amyloidogenesis. However, it was markedly less toxic (LD50 11.3 mg kg-1 vs. 1.6 mg kg-1). Thiocolchicine was toxic (LD50 1.0 mg kg-1) and 2,3 didemethyl-colchicine was far less effective. The effect of 3-dimethylthiocolchicine on polymorphonuclear leukocytes was then compared to colchicine. The effect of this analogue on inhibition of chemotaxis was equivalent to that of colchicine whereas the latter was superior to the analogue in the suppression of phagocytosis (by a ratio of 2:1) and in the inhibition of bactericidal activity (by a ratio of 10:1). Since in therapeutic concentrations the only detectable effect of colchicine on PMNs is inhibition of chemotaxis, our data may point to 3-demethylthiocolchicine as an optional, perhaps superior alternative to colchicine for some of its therapeutic indications.

Colchicine: A Promising Drug in Clinical Translation, A Minireview Focused on Cardiovascular Diseases

“…Indeed, 3-demethylcolchicine and 3-demethylthiocolchicine (3-demethyl-10-thiomethylcolchicine) and their glucosides have been shown to possess superior pharmacological properties, accompanied by decreased toxicity. In a mouse model of amyloidogenenesis, 3-demethylthiocolchicine was equipotent to colchicine in the blockage of casein induced amyloidogenesis, but it was markedly less toxic [20] . Thiocolchicine exerts its effect through interaction with tubulin at the same site as colchicine but probably with higher efficacy and affinity [21] as well as the other derivative N-acetylcolchinol O-methyl ether (NCME) [22] .…”

Cytotoxic Colchicine Alkaloids: From Plants to Drugs

“…After many years of searching colchicine derivatives as good cytotoxic agents, it was established that exchange of methoxyl substituent ─OCH 3 at C-10 position to amino group (NH 2 , NHR 1 , or NR 1 R 2 ) and especially to methylthio (CH 3 S─) 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.…”

Plausibility of patient-centred care in high-intensity methadone treatment: reflections of providers and patients

“…Patient centered care (PCC) reorients care to focus on essential outcomes to the patient and creates space for the patient’s to be engaged as equals, all while acknowledging them as individuals with unique values, experiences, and goals [ 15 – 17 ]. Because patients on methadone treatment are often socially marginalized, they lack social support and advocates [ 6 ]; therefore, HCPs have moral and ethical obligations to advocate and support patients in their treatment journey regardless of their conditions [ 18 , 19 ], PCC is a beneficial framework when working with this community. PCC framework contradicts the paternalistic biomedical model of care because it considers patients' preferences or wishes [ 20 ].…”