Colchicine is a well-known compound with strong antiproliferative activity that has had limited use in chemotherapy because of its toxicity. In order to create more potent anticancer agents, a series ...of novel colchicine derivatives have been obtained by simultaneous modification at C7 (amides and sulfonamides) and at C10 (methylamino group) positions and characterized by spectroscopic methods. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX and BALB/3T3 cell lines. Additionally, the activity of the studied compounds was investigated using computational methods involving molecular docking of the colchicine derivatives to β-tubulin. The majority of the obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin or cisplatin against tested cancer cell lines. Furthermore, molecular modeling studies of the obtained compounds revealed their possible binding modes into the colchicine binding site of tubulin.
(−)-Colchicine, an anti-microtubulin polymerization agent, is a valuable medication and the drug of choice for gout, Behçet’s disease and familial Mediterranean fever. It has a narrow therapeutic ...index due to its high toxicity towards normal cells. Nonetheless, numerous (−)-colchicine derivatives have been synthesized and studied for their structure-activity relationship and preferential toxicity. Different functional groups such as amides, thioamides, N-arylurea and 8,12-diene cyclic have been incorporated into (−)-colchicine, resulting in derivatives (with moieties) that include electron-withdrawing and electron-donating groups. This review article focuses on recent developments in the chemical synthesis of (−)-colchicine derivatives, the substituents used, the functional groups linked to the substituents, the moieties and biological studies. Moreover, the current classification of derivatives based on the (−)-colchicine rings, namely ring A, B, and C (−)-colchicine derivatives, is discussed. This work demonstrates and summarizes the significance of (−)-colchicine derivatives in the biological field, and discusses their promising therapeutics for the future.
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•(−)-Colchicine is an anti-microtubulin polymerization agent with low therapeutic index.•Derivatization of (−)-colchicine improve the activity and lower the cytotoxicity.•Several functional groups were incorporated to (−)-colchicine with different moieties.•Structure-Activity Relationship (SAR) were studied on different (−)-colchicine derivatives.•The moiety position on (−)-colchicine and the functional group play an important role on SAR.
Few complete pathways have been established for the biosynthesis of medicinal compounds from plants. Accordingly, many plant-derived therapeutics are isolated directly from medicinal plants or plant ...cell culture
. A lead example is colchicine, a US Food and Drug Administration (FDA)-approved treatment for inflammatory disorders that is sourced from Colchicum and Gloriosa species
. Here we use a combination of transcriptomics, metabolic logic and pathway reconstitution to elucidate a near-complete biosynthetic pathway to colchicine without prior knowledge of biosynthetic genes, a sequenced genome or genetic tools in the native host. We uncovered eight genes from Gloriosa superba for the biosynthesis of N-formyldemecolcine, a colchicine precursor that contains the characteristic tropolone ring and pharmacophore of colchicine
. Notably, we identified a non-canonical cytochrome P450 that catalyses the remarkable ring expansion reaction that is required to produce the distinct carbon scaffold of colchicine. We further used the newly identified genes to engineer a biosynthetic pathway (comprising 16 enzymes in total) to N-formyldemecolcine in Nicotiana benthamiana starting from the amino acids phenylalanine and tyrosine. This study establishes a metabolic route to tropolone-containing colchicine alkaloids and provides insights into the unique chemistry that plants use to generate complex, bioactive metabolites from simple amino acids.
Patients with chronic coronary disease were randomly assigned to receive 0.5 mg of colchicine once daily or matching placebo. The incidence of the composite end point of cardiovascular death, ...spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was significantly lower with colchicine than with placebo.
Colchicine: Old and New Slobodnick, Anastasia, MD; Shah, Binita, MD, MSCI; Pillinger, Michael H., MD ...
The American journal of medicine,
05/2015, Letnik:
128, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Abstract Although colchicine has been a focus of research, debate, and controversy for thousands of years, the US Food and Drug Administration just approved it in 2009. Over the past decade, advances ...in the knowledge of colchicine pharmacology, drug safety, and mechanisms of action have led to changes in colchicine dosing and to potential new uses for this very old drug. In this review, we discuss the pharmacologic properties of colchicine and summarize what is currently known about its mechanisms of action. We then discuss and update the use of colchicine in a variety of illnesses, including rheumatic and, most recently, cardiovascular diseases.
•Colchicine binding site inhibitors (CBSIs) emerge as new generations of tubulin inhibitors.•CBSIs are less susceptible to multidrug resistance than FDA-approved tubulin inhibitors.•X-ray structures ...provide detail molecular interactions for the flexible colchicine binding site.•X-ray crystallography helps the design of novel CBSIs since the first structure reported in 2004.•CBSIs are generally suitable for X-ray structure guided structural optimizations.
Tubulin is an important cancer drug target. Compounds that bind at the colchicine site in tubulin have attracted significant interest as they are generally less affected by multidrug resistance than other potential drugs. Modeling is useful in understanding the interactions between tubulin and colchicine binding site inhibitors (CBSIs), but because the colchicine binding site contains two flexible loops whose conformations are highly ligand-dependent, modeling has its limitations. X-ray crystallography provides experimental pictures of tubulin–ligand interactions at this challenging colchicine site. Since 2004, when the first X-ray structure of tubulin in complex with N-deacetyl-N-(2-mercaptoacetyl)-colchicine (DAMA-colchicine) was published, many X-ray crystal structures have been reported for tubulin complexes involving the colchicine binding site. In this review, we summarize the crystal structures of tubulin in complexes with various CBSIs, aiming to facilitate the discovery of new generations of tubulin inhibitors.
Abstract Aim Familial Mediterranean Fever (FMF) is the most common recurrent autoinflammatory fever syndrome. Still, many issues—e.g.: colchicine dosage adjustment, maximum dosage of colchicine in ...children and adults, definition of colchicine resistance, alternative treatment solutions in colchicine-resistant patients, and genetic screening for asymptomatic siblings—have not yet been standardized. The current paper aims at summarizing consensus recommendations to approach these issues. Methods A literature review concerning these practical management questions was performed through PubMed. On the basis of this analysis, expert recommendations were developed during a consensus meeting of caregivers from France and Israel. Results A patient experiencing more than four FMF attacks a year needs colchicine dose adjustment. In case of persistent attacks (≥6 per year) in patients with maximum doses of colchicine (2 mg in children; 3 mg in adults), alternative treatment to colchicine with IL1 inhibitors should be considered. Routine genetic testing for MEFV mutations in asymptomatic siblings of an index case is not recommended. Conclusion This is a first attempt to resolve practical questions in the daily management of FMF patients.
Summary
Colchicine is a treatment for gout that has been used for more than a millennium. It is the treatment of choice for familial Mediterranean fever and its associated complication, amyloidosis. ...The 2009 U.S. Food and Drug Administration approval of colchicine as a new drug had research consequences. Recent investigations with large cohorts of patients with gout who have been taking colchicine for years have demonstrated novel applications within oncology, immunology, cardiology and dermatology. Some emerging dermatological uses include the treatment of epidermolysis bullosa acquisita, leucocytoclastic vasculitis, aphthous stomatitis and others. In this work we relate the history and the new horizon of this ancient medicine.
What's already known about this topic?
Colchicine has a safe long‐term profile as an anti‐inflammatory agent.
Colchicine is most effective in treating neutrophilic inflammation.
It is the treatment of choice for gout and familial Mediterranean fever.
What does this study add?
A review of recent studies with a fresh look at colchicine.
We examine new indications for colchicine as a repurposed medication including for dermatological conditions and cardiovascular disease, and its potential application as a chemopreventative agent for solid tumours.
Plain language summary available online
Inflammation appears to play a role in atherosclerosis, raising the possibility that treatments that reduce inflammation could prevent cardiovascular events. In a randomized, placebo-controlled trial ...involving 4745 patients with recent myocardial infarction, low-dose colchicine (0.5 mg once daily) prevented ischemic cardiovascular events.
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