Agents Colchicine Research Articles

Colchicine to reduce coronavirus disease-19-related inflammation and cardiovascular complications in high-risk patients post-acute infection with SARS-COV-2—a study protocol for a randomized controlled trial

BackgroundThere is no known effective pharmacological therapy for long COVID, which is characterized by wide-ranging, multisystemic, fluctuating, or relapsing symptoms in a large proportion of survivors of acute COVID. This randomized controlled trial aims to assess the safety and efficacy of an anti-inflammatory agent colchicine, to reduce symptoms among those at high risk of developing long COVID.MethodsThis multi-centre, parallel arm, 1:1 individual randomized, placebo-controlled, double-blind superiority trial will enrol 350 individuals with persistent post-COVID symptoms. Participants will be randomized to either colchicine 0.5 mg once daily (< 70 kg) or twice daily (≥ 70 kg) or matched placebo for 26 weeks and will be followed up until 52 weeks after randomization. The primary trial objective is to demonstrate the superiority of colchicine over a placebo in improving distance walked in 6 min at 52 weeks from baseline. The secondary objectives are to assess the efficacy of colchicine compared to placebo with respect to lung function, inflammatory markers, constitutional symptoms, and mental health state. In a sub-sample of 100 participants, cardiac biomarkers of myocardial injury and myocardial oedema using MRI will be compared.DiscussionPersistent inflammatory response following SARS-CoV-19 is one of the postulated pathophysiological mechanisms of long COVID. Colchicine, a low-cost anti-inflammatory agent, acts via multiple inflammatory pathways and has an established safety profile. This trial will generate evidence for an important health priority that can rapidly translate into practice.Trial registrationThis clinical trial has been registered prospectively on www.clinicaltrials.gov with registration CTRI/2021/11/038234 dated November 24, 2021.

A molecular analysis of substituted phenylethylamines as potential microtubule targeting agents through in silico methods and in vitro microtubule-polymerization activity

Natural phenethylamines are trace amine neurotransmitters associated with dopamine transmission and related illnesses such Parkinson’s disease, and addiction. Synthetic phenethylamines can have psychoactive and hallucinogenic effects due to their high affinity with the 5-HT2A receptor. Evidence indicates phenethylamines can directly alter the microtubule cytoskeleton being structurally similar to the microtubule destabilizing agent colchicine, however little work has been done on this interaction. As microtubules provide neuron structure, intracellular transport, and influence synaptic plasticity the interaction of phenethylamines with microtubules is important for understanding the potential harms, or potential pharmaceutical use of phenethylamines. We investigated 110 phenethylamines and their interaction with microtubules. Here we performed molecular docking of these compounds at the colchicine binding site and ranked them via binding energy. The top 10% of phenethylamines were further screened based on pharmacokinetic and physicochemical properties derived from SwissADME and LightBBB. Based on these properties 25B-NBF, 25C-NBF, and DMBMPP were tested in in vitro microtubule polymerization assays showing that they alter microtubule polymerization dynamics in a dose dependent manner. As these compounds can rapidly cross the blood brain barrier and directly affect cytoskeletal dynamics, they have the potential to modulate cytoskeletal based neural plasticity. Further investigations into these mechanisms are warranted.

The potential of colchicine for lowering the risk of cardiovascular events in type 1 diabetes.

In type 1 diabetes, average life expectancy is reduced by ˃10 years as compared with outside of diabetes. Residual cardiovascular risk defines high cardiovascular event rate despite modern, guideline-recommended standard of care of established risk factors like hypertension, dyslipidaemia, and glycaemic control, and it adds importantly to these lost years of life in type 1 diabetes due to atherosclerotic cardiovascular diseases like myocardial infarction and ischaemic stroke. With a growing understanding of inflammation as an important driver of atherosclerotic cardiovascular disease, residual inflammatory risk is a novel and common risk factor and a promising target for lowering residual cardiovascular risk in type 1 diabetes. Interestingly, the inexpensive anti-inflammatory agent colchicine reduced the risk of major adverse cardiovascular events by 25% in cardiovascular outcome trials in the secondary prevention of atherosclerotic cardiovascular disease. Here, we summarize the role of inflammation as a driver of atherosclerosis and review current evidence linking inflammation and atherosclerotic cardiovascular disease in type 1 diabetes. Also, we provide an overview of the evidence base for targeting residual inflammatory risk with colchicine for lowering residual cardiovascular risk in type 1 diabetes.

Colchicine as a Modulator of Platelet Function: A Systematic Review.

The microtubule inhibitor and anti-inflammatory agent colchicine is used to treat a range of conditions involving inflammasome activation in monocytes and neutrophils, and is now known to prevent coronary and cerebrovascular events. In vitro studies dating back more than 50 years showed a direct effect of colchicine on platelets, but as little contemporary attention has been paid to this area, we have critically reviewed the effects of colchicine on diverse aspects of platelet biology in vitro and in vivo. In this systematic review we searched Embase, Medline, and PubMed for articles testing platelets after incubation with colchicine and/or reporting a clinical effect of colchicine treatment on platelet function, including only papers available in English and excluding reviews and conference abstracts. We identified 98 relevant articles and grouped their findings based on the type of study and platelet function test. In vitro, colchicine inhibits traditional platelet functions, including aggregation, clotting, degranulation, and platelet-derived extracellular vesicle formation, although many of these effects were reported at apparently supraphysiological concentrations. Physiological concentrations of colchicine inhibit collagen- and calcium ionophore-induced platelet aggregation and internal signaling. There have been limited studies of in vivo effects on platelets. The colchicine-platelet interaction has the potential to contribute to colchicine-mediated reduction in cardiovascular events, but there is a pressing need for high quality clinical research in this area.

Association between Clinical Use of Colchicine and Risk of Type 2 Diabetes Mellitus among Gouty Patients: A Nationwide Cohort Study.

Background: Gout is the most common form of inflammatory arthritis in adults. Even though a link between gouty arthritis and type 2 diabetes mellitus (T2DM) has been reported, there is a limited understanding of the association between the anti-inflammatory agent colchicine and the risk of T2DM. This aim of this study was to assess the association between the use of colchicine and the risk of T2DM in an Asian cohort. Methods: A retrospective cohort study was conducted using the National Health Insurance Research Database (NHIRD) in Taiwan from 2000 to 2013. The study cohorts comprised 3841 gouty patients using colchicine (the exposed cohort) and 7682 gouty patients not using colchicine (the unexposed -cohort). The primary outcome was incident DM. The hazard ratios (HRs) and 95% confidence intervals (CIs) derived from a Cox proportional regression model were used to assess the association between colchicine use and the risk of diabetes. Results: The cumulative incidence of T2DM was significantly lower in the exposed cohort (18.8%) than in the unexposed cohort (25.0%). The risk of T2DM was significantly lower in colchicine users than in non-users (adjusted HR, 0.74; 95% CI, 0.36–0.87). The inverse relationship between colchicine use and diabetes risk remained consistent across sex and age groups. Conclusions: This cohort study provides longitudinal evidence that the use of colchicine is associated with a reduced risk of T2DM. This conclusion, however, needs to be interpreted cautiously given the lack of body mass index data in the NHIRD. Further studies are needed to determine the clinical implications of this study.

Inhibition of Microtubule Dynamics in Cancer Cells by Indole-Modified Latonduine Derivatives and Their Metal Complexes

Indolo[2,3-d]benzazepines (indololatonduines) are rarely discussed in the literature. In this project, we prepared a series of novel indololatonduine derivatives and their RuII and OsII complexes and investigated their microtubule-targeting properties in comparison with paclitaxel and colchicine. Compounds were fully characterized by spectroscopic techniques (1H NMR and UV–vis), ESI mass-spectrometry, and X-ray crystallography, and their purity was confirmed by elemental analysis. The stabilities of the compounds in DMSO and water were confirmed by 1H and 13C NMR and UV–vis spectroscopy. Novel indololatonduines demonstrated anticancer activity in vitro in a low micromolar concentration range, while their coordination to metal centers resulted in a decrease of cytotoxicity. The preliminary in vivo activity of the RuII complex was investigated. Fluorescence staining and in vitro tubulin polymerization assays revealed the prepared compounds to have excellent microtubule-destabilizing activities, even more potent than the well-known microtubule-destabilizing agent colchicine.

Colchicine reduces atherosclerotic plaque vulnerability in rabbits

Background and aimsThe anti-inflammatory agent colchicine is gaining interest as a treatment for coronary artery disease. However, the effects of colchicine in atherosclerotic animal models are mostly unknown. This study aimed to evaluate colchicine in a rabbit model of atherosclerosis. MethodsTwenty-two rabbits were fed a 0.5% cholesterol-enriched diet for 10 weeks and then randomized to receive either oral saline (n=11) or colchicine (350 μg/kg/day; n=11) for 6 weeks, with 0.2% cholesterol-diet during the treatment period. We performed intravascular ultrasound imaging (at start and end of treatment) and histology analyses of the descending thoracic aorta. Leucocyte activation was assessed in vitro on blood samples obtained during treatment. ResultsColchicine prevented positive aortic vascular remodelling (p=0.029 vs placebo). This effect was even more marked at high plasma cholesterol level (third quartile of plasma cholesterol, p=0.020). At high cholesterol level, both atherosclerotic plaque and media areas on histomorphology were reduced by colchicine compared to placebo (p=0.031 and p=0.039, respectively). Plaque fibrosis and macrophage area were reduced by colchicine (Masson's trichrome stain: p=0.038; RAM-11: p=0.026). The plaque vulnerability index, assessed by histology, was reduced by colchicine (p=0.040). Elastin/type I collagen ratio in media was significantly higher with colchicine compared to placebo (p=0.013). At a high level of plasma cholesterol, in vitro LPS challenge revealed a decrease in monocyte activation following treatment with colchicine (p<0.001) and no change in the placebo group (p=0.353). ConclusionsColchicine decreases plaque vulnerability with reductions in plaque inflammation, medial fibrosis, outward vascular remodelling and ex vivo monocyte activation.

In vivo polyploidy induction of Phalaenopsis amabilis in a bubble bioreactor system using colchicine

Abstract Phalaenopsis amabilis Blume var. grandiflora Bateman is economically important as cut and pot flower. Polyploidy is considered as a valuable tool in improvement and evolution of ornamental plants. Protocorm-like bodies (PLBs) of P. amabilis were cultured on Murashige and Skoog medium containing 0.20 mg L-1 IBA together with 2.00 mg L-1 KIN and 1.00 g L-1 activated charcoal and grown for a period of five months. Fully-developed plantlets from in vitro grown PLBs were immersed in a bubble reactor filled with half-strength Hoagland solution containing the antimitotic agent colchicine (0.05%, 0.10% and 0.15%, w/v) for 72 h with a few drops (1 mL of 0.1%) of octylphenoxypolyethoxyethanol or Nonidet (P-40) as a surfactant. Plantlets were aerated to prevent hypoxia. Colchicine-treated and untreated plantlets were transferred to pots for a period of 60 days. Tetraploidy was successfully induced by 0.15% colchicine. Polyploidy levels were firstly detected using flow cytometry and then confirmed by cytological and morphological observations. The chromosome number was 2n = 2x = 38 in diploids and 2n = 4x = 76 in tetraploid. Incubation of plantlets in liquid medium containing 0.15% colchicine induced the maximum recovered tetraploids with minimum frequency of survival (50%). The tetraploid plants were more compact and exhibited round and thick leaves with darker green color than diploids. Stomata size in tetraploids were larger with less density than diploids. Chloroplast number in guard cells of tetraploids was about two times more than that of control. These results indicate that induction of tetraploids are a reliable and powerful tool for generation of novel phenotypes with ornamental and horticultural value for genetic improvement and breeding. Produced tetraploids in current study have potential in the ornamental/floriculture trade.

Microtubule-dependent mechanism of anti-inflammatory effect of SOCS1 in endothelial dysfunction and lung injury.

Suppressors of cytokine signaling (SOCS) provide negative regulation of inflammatory reaction. The role and precise cellular mechanisms of SOCS1 in control of endothelial dysfunction and barrier compromise associated with acute lung injury remain unexplored. Our results show that siRNA-mediated SOCS1 knockdown augmented lipopolysaccharide (LPS)-induced pulmonary endothelial cell (EC) permeability and enhanced inflammatory response. Consistent with in vitro data, EC-specific SOCS1 knockout mice developed more severe lung vascular leak and accumulation of inflammatory cells in bronchoalveolar lavage fluid. SOCS1 overexpression exhibited protective effects against LPS-induced endothelial permeability and inflammation, which were dependent on microtubule (MT) integrity. Biochemical and image analysis of unstimulated EC showed SOCS1 association with the MT, while challenge with LPS or MT depolymerizing agent colchicine impaired this association. SOCS1 directly interacted with N2 domains of MT-associated proteins CLIP-170 and CLASP2. Furthermore, N-terminal region of SOCS1 was indispensable for these interactions and SOCS1-ΔN mutant lacking N-terminal 59 amino acids failed to rescue LPS-induced endothelial dysfunction. Depletion of endogenous CLIP-170 or CLASP2 abolished SOCS1 interaction with Toll-like receptor-4 and Janus kinase-2 leading to impairment of SOCS1 inhibitory effects on LPS-induced inflammation. Altogether, these findings suggest that endothelial barrier protective and anti-inflammatory effects of SOCS1 are critically dependent on its targeting to the MT.

C(7)-Derivatives of colchicine with guanosine and biphenyl moieties: molecular modeling, synthesis, and tubulin clustering effect in cancer cells

Two novel C(7)-derivatives of natural anticancer agent colchicine were designed with the purpose to study their ability to induce tubulin clustering in cancer cells. The compounds were synthesized via amidation of N-deacetylcolchicine and Steglich esterification. The conjugate of colchicine with the guanosine derivative possesses moderate cytotoxicity to these cells (EC50 = 13.7 µmol L−1) inducing the depolymerization of microtubules of human lung carcinoma A549 cells but does not stimulate the formation of tubulin clusters. The colchicine conjugate with the biphenyl moiety causes a strong tubulin clustering comparable to that of anticancer agent tubuloclustin. This effect was observed for the first time for the colchicine derivative bearing no substituent at the acetyl group capable of forming hydrogen bonds with target protein.

Prescription of Colchicine with Other Dangerous Concomitant Medications: A Nation-Wide Survey Using the Japanese Claims Database.

The anti-inflammatory agent colchicine may cause toxic effects such as rhabdomyolysis, pancytopenia, and acute respiratory distress syndrome in cases of overdose and when patients have renal or liver impairment. As colchicine is a substrate for CYP3A4 and P-glycoprotein (P-gp), drug-drug interactions are important factors that cause fatal colchicine-related side effects. Thus, we conducted a nation-wide survey to determine the status of inappropriate colchicine prescriptions in Japan. Patients prescribed the regular use of colchicine from April 2014 to March 2017 were identified using the Japanese large health insurance claims database. As the primary endpoint, we evaluated the concomitant prescription proportions of strong CYP3A4 and/or P-gp inhibitors classified as "contraindications for co-administration" with colchicine in patients with renal or liver impairment. We defined these cases as "inappropriate colchicine prescriptions." Additionally, factors affecting inappropriate colchicine prescriptions were analyzed. Among the 3302 enrolled patients, 43 (1.30%) were inappropriately prescribed colchicine. Of these 43 patients, 11 had baseline renal and/or liver impairment. By multiple regression analysis, the primary diseases "gout" and "Behçet's disease" were extracted as independent factors for inappropriate colchicine prescriptions with odds ratios of 0.40 (95% confidence interval: 0.19-0.84) and 4.93 (95% confidence interval: 2.12-11.5), respectively. We found that approximately 1% of patients had important colchicine interactions. Particularly, Behçet's disease was a risk factor for inappropriate prescriptions, with approximately 25% of patients showing renal and/or liver impairment (classified as "contraindications for co-administration"). These findings may be useful for medical professionals who prescribe colchicine therapy.

Synthesis, Characterization, in silico and in vitro Studies of Transition Metal Complexes with Biologically Active Ligand as Antigout Agent Colchicine

Colchicine is essentially useful in the treatment of gout. In the present work Colchicine Complexes has been prepared with transition metals viz; Copper(II) [Cu(II)], Zinc (II) [Zn(II)], Cobalt (II) [Co(II)], Nickel (II) [Ni(II)] and those checked for molecular docking, it has been observed that Zn(II) and Ni(II) complex has revealed good binding energy than the parent ligand, the increased binding energy of colchicine metal complexes indicates that, the tubulin polymerization inhibitor tendency is enhanced, consequently antigout property is also increased. As transition metals have antimicrobial activity in themselves, complexes are also characterized for the antimicrobial activity which is enhanced for Cu(II) and Co(II) metals.

From CANTOS to CIRT to COLCOT to Clinic: Will All Atherosclerosis Patients Soon Be Treated With Combination Lipid-Lowering and Inflammation-Inhibiting Agents?

From CANTOS to CIRT to COLCOT to Clinic: Will All Atherosclerosis Patients Soon Be Treated With Combination Lipid-Lowering and Inflammation-Inhibiting Agents?

EVALUATION OF [11C]MPC-6827 AS A MICROTUBULE TARGETING PET RADIOTRACER IN CANCER CELL LINES

Objective: The objective of this study was to evaluate the uptake and specificity of [11C]MPC-6827, a MT targeted PET ligand in prostate, glioblastoma and breast cancer cells.&#x0D; Methods: [11C]MPC-6827 was synthesized by reacting corresponding desmethyl precursors with [11C]CH3I in a GE-FX2MeI/FX2M radiochemistry module. In vitro binding of [11C]MPC-6827 was performed in breast cancer MDA-MB-231, glioblastoma (GBM) patient-derived tumor (GBM-PDX), GBM U251 and prostate cancer 3 (PC3) cell lines at 37 °C in quadruplicate at 5, 15, 30, 60, and 90 minute incubation time. The nonspecific bindings were determined by incubation with unlabeled microtubule targeting agents MPC-6827, HD-800, colchicine, paclitaxel and docetaxel (5.0 mM).&#x0D; Results: [11C]MPC-6827 provided the highest binding in the breast cancer cell, MDA-MB-231, among all the cells studied, with 90% specific binding. [11C]MPC-6827 binds to glioblastoma PDX and U251 cells with ~50% and 40% specific binding, whereas, prostate cancer cell line, PC3 cells showed 40% specific binding. [11C]MPC-6827 also exhibits binding to the taxane and colchicine binding sites of MTs, in MDA-MB-231 cells.&#x0D; Conclusion: These data indicate that [11C]MPC-6827 can be a promising PET radiotracer for preclinical imaging of the brain and peripheral cancers.

Equilibrium transport velocity of deformable cells and rigid spheres in micro-channels under laminar flow conditions

Inertial migration of particles to a characteristic lateral equilibrium position in laminar micro-flows has been investigated under various aspects during the last decades. The majority of the studies deal with the equilibrium position of rigid particles and viscous droplets. Here, we compare the equilibrium velocity of viscoelastic cells and rigid polystyrene spheres in flow by applying the method of spatially modulated emission. The technique allows the precise determination of the equilibrium velocity of an object in flow, which has been found to depend on object characteristics like size in earlier studies. Here, we first show that the deformable cells move at higher equilibrium velocity than rigid polystyrene particles, thus revealing that a particle’s equilibrium velocity is related to its deformability—in addition to size. In a second set of experiments, we treat cells with the cytostatic agent colchicine, which results in a systematic decrease of the equilibrium velocity that is attributed to cell stiffening. This study thus provides evidence that the parameter cell deformability can be extracted from the equilibrium velocity based on spatially modulated emission, which opens up an alternative way for high-throughput cell-deformability characterization.

Evaluation of anti-tumour properties of two depsidones - Unguinol and Aspergillusidone D - in triple-negative MDA-MB-231 breast tumour cells.

There is an ongoing search for new compounds to lower the mortality and recurrence of breast cancer, especially triple-negative breast cancer. Naturally occurring depsidones, extracted from the fungus Aspergillus, are known for their wide range of biological activities such as cytotoxicity, aromatase inhibition, radical scavenging, and antioxidant properties. Research showed the potential of depsidones as a treatment option for hormone receptor-positive breast cancer treatment, yet its effects on hormone receptor-negative breast cancer are still unkown. This study, therefore, investigated the potential of two depsidones (Unguinol and Aspergillusidone D) to induce apoptosis, cell cycle arrest and cytotoxicity, and reduce cell proliferation in the triple-negative MDA-MB-231 breast cancer cell line. Results were compared with the effects of the cytostatic drug doxorubicin, antimitotic agent colchicine and endogenous hormones 17β-estradiol, testosterone and dihydrotestosterone. The cytostatic drugs and hormones affected the MDA-MB-231 cell line comparable to other studies, showing the usefulness of this model to study the effects of depsidones on a triple-negative breast cancer cell line. At sub μM levels, Unguinol and Aspergillusidone D did not influence cell proliferation, while cell viability was reduced at concentrations higher than 50 μM. Both depsidones induced apoptosis, albeit not statistically significantly. In addition, Unguinol induced cell cycle arrest in MDA-MB-231 cells at 100 μM. Our research shows the potential of two depsidones to reduce triple-negative breast cancer cell survival. Therefore, this group of compounds may be promising in the search for new cancer treatments, especially when looking at similar depsidones.

In vitro polyploidisation of tulips (Tulipa gesneriana L.) — Phenotype assessment of tetraploids

Abstract In vitro adventitious shoot cultures of three diploid tulip cultivars ('Fringed Black', 'Victor' and Pol-D 32) were treated with antimitotic agents (colchicine 200 mg L−1, oryzalin 5 mg L−1, amiprophos methyl 15 mg L−1 or trifluralin 100 mg L−1) in order to obtain tetraploids. The treatments with colchicine were the most phytotoxic, resulting in the reduction of the survival rate to 50% in ‘Fringed Black’ and to 0–12.5% in two other cultivars. Among the three tulip cultivars, homogenous polyploids were obtained only for 'Fringed Black' (28 tetraploids and 4 octoploids). Each of the antimitotic agents induced the formation of polyploids, with the highest number for colchicine treatments; in total, 20 polyploids were detected. Phenotype observations were performed in the fifth growing season. Compared to diploids, in tetraploids the percentage of flowering plants was lower and flowering was delayed on average by six days. Mitotic polyploidisation had also negative side effects on leaves and flowers, which in tetraploids were significantly smaller: leaf width reduced by 30%, tepals reduced by 45%. Tepals were more rounded and more fringed in tetraploids. Flower scapes of tetraploids were shorter by 40% but their diameters were slightly larger as compared to diploids. Stomata were longer by 30% and pollen grain diameter was larger by 25% in tetraploids. Tetraploid were fertile, pollen germination was on average 6.3%, whereas in diploids it was 30.3%. Microscopic observation of flower scapes on transverse sections revealed increased cell diameters of the epidermis and the cortex and significant reduction of collenchyma layers in tetraploids, resulting in higher fragility of the scape.

Abstract 127: Colchicine Attenuates Vein Wall Scarring in Murine Venous Thrombosis: Implications for Limiting the Post-Thrombotic Syndrome

Objective: In this study, we investigated the effects of colchicine on vein wall inflammation and scarring, and thrombus burden/VT resolution, key drivers of the PTS. Methods: Inferior vena cava (IVC) stasis VT were created in C57BL/6 mice (n=60). Colchicine (0.2 or 0.02 mg/kg for high or low dose, respectively) was administered daily via intraperitoneal injection starting 24 hours after VT initiation. At VT timepoints of day 4, 8 and 14, mice were sacrificed and VT were resected for measurements of thrombus. Picrosirius-red staining of VT sections assessed vein wall thickness. Serial sections were processed for Carstairs fibrin staining and immunostaining. The number of vein wall fibroblasts and macrophages per 5 high-power fields (400х) were calculated. Results: Colchicine significantly decreased venous thrombus-induced vein wall scarring at Day 8 (PBS 71.53±6.97μm, Col lo 55.11±5.48μm, Col hi 46.84±2.03μm; n=5 per group; PBS vs Col lo, P &lt; 0.01; Col lo vs Col hi, P &lt; 0.05) and at Day 14 (PBS 55.29±8.97μm, Col lo 45.20±2.73μm, Col hi 42.68±3.57μm; n=4-7 per group; PBS vs Col lo, P &lt; 0.05; PBS vs Col hi, P &lt; 0.05; Col lo vs Col hi, P &gt; 0.05). Colchicine reduced the number of vein wall F4/80+ macrophages (PBS vs Col hi, 73.33±8.63 vs 55.87±8.07, n=5 per group, P &lt; 0.01) and FSP1+ cells (PBS vs Col hi, 73.80±8.01 vs 41.60±8.37, n=5 per group, P &lt; 0.01) in DVT D8. Also, colchicine reduced RNA expression of both profibrotic (collagen I, collagen III, procollagen I, procollagen III, FSP1) and proinflammatory (IL-1β, CD68) markers in DVT D8 (n=8 per group, P &lt; 0.05). Of note, despite possessing anti-inflammatory actions, colchicine did not impair VT resolution (measured by thrombus mass) at D4 PBS vs Col hi, 27.00±5.11 vs 23.47±6.03mg/cm, n=9-12 per group, P &gt; 0.05) nor at D8 (PBS vs Col hi, 19.05±5.23 vs 15.58±6.52mg/cm, n=12 per group, P &gt; 0.05). Conclusion: The FDA-approved agent colchicine reduces experimental VT-induced vein wall scarring without impairing thrombus resolution. Anti-scarring effects may be related to attenuated inflammation of fibrotic mediators in the vein wall and adherent thrombus. Colchicine may offer a clinically viable option to reduce the post-thrombotic syndrome induced by deep vein thrombosis.

New 3-Substituted-2-(4-hydroxyanilino)pyridine Derivatives: Synthesis, Antitumor Activity, and Tubulin Polymerization Inhibition.

A series of new pyridine derivatives 4a-c, 5a-d, 6a-d, 7a-f, and 8a-f structurally related to ABT-751 were synthesized and characterized by spectroscopic means and elemental analysis. All the synthesized compounds were tested for their cytotoxic activity in vitro against the HCT-116 and HepG-2 cancer cell lines using the MTT assay. The results showed that compound 8d has higher cytotoxic activity than the reference antimitotic agent colchicine, against both tested cell lines, with IC50 = 0.52 and 1.40 μM, respectively. The three most active compounds, 5d, 8b, and 8d, were further screened in vitro for inhibition of tubulin and showed remarkable results in comparison to colchicine.

Synthesis of colchifulvin, a colchicine–griseofulvin hybrid

Since the antimitotic agent colchicine (4) and the antifungal antibiotic griseofulvin (5) bind the same target (tubulin), we have explored the possibility of combining the potency of 4 and the low-toxicity of 5 into a hybrid [colchifulvin (6)], where the aromatic A-ring of 4 is bound to a dienone C-ring in a spiro fashion reminiscent of 5. To this purpose, the intramolecular oxidative cyclization of bibenzyl and stilbenoid precursors of spiro[4.5]decadienones was investigated, eventually taming the unexpected subtleties of the reaction. Disappointingly, rac-6 did not share the biological profile of the two inspiring lead structures.