curcumin and dibenzylidene-acetone

Visceral leishmaniasis (VL, also known as kala-azar) is a vector borne disease caused by obligate intracellular protozoan parasite Leishmania donovani. To overcome the limitations of currently available drugs for VL, molecular target-based study is a promising tool to develop new drugs to treat this neglected tropical disease. One such target we recently identified from L. donovani (Ld) genome (WGS, clinical Indian isolate; BHU 1220, AVPQ01000001) is a small GTP-binding protein, Rab6 protein. We now report a specific inhibitor of the GTPase activity of Rab6 protein of L. donovani (LdRab6) without restricting host enzyme activity. First, to understand the nature of LdRab6 protein, we generated recombinant LdRab6 mutant proteins (rLdRab6) by systematically introducing deletion (two cysteine residues at C-terminal) and mutations [single amino acid substitutions in the conserved region of GTP (Q84L)/GDP(T38N) coding sequence]. The GTPase activity of rLdRab6:GTP and rLdRab6:GDP locked mutant proteins showed ~ 8-fold and ~ 1.5-fold decreases in enzyme activity, respectively, compared to the wild type enzyme activity. The mutant protein rLdRab6:ΔC inhibited the GTPase activity. Sequence alignment analysis of Rab6 protein of L. donovani with Homo sapiens showed identical amino acids in the G conserved region (GTP/GDP-binding sites) but it differed in the C-terminal region. We then evaluated the inhibitory activity of trans-dibenzalacetone (DBA, a synthetic analog of curcumin with strong antileishmanial activity reported earlier by us) in the GTPase activity of LdRab6 protein. Comparative molecular docking analysis of DBA and specific inhibitors of Rab proteins (Lovastatin, BFA, Zoledronate, and NE10790) indicated that DBA had optimum binding affinity with LdRab6 protein. This was further confirmed by the GTPase activity of DBA-treated LdRab6 which showed a basal GTP level significantly lower than that of the wild-type rLdRab6. The results confirm that DBA inhibits the GTPase activity of LdRab6 protein from L. donovani (LdRab6), a potential target for its antileishmanial effect.

Topics: Amino Acid Sequence; Antiprotozoal Agents; Binding Sites; Curcumin; Enzyme Inhibitors; Humans; Leishmania donovani; Leishmaniasis, Visceral; Molecular Docking Simulation; Pentanones; Protozoan Proteins; rab GTP-Binding Proteins; Sequence Alignment

Curcumin is the major phenolic compound found in turmeric, a dry powder of rhizomes and roots of the plant, Curcuma longa L., which is widely used as spice and food colorant around the world, and in herbal medicinal practice in Asian countries. The present study reports the leishmanicidal activity of trans-dibenzalacetone (DBA), a synthetic monoketone analog of curcumin, against Leishmania donovani parasites. We for the first time report the antiproliferative effect of a curcumin analog (DBA) on the intracellular amastigotes of L. donovani, the clinically more relevant stage of the parasite than its promastigotes stage. The leishmanicidal effect of DBA was further confirmed by scanning and transmission electron microscopies. Cell growth was arrested in G0/G1 phase with increased concentration of cytosolic calcium and dissipation of mitochondrial membrane potential. Further, the unique trypanothione/trypanothione reductase (TR) system of Leishmania cells was significantly inhibited by DBA. This economically synthesizable simple monoketone analog of curcumin has the potential for field use against visceral leishmaniasis which is currently widespread in tropical and subtropical developing countries of the world. In conclusion, we have identified an analog of curcumin for potential applications against leishmaniasis, based on its strong antiparasitic activity and low toxicity. This curcumin analog compares favorably, at least in vitro, with the existing medication miltefosine.

Topics: Animals; Antiprotozoal Agents; Apoptosis; Calcium; Cell Proliferation; Chemoprevention; Curcumin; Cytoplasm; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Membrane Potential, Mitochondrial; Mice; Microscopy, Electron, Scanning; Mitochondria; Pentanones

The polyphenolic compound curcumin has been reported for its antimalarial properties in various scientific studies. Plasmodium falciparum ATP6, the parasite orthologue of mammalian sarcoplasmic Ca

Topics: Acetophenones; Antigens, CD1; Antimalarials; Benzaldehydes; CD8 Antigens; Chalcone; Curcumin; Drug Evaluation, Preclinical; Inhibitory Concentration 50; Ligands; Molecular Docking Simulation; Pentanones; Plasmodium falciparum; Tetraspanin 29

Effects of curcumin and related compounds on product formation in radiolysis of aerated and deaerated ethanol were studied. Ab initio calculations of enthalpy values relating to O-H bond dissociation and H-atom addition to > C = O bonds of the compounds under study have been performed. The obtained data allowed the conclusion that the presence of a 7-carbon chain containing conjugated > C = C < and > C = O bonds in the structures of curcumin and its analogues makes these compounds capable of inhibiting the reactions involving α-hydroxyl-containing carbon-centered radicals. This finding broadens the existing views concerning radical-regulating properties of curcuminoids, and it should be taken into account when practical use of these compounds is envisaged.

Topics: Acrolein; Aldehydes; Antioxidants; Chalcone; Curcumin; Ethanol; Free Radicals; Guaiacol; Hexanones; Hydrogen; Molecular Structure; Oxygen; Pentanones; Pulse Radiolysis; Structure-Activity Relationship; Styrenes; Thermodynamics

Curcumin, a diferuloylmethane, has been shown to exhibit anti-inflammatory and anti-proliferative activities. Whereas curcumin has both a Michael acceptor and a Michael donor units, its analogues dibenzoylmethane (DBM, a component of licorice) and dibenzoylpropane (DBP) have a Michael donor but not a Michael acceptor unit, and the analogue dibenzylideneacetone (DBA) has a Michael acceptor unit. In the current report, we investigated the potency of DBM, DBP, and DBA in relation to curcumin for their ability to suppress TNF-induced NF-κB activation, NF-κB-regulated gene products, and cell proliferation. We found that all four agents were active in suppressing NF-κB activation; curcumin was most active and DBM was least active. When examined for its ability to inhibit the direct DNA binding activity of p65, a subunit of NF-κB, only DBP inhibited the binding. For inhibition of TNF-induced IKK activation, DBA was most active. For suppression of TNF-induced expression of NF-κB-regulated gene products such as COX-2 (inflammation marker), cyclin D1 (proliferation marker), and VEGF (angiogenesis marker), DBA and curcumin were more active than DBM. Similarly for suppression of proliferation of leukemia (KBM-5), T cell leukemia (Jurkat), prostate (DU145), and breast (MDA-MB-231) cancer cells, curcumin and DBA were most active and DBP was least active. Overall, our results indicate that although curcumin and its analogues exhibit activities to suppress inflammatory pathways and cellular proliferation, a lack of Michael acceptor units in DBM and DBP can reduce their activities.

Topics: Angiogenic Proteins; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Tumor; Cell Proliferation; Chalcones; Curcumin; Gene Expression Regulation; Humans; MAP Kinase Kinase Kinases; Molecular Structure; Pentanones; Tumor Necrosis Factor-alpha