Total synthesis and anti-leishmanial activity of some curcumin analogues

Curcumin (1) an important yellow dye isolated from Curcuma longa rhizomes, exhibits a variety of pharmacological effects such as anti-inflammatory, antioxidant and antiviral activity. Ten curcuminoids (2-11) were synthesized by the condensation of 2,4-pentanedione with differently substituted benzaldehydes, using the boron complex approach, which avoided Knoevenagel condensation at C-3 of the diketone. The curcuminoids were assayed in vitro against Leishmania amazonensis promastigotes using pentamidine isethionate (CAS 140-64-7) as the reference drug. Compound (5) 1,7-bis-(2-hydroxy-4-methoxyphenyl)-1,6-heptadiene-3,5-dione) was the most effective.     

Effect of curcumin on platelet aggregation and vascular prostacyclin synthesis

In vitro and ex vivo effects of 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (diferuloylmethane, curcumin) and acetylsalicylic acid (ASA) on the synthesis of prostacyclin (PGI2) and on platelet aggregation has been studied in rat. Both drugs inhibited adenosine diphosphate (ADP)-, epinephrine (adrenaline)- and collagen-induced platelet aggregation in monkey plasma. Pretreatment with ASA (25-100 mg/kg), but not curcumin (100-300 mg/kg), inhibited PGI2 synthesis in rat aorta. In the in vitro system, too, curcumin caused a slight increase in the synthesis of PGI2, while ASA inhibited it. Curcumin may, therefore, be preferable in patients prone to vascular thrombosis and requiring antiarthritic therapy.     

Inhibition of interleukin-12 production in lipopolysaccharide-activated macrophages by curcumin

Pharmacological control of interleukin-12 production may be a key therapeutic strategy for modulating immunological diseases dominated by type-1 cytokine responses. In this study we investigated the effects of curcumin (1,7-bis[4-hydroxy-3-methoxyphenyl]-1, 6-heptadiene-3,5-dione) on the production of interleukin-12 from mouse macrophages stimulated with lipopolysaccharide. Curcumin potently inhibited the production of interleukin-12 in a dose-dependent manner. The effect of curcumin on interleukin-12 p40 promoter activation was analyzed by transfecting RAW264.7 monocytic cells with p40 promoter/reporter constructs. The repressive effect mapped to a region in the p40 promoter containing a binding site for nuclear factor kappaB (p40-kappaB). Furthermore, activation of macrophages by lipopolysaccharide resulted in markedly enhanced binding activity to the kappaB site, which significantly decreased upon addition of curcumin. These results suggest that curcumin-induced inhibition of interleukin-12 production in macrophages may explain some of the biological effects of curcumin including its anti-inflammatory activity.     

Synergistic effect of the anti-PD-1 antibody with blood stable and reduction sensitive curcumin micelles on colon cancer

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a potent anticancer drug with versatile biological activities, while the clinical translation of curcumin is severely limited due to its hydrophobicity, rapid elimination, and metabolism in the blood circulation. Herein, we aim to unravel the potential of curcumin as a synergistic agent with immunotherapy in the treatment of cancers. In an effort to minimize premature release and improve the systemic bioavailability, a superior blood stable and reduction sensitive curcumin micellar formulation, of which the release can be triggered by cancer cells, is rationally designed. We have synthesized a telodendrimer (mPEG-PLA-(LA)₄) capable of forming reversible disulfide crosslinked micelles (DCMs). The curcumin loaded DCMs (Cur/DCMs) are spherical with a uniform size of 24.6 nm. The in vitro release profile demonstrates that curcumin releases significantly slower from DCMs than that from non-crosslinked micelles (NCMs), while the release can be accelerated with the increasing concentration of reducing agent glutathione (GSH). Intravenous administration of Cur/DCMs stably retains curcumin in the bloodstream and efficiently improves the systemic bioavailability. Furthermore, Cur/DCMs exhibit synergistic anticancer efficacy when combined with the anti-PD-1 antibody in an MC-38 colon cancer xenograft model. Our results potentiate the integration of blood stable curcumin nanoformulation and immunotherapy for cancer treatment.     

Loading of curcumin into macrophages using lipid-based nanoparticles

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, Cm) is a natural compound which possesses antioxidant, anti-inflammatory and anti-tumor ability. Here, phospholipid vesicles or lipid-nanospheres embedding Cm (CmVe or CmLn) were formulated to deliver Cm into tissue macrophages through intravenous injection. Cm could be solubilized in hydrophobic regions of these particles to form nanoparticle dispersions, and these formulations showed ability to scavenge reactive oxygen species as antioxidants in dispersions. At 6h after intravenous injection in rats via the tail vein (2mg Cm/kg bw), confocal microscopic observations of tissue sections showed that Cm was massively distributed in cells assumed as macrophages into the bone marrow and spleen. Taken together, these results indicate that the lipid-based nanoparticulates provide improved intravenous delivery of Cm to tissues macrophages, specifically bone marrow and splenic macrophages in present formulation, which has therapeutic potential as an antioxidant and anti-inflammatory.     

Different Curcuminoids Inhibit T-Lymphocyte Proliferation Independently of Their Radical Scavenging Activities

PURPOSE: We investigated the inhibitory effects of curcumin, curcumin derivatives and degradation products on OKT3-induced human peripheral blood mononuclear cell (PBMC) proliferation and the role of their radical scavenging activity. METHODS: OKT3-induced human PBMC proliferation was determined by measuring 3H-thymidine incorporation. Radical scavenging activity was evaluated by using an in vitro DPPH assay. RESULTS: OKT3-induced PBMC proliferation was inhibited by curcumin, isocurcumin, bisdesmethoxy-, diacetyl-, tetrahydro-, hexahydro-, and octahydrocurcumin as well as by vanillin, ferulic acid, and dihydroferulic acid with IC50-values of 2.8, 2.8, 6.4, 1.0, 25, 38, 82, 729, 457, and >1,000 microM, respectively. The investigated substances with the strongest effect on radical scavenging were tetrahydro-, hexahydro-, and octahydrocurcumin with IC50 values of 10.0, 11.7, and 12.3 microM, respectively. IC50-values of dihydroferulic acid, ferulic acid, and curcumin were 19.5, 37, and 40 microM. The substances with the lowest radical scavenging activities were vanillin, isocurcumin, diacetylcurcumin, and bisdesmethoxycurcumin with IC50 values higher than 100 microM each. CONCLUSIONS: Curcuminoid-induced inhibition of OKT3-induced PBMC proliferation depends on the number of carbon atoms and double bonds of the 1,6-heptadiene-3,5-dione structure as well as on the phenolic ring substitutes of the curcuminoids but is not correlated to their respective radical scavenging activity.     

Curcumin inhibits WEHI-3 leukemia cells in BALB/c mice in vivo

Curcumin (1, 7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5- dione), a natural polyphenol product of the plant Curcuma longa, exhibited potent inhibitory activities against proliferation, induced cell cycle arrest and exhibited the induction of apoptosis in several tumor cell lines. In our previous studies, we have shown that curcumin induced cell cycle arrest and apoptosis on human leukemia HL-60 and mouse leukemia WEHI-3 cells; there are no reports regarding whether or not it affects leukemia cells in vivo. In the present study, we investigated the effects of curcumin on WEHI-3 in BALB/c mice and the results indicated that curcumin reduces the percentage of Mac-3 marker, which is the precursor of macrophage. Curcumin induced significant effects on the population of B cells from murine leukemia in vivo. We also investigated the weights of spleen and liver from murine leukemia and the results showed that curcumin reduced the weight of the liver and spleen. From the pathological examinations, the effects of curcumin on the liver and spleen from mice after being injected with WEHI-3 cells were apparent. Both organs were enlarged. In conclusion, curcumin affect WEHI-3 cells in vivo.     

姜黄素与丙酸酐不对称反应产物的合成

目的:合成姜黄素与丙酸酐的不对称反应产物——1-(4-丙酰氧基-3-甲氧基苯基)-7-(4-羟基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(化合物1)。方法:以姜黄素和丙酸酐为原料,吡啶为催化剂,二氯甲烷/N,N-二甲基甲酰胺(DMF)为溶剂,进行不对称反应,经柱层析分离纯化,得目标化合物1,并进行核磁共振结构表征,以收率为指标,确定最佳反应条件(投料比、温度、时间、吡啶用量)。结果:制备得到了化合物1(收率:81.2%,纯度:99.0%),并经结构表征证实。化合物1的最佳反应条件是姜黄素与丙酸酐比为1∶1.5(m/m),反应温度为30Ⅸ,时间为30 min,吡啶用量为0.5%。结论:以确定的反应条件可得到目标化合物1。该工艺操作简便,收率和纯度高,可为姜黄素结构修饰的进一步研究提供参考。     

Health Benefits and Therapeutic Applications of Curcumin

Curcumin [1,7-bis (4-hydroxy-3-methoxyphenyl)-1, 6-heptadiene 3,5-dione], the major yellow pigment extracted from turmeric has traditionally been used for treatment of inflammation and skin wounds. It has shown cancer chemoprotective, antineoplastic and anti-inflammatory properties. Curcumin has also been reported to exhibit activities against cardiovascular diseases, diabetes, Alzheimer's disease and multiple sclerosis. Curcumin exhibits a diverse array of metabolic, cellular and molecular activities that may individually or in combination have a number of therapeutic effects. The extensive information available on the activities of curcumin has been discussed under its anticancer properties, effect on atherosclerosis and myocardial infarction, and as other benefits.     

A screening of curcumin derivatives for antibacterial phototoxic effects studies on curcumin and curcuminoids. XLIII

Curcumin, bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, has potential as a photosensitiser for photodynamic treatment of localised superficial infections in e.g., the mouth or skin. The aim of the present study was to evaluate the in vitro antibacterial phototoxic potential of a series of five curcumin derivatives. The gram-positive Enterococcus faecalis and the gram-negative Escherichia coli were used as bacterial models. The bacteria were exposed to curcuminoid preparations in two concentrations (2.5 and 25.0 microM) in combination with a constant irradiation dose (5 J/cm2). The UV-VIS absorption spectrum of the curcuminoids was in the same range as curcumin, 300-500 nm. Compound 1 (dimethoxycurcumin; C1) and compound 3 (bisdemethoxycurcumin; C3) were strongly phototoxic towards E. faecalis (no surviving bacteria) and showed a lower but significant effect towards E. coli (< or = 0.5 log reductions and 1 - 4 log reductions, respectively). Compound 2 (C2) and compound 4 (C4) in combination with blue light reduced the colony forming ability of E. faecalis (approximately 1-4 log reductions). The phototoxic effect of the curcuminoids varied with concentration, and for compounds C1, C2 and C3 it was further influenced by the addition of polyethylene glycol 400 (PEG 400) to the preparations. 2,6-Divanillylidenecyclohexanone (C5) showed very low phototoxic potential (< 0.2 log reductions) under the conditions used in the present study. The addition of polyethylene glycol 400 (PEG 400) seemed to increase the solubility of compound C1, C3 and C5 in phosphate buffered saline (PBS). This investigation demonstrates the importance and influence of the substituents on the phenolic rings and the keto-enol moiety for the phototoxic potential of curcumin and its derivatives.     

1,7-双[2-二烃氦甲基-4-替代基-苯氧基]庚烷衍生物的合成

本文报导合成了1,7-双-[2-二烃氨甲基-4-替代基苯氧基]-庚烷衍生物七种,其中除1,7-双-[2-二乙氨甲基-4-氨基苯氧基]庚烷,由1,7-双-[2-二乙氨甲基-4-乙酰氨基苯氧基]庚烷水解制得外,其它均由相应的苯酚与1,7-二溴庚烷作用制取。制备苯酚类时的Mannich反应,系采用双-(二經氨基)甲烷为試剂。     

Bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione (a curcumin analog) ameliorates DMH-induced hepatic oxidative stress during colon carcinogenesis.

The protective effect of a curcumin analog [bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione] was investigated on hepatic lipid peroxidation (LPO) and antioxidant status during 1,2-dimethylhydrazine-induced colon carcinogenesis in male Wistar rats. The effects were compared with that of curcumin, a known antioxidant and anticarcinogen. Colon cancer was induced by sub-cutaneous injection of DMH at a dosage of 20mg/kg body weight (15 doses, at 1-week intervals). DMH administered rats developed gross tumours in the colon. Enhanced lipid peroxidation in the liver of colon tumour bearing rats was accompanied by a significant decrease in the activities of glutathione peroxidase (GPx), glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT). Intragastric administration of curcumin (80mg/kg body weight) and curcumin analog (80mg/kg body weight) to DMH-injected rats significantly reduced the number and size of tumour in the colon, lowered lipid peroxidation and enhanced the activities of GPx, GST, SOD and CAT in the liver. We speculate that the curcumin analog used in the present study exerts chemoprevention against cancer development at extrahepatic sites by modulating hepatic biotransformation enzymes and antioxidant status. The effect is comparable with that of curcumin. This shows that the hydroxyl group in the aromatic ring is responsible for the protective effect rather than the methoxy group.     

��2,3 -Ivermectin ethyl secoester, a conjugated ivermectin derivative with leishmanicidal activity but without inhibitory effect on mammalian P-type ATPases

Looking at a new putative target for the large spectrum antiparasitic drug ivermectin, we recently showed that avermectin-derived drugs are active against promastigote and amastigote forms of Leishmania amazonensis at low micromolar concentrations. However, we then reported that at this concentration range ivermectin is also able to inhibit three important mammalian P-type ATPases so that unacceptable adverse effects could occur if this drug were used at such high doses therapeutically. The present work aimed to test the activity of ten ivermectin analogs on these rat ATPases in search of a compound with similar leishmanicidal activity but with no effect on the mammalian (host) ATPases at effective concentrations. We synthesized three new ivermectin analogs for testing on rat SERCA (1a and 1b), Na+, K+-ATPase (α? and α?/α? isoforms) and H+/K+-ATPase activity, along with seven analogs already characterized for their leishmanicidal activity. Our main finding is that one of the prepared derivatives, Δ2,3-ivermectin ethyl secoester 8, is equipotent to ivermectin 1 for the in vitro leishmanicidal effects but is nearly without effect on the rat ATPases, indicating that it could have a better therapeutic index in vivo and could serve as a candidate for hit-to-lead progression. This conclusion is further supported by the fact that compound 8 produced only 6% (vs 77% for ivermectin) inhibition of the human kidney enzyme at 5 μM, a concentration corresponding to the IC?? for the activity against L. amazonensis amastigotes.     

Reaction of 1,2-diphenyl-4-bis-(methylthio)methylenepyrazolidin-3,5-dione with serine, cysteine and their derivatives]

The reaction between 1,2-diphenyl-4-bis-(methylthio)methylenepyrazolidin-3,5-dione with serine and cysteine and their derivatives is described. The structure of the resulting compounds is assigned spectrophotometrically.     

Antitumor agents. 217. Curcumin analogues as novel androgen receptor antagonists with potential as anti-prostate cancer agents

A number of curcumin analogues were prepared and evaluated as potential androgen receptor antagonists against two human prostate cancer cell lines, PC-3 and DU-145, in the presence of androgen receptor (AR) and androgen receptor coactivator, ARA70. Compounds 4 [5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one], 20 [5-hydroxy-1,7-bis[3-methoxy-4-(methoxycarbonylmethoxy)phenyl]-1,4,6-heptatrien-3-one], 22 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]-5-oxohepta-4,6-dienoic acid ethyl ester], 23 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]5-oxohepta-4,6-dienoic acid], and 39 [bis(3,4-dimethoxyphenyl)-1,3-propanedione] showed potent antiandrogenic activities and were superior to hydroxyflutamide, which is the currently available antiandrogen for the treatment of prostate cancer. Structure-activity relationship (SAR) studies indicated that the bis(3,4-dimethoxyphenyl) moieties, the conjugated beta-diketone moiety, and the intramolecular symmetry of the molecules seem to be important factors related to antiandrogenic activity. The data further suggest that the coplanarity of the beta-diketone moiety and the presence of a strong hydrogen bond donor group were also crucial for the antiandrogenic activity, which is consistent with previous SAR results for hydroxyflutamide analogues. When the pharmacophoric elements of dihydrotestosterone (DHT) and compound 4 are superposed, the resulting construct implies that the curcumin analogues may function as a 17alpha-substituted DHT. Compounds 4, 20, 22, 23, and 39 have been identified as a new class of antiandrogen agents, and these compounds or their new synthetic analogues could be developed into clinical trial candidates to control androgen receptor-mediated prostate cancer growth.     

In vitro antiproliferative effects of several diaryl derivatives on Leishmania spp

In a previous works searching for new drugs with high efficiency, we reported the in vitro and in vivo antileishmanial activity of a series of diarylheptanoid structurally related to curcumin against L. amazonensis. This work describes the in vitro antileishmanial activity of a new series of diarylheptanoids and diarylpentanoids derivatives. These drugs were assayed against Leishmania amazonensis, L. braziliensis and L. chagasi promastigotes containing a high percentage of metacyclic forms and the axenic amastigote form of L. amazonensis and using Pentamidine Isethionate as reference drug. Parasites in the log late phase culture were incubated with several concentrations of the drugs solubilized in dimethyl sulphoxide (DMSO) and then counted in a Neubauer's chamber. Controls without the drugs and with DMSO were done in parallel. The results showed that all diarylheptanoids and diarylpentanoids had a very good antileishmanial activity.     

4‐Aminoquinoline Derivatives as Potential Antileishmanial Agents

The leishmanicidal activity of a series of 4‐aminoquinoline ( AMQ ) derivatives was assayed against Leishmania amazonensis. This activity against the intracellular parasite was found stronger than for L. amazonensis promastigotes. Neither compound was cytotoxic against macrophages. The compound AMQ ‐j , which exhibited a strong activity against promastigotes and amastigotes of L. amazonensis (IC₅₀ values of 5.9 and 2.4 μg/mL, respectively) and similar leishmanicidal activity to reference drugs, was chosen for studies regarding its possible mechanism of action toward parasite death. The results showed that the compound AMQ ‐j induced depolarization of the mitochondrial membrane potential in promastigotes and in L. amazonensis‐infected macrophages, but not in uninfected macrophages. Furthermore, the depolarization of the mitochondrial membrane potential was dose dependent in infected macrophages. We have established that promastigotes and L. amazonensis‐infected macrophages treated with AMQ ‐j were submitted to oxidative stress. This is in line with the increase in the level of reactive oxygen species (ROS). Leishmania amazonensis‐infected macrophages treated with AMQ ‐j did not show a significant increase in the production of nitric oxide. Our results indicate the effective and selective action of AMQ ‐j against L. amazonensis, and its mechanism of action appears to be mediated by mitochondrial dysfunction associated with ROS production.     

Prevention of 1,2-dimethylhydrazine-induced circulatory oxidative stress by bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione during colon carcinogenesis

We have performed this study to investigate the modulatory effect of bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione, a bisdemethoxy curcumin analog (BDMCA) on circulatory lipid peroxidation (LPO) and antioxidant status during 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in male Wistar rats. The effects were compared with that of the reference drug, curcumin. Increased tumor incidence as well as enhanced LPO in the circulation of tumor bearing rats was accompanied by a significant decrease in the level of reduced glutathione and activities of glutathione peroxidase (GPx), glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT). Intragastric administration of BDMCA or curcumin to DMH-treated rats significantly decreased colon tumor incidence and the circulatory LPO, with simultaneous enhancement of GSH content and GPx, GST, SOD and CAT activities. We report that BDMCA exert its chemopreventive effect by decreasing the colon tumor incidence as well as by modulating circulatory oxidative stress in DMH-treated rats through its influence on LPO and antioxidant status. The effects of BDMCA were comparable with that of the reference compound curcumin, a well known anticarcinogen and antioxidant. Thus, it would be suggested that the methoxy group is not responsible for the beneficial effects, however, the terminal phenolic moieties or the central 7-carbon chain may play a role.     

Synthesis and antichagasic properties of new 1,2,6-thiadiazin-3,5-dione 1,1-dioxides and related compounds.

In a search for antichagasic drugs, 14 new 4-(nitroarylidene)-1,2,6-thiadiazin-3,5-dione 1,1-dioxide derivatives were synthesized and tested in vitro against the epimastigote form of Trypanosoma cruzi and some of them showed important antiprotozoan activity. Attempts to synthesize new 4-(nitroarylidene)-3,5-diamino-1,2,6-thiadiazine 1,1-dioxides were unsuccessful. The antichagasic properties of nitroarylidene-malononitrile and nitroarylidene-cyanoacetamide derivatives, thus obtained, were also tested. The cytotoxic properties against Vero cells of compounds which showed remarkable in vitro antichagasic activity were evaluated. All compounds tested exhibited high toxicity percentages at 100 micrograms/ml. However, compound 3c showed in vitro antichagasic and cytotoxic properties such as nifurtimox at the dose of 10 micrograms/ml.     

Cytotoxic activities of diarylheptanoids from Alnus japonica

The diarylheptanoids (1–10) 1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-O-β-D-glucopyranosyl(1→3)-β-D-xylopyranoside (1), 1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-O-β-D-apiofuranosyl(1→6)-β-D-glucopyranoside (2), 1,7-bis-(3,4-dihydroxyphenyl)-heptane-5-O-β-D-glucopyranoside (3), 1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptane (4), 1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-one-5-O-β-D-glucopyranoside (5), oregonin (6), hirsutanonol (7), hirsutenone (8), 1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptane-3-O-β-D-xylopyranoside (9), and platyphylloside (10), isolated from the bark of Alnus japonica, were analyzed for their cytotoxic activities on various human and mouse cancer cell lines. The cytotoxic activities of these ten compounds were evaluated against murine B16 melanoma, human SNU-1 gastric cancer, human SNU-354 hepatoma cancer and human SNU-C4 colorectal cell lines. The diarylheptanoids showed potent cytotoxic activities against murine B16 melanoma cells and human SNU-C1 gastric cancer cell when the cell viability was analyzed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay.