Anticancer mechanism of coumarin-based derivatives.

The structural motif of coumarins is related with various biological activities and pharmacological properties. Both natural coumarin extracted from various plants or a new coumarin derivative synthesized by modification of the basic structure of coumarin, in vitro experiments showed that coumarins are a promising class of anti-tumor agents with high selectivity. Cancer is a complex and multifaceted group of diseases characterized by the uncontrolled and abnormal growth of cells in the body. This review focuses on the anticancer mechanism of various coumarins synthesized and isolated in more than a decade. Isopentenyloxycoumarins inhibit angiogenesis by reducing CCl2 chemokine levels. Ferulin C is a potent colchicine-binding agent that destabilizes microtubules, exhibiting antiproliferative and anti-metastatic effects in breast cancer cells through PAK1 and PAK2-mediated signaling. Trimers of triphenylethylene-coumarin hybrids demonstrated significant proliferation inhibition in HeLa, A549, K562, and MCF-7 cell lines. Platinum(IV) complexes with 4-hydroxycoumarin have the potential for high genotoxicity against tumor cells, inducing apoptosis in SKOV-3 cells by up-regulating caspase 3 and caspase 9 expression. Derivatives of 3-benzyl coumarin seco-B-ring induce apoptosis, mediated through the PI3K/Akt/mTOR signaling pathway. Sesquiterpene coumarins inhibit the efflux pump of multidrug resistance-associated protein. Coumarin imidazolyl derivatives inhibit the aromatase enzyme, a major contributor to estrogen overproduction in estrogen-dependent breast cancer.

Current Insight into Novel Delivery Approaches of Resveratrol for Improving Therapeutic Efficacy and Bioavailability with its Clinical Updates.

Resveratrol (RSV) is a polyphenolic phytoalexin, and belongs to the stilbene family. RSV has several therapeutic activities such as cardioprotective, anticancer, and antioxidant. Apart from its therapeutic benefits, its pharmacological uses are limited due to low solubility, poor bioavailability, and short biological halflife. A researcher continuously focuses on overcoming the limitations of RSV through nanotechnology platforms to get the optimum health benefits. In this context, nanocarriers are pioneering to overcome these drawbacks. Nanocarriers possess high drug loading capacity, thermal stability, low production cost, longer shelflife, etc. Fortunately, scientists were proficient in delivering resveratrol-based nanocarriers in the present scenario. Nanocarriers can deliver drugs to the target sites without compromising the bioavailability. Thus, this review highlights how the latest nanocarrier systems overcome the shortcomings of RSV, which will be good for improving therapeutic efficacy and bioavailability. Moreover, recent updates on resveratrol-based novel formulations and their clinical trials have been addressed to manage several health-related problems.

5-Methoxyisatin N(4)-Pyrrolidinyl Thiosemicarbazone (MeOIstPyrd) Restores Mutant p53 and Inhibits the Growth of Skin Cancer Cells, In Vitro.

A series of novel thiosemicarbazone derivatives containing 5-methoxy isatin were designed and synthesized with modification on N(4) position. Derivatives considering structure-activity relationship have been designed and synthesized by condensing thiosemicarbazide with 5-methoxy isatin. The synthesized compounds were characterized by elemental analysis, FT-IR spectroscopy, UV-visible spectroscopy, NMR (1H, 13C) spectroscopy, mass spectrometry, and a single-crystal study. Biological evaluation of the synthesized compounds revealed that MeOIstPyrd is the most promising compound against skin cancer cell line, A431, with an IC50 value of 0.9 µM. In addition, MeOIstPyrd also exhibited low toxicity against the normal human fibroblast and the human embryonic kidney 293 cell line, HLF-1, and HEK293, respectively. Furthermore, the mechanistic study revealed that MeOIstPyrd efficiently inhibited cell proliferation, migration, and spheroid formation by activating the mitochondrial intrinsic apoptotic pathway. MeOIstPyrd also induces DNA damage and activates p53 irrespective of the p53 status. It increases the half-life of p53 and stabilizes p53 by phosphorylating it at ser15. Moreover, MeOIstPyrd was found to bind to MDM2 in the p53 sub-pocket and, therefore, block p53-MDM2 interaction. Our result exhibited potential anticancer activity of MeOIstPyrd in the A431 cell line and its ability in restoring mutant p53, which is an interesting and promising strategy for cancer therapeutics.

Synthesis, characterization, and anticancer activity of chitosan functionalized isatin based thiosemicarbazones, and their copper(II) complexes.

The one-pot synthetic method of condensation of isatin and 5-chloroisatin on to amino group at C2 position of the pyranose ring chitosan in chitosan thiosemicarbazide was employed to get these chitosan thiosemicarbazones (TSCs). The partial incorporation of thiosemicarbazone moiety in chitosan was shown by FT-IR and 13C NMR spectroscopic studies, powder X ray diffraction, and CHNS microanalysis. The NOS tridentate coordination behavior of TSCs with copper(II) chloride to give the square planar complexes was established by FT-IR spectroscopic data, magnetic susceptibility measurement, and EPR spectral analysis. The thermal stability of these biomaterial chitosan derivatives till the commencement of chain disruption at 200C was shown by thermal studies. As revealed by colorimetric MTT assays, the in vitro anticancer activity enhancement accorded with the functionalization of chitosan as isatin based chitosan TSCs, and NOS tridentate coordination of TSCs plus a monodentate coordination of chloride ion with copper(II) ion. Only a marginal activity difference of these compounds was observed against the tumorigenic MDCK and MCF-7 cancer cell lines, irrespective of unit molecular weight (Mw) and degree of deacetylation (DDA) of ring chitosan. The 5-chloroisatin chitosan TSCs showed better activity than isatin chitosan TSCs against both the cell lines.

Pyridine-Based NNS Tridentate Chitosan Thiosemicarbazones and Their Copper(II) Complexes: Synthesis, Characterization, and Anticancer Activity.

Chitosan-functionalized pyridine-based thiosemicarbazones and their copper(II) complexes have been found to own a substantial antiproliferative activity against the tumorigenic Madin Darby canine kidney (MDCK) and MCF-7 cancer cell lines. In the current study, chitosan oligosaccharide (CS) (87% DDA, Mw < 3000 Da) and crab shell chitosan (CCS) (67% DDA, M w 350 kDa) were functionalized as chitosan pyridine-2-thiosemicarbazones and chitosan 2-acetyl pyridine-2-thiosemicarbazones, and their copper(II) complexes were synthesized. The formation of chitosan thiosemicarbazones and their NNS tridentate behavior to give the square planar copper(II) chitosan thiosemicarbazone complexes were established by spectroscopic studies, powder X-ray diffraction, elemental analysis, and magnetic moment measurements. The thermal study showed a marked stability of these derivatives before the outset of chitosan backbone degradation at 200 °C. The colorimetric MTT assay revealed a higher activity of CS thiosemicarbazones, viz., CSTSC series (IC50 375-381 µg mL-1 in the MDCK cell line and 281-355 µg mL-1 in the MCF-7 cell line) than that of high-molecular-weight CCS thiosemicarbazones, viz., CCSTSC series (IC50 335-400 µg mL-1 in the MDCK cell line and 365-400 µg mL-1 in the MCF-7 cell line), showing an enhanced activity with a decrease in Mw and an increase in DDA of constituent chitosan, a higher activity of both of these series of thiosemicarbazones than that of their native chitosan, viz., CS (IC50 370 µg mL-1 in the MCF-7 cell line and >400 µg mL-1 in the MDCK cell line) and CCS (IC50 > 400 µg mL-1 in both cell lines), and a higher activity of the Cu-CSTSC complexes (IC50 322-342 µg mL-1 in the MDCK cell line and 278-352 µg mL-1 in the MCF-7 cell line) and Cu-CCSTSC complexes (IC50 274-400 µg mL-1 in the MDCK cell line and 231-352 µg mL-1 in the MCF-7 cell line) than that of their respective ligands.

Atherogenic index of plasma predicts coronary artery disease severity and major adverse cardiac events in absence of conventional risk factors.

BACKGROUND: Various overlapping risk factors lead to coronary artery disease (CAD). The atherogenic index of plasma (AIP) is a marker for CAD severity and progression. However, little is known about its contribution to the residual risk of CAD observed in the absence of all typical risk factors. METHODS: A prospective cohort study of 366 Indian patients undergoing coronary computed tomography (CT) angiography and diagnosed with stable CAD. Diabetes, hypertension, hypercholesterolemia, smoking, previous CAD, alcohol or lipid-lowering medication intake, renal, liver or thyroid dysfunction were exclusion criteria. Coronary stenosis was graded using the CAD-reporting and data system (CAD-RADS™) system. Lipid profile, HbA1c, uric acid, highly sensitive C-reactive protein (hsCRP) and anthropometric measurements were taken. AIP, triglyceride/high-density lipoprotein cholesterol (HDLc) and total cholesterol (Tc)/HDLc ratios were calculated. Independent predictors of CAD severity and the occurrence of major adverse cardiac events (MACE) during 2.57 (0.52) years of follow-up were identified using logistic regression and Cox proportional hazards regression. RESULTS: Sixty patients experienced a MACE during a cumulative 887.03 person-years. HbA1c, uric acid, hsCRP, Tc/HDLc and AIP were independent predictors of severe coronary lesions (CAD-RADS 4,5) on multivariate analysis with odds ratio 4.52 (2.37-8.61), 1.41 (1.08-1.84), 1.33 (1.09-1.62), 1.76 (1.27-2.44) and 1.29 (1.11-1.50), respectively. Only AIP and Tc/HDLc were independent predictors of MACE with hazard ratios of 1.41 (1.20-1.65) and 1.78 (1.33-2.39) besides patient age and CAD severity. CONCLUSION: AIP is associated with both the severity of CAD and the occurrence of MACE within 3 years. It could serve as an effective marker of residual risk of CAD in patients devoid of traditional risk factors. Lipid-profile ratios, such as AIP are cost-effective and accessible parameters suitable for low and middle-income settings.

Anticancer Potential of Coumarin and its Derivatives.

Coumarins are found in higher plants like Rutaceae and Umbelliferae and essential oils of cinnamon bark, cassia leaf, and lavender oil. Coumarin compounds show different biological properties, viz antimicrobial, antibacterial, antifungal, antioxidant, antitumor, anti-HIV, antihypertension, anticoagulant, anticancer, antiviral, anti-inflammatory, analgesics, antidiabetic, anti-depressive, and other bioactive properties. Coumarin and its derivatives possess anticancer activity against different types of cancers such as prostate, renal, breast, laryngeal, lung, colon, CNS, leukemia, malignant melanoma. In this review, current developments of coumarin-based anticancer agents viz simple coumarin, furanocoumarin, pyranocoumarin, pyrone-substituted coumarin, and their important derivatives have been discussed. The coumarin-triazole, coumarin-chalcone, coumarin-thiosemicarbazone derivatives, and coumarin-metal complexes have been found more potent than coumarin. Hence, further study and structural improvement on coumarin and its derivatives may lead to the design and development of more potent anticancer agents.

Anticancer potency of copper(II) complexes of thiosemicarbazones.

Being a structural and catalytic cofactor in a number of biological pathways, copper accumulates in tumors owing to selective permeability of the cancer cell membranes. Copper(II) ion forms the active centers in a large number of metalloproteins. The coordination of Schiff's base ligands to the metal ion results in the high extent of increase in anticancer activity. The copper(II) complexes can cleave DNA through oxidative and hydrolytic pathways, cell apoptosis via intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway due to excessive production of ROS and hence, are found more active than Ni and Pt complexes. Flexible Cu(I/II) redox behavior helps the copper complexes to form more potent, clinically effective and less toxic copper based antiproliferative drugs of lower IC50 value and higher growth inhibitory activity. Copper(II) complexes of thiosemicarbazones of Isatin, Pyridine, Benzoyl pyridine, Diacetyl/Dimethyl glyoxal, Acetophenone/Acetoacetanalide, Thiazole/Pyrazole, Quinoline, Carboxybenzaldehyde, Cinnamaldehyde/Cuminaldehyde, Citronellal, Chromone, Pyridoxal, 8-Ethyl-2-hydroxytricyclo (7.3.1.02,7) tridecan-13-one, Acyl Diazines, Naphthalene, Proline, 5-Formyluracil, 2-Hydroxy-8-propyltricyclo (7.3.1.02,7) tridecan-13-one, 9-cis-Retinal, Curcumin, Helicin (Salicylaldehyde-ß-D-glucoside), Thiophene carboxaldehyde, Salicylaldehyde, Iminodiacetate, and 3-Formyl-4-hydroxy benzenesulfonic acid have been found to exhibit more anticancer activity toward HCT116, MCF7, A549, U937, HeLa, HepG2, SGC-7901, A2780 cell lines than that of their corresponding thiosemicarbazones and standard topoisomerase-II inhibitors.

Physical and chemical characteristics of soils in Ephedra gerardiana and E. pachyclada habitats of Kali Gandaki Valley in Central Nepal.

In the Kali Gandaki Valley in Central Nepal, Ephedra gerardiana and E. pachyclada show species specificity for physical and chemical characteristics of soils. Here, the relationship between soil characteristics and ephedrine and pseudoephedrine contents was examined. E. gerardiana grew in moist alpine scrub and upper alpine meadow from 3735 to 4156 m a.s.l., while E. pachyclada grew in the lower Caragana steppe and dry alpine scrub from 2629 to 3671 m a.s.l. The soil texture of E. gerardiana and E. pachyclada collection sites were classified as loam or sandy loam mainly composed of sand and silt. Loss on ignition (%) of soil in E. gerardiana habitats (28.4-35.0%) was markedly higher than for that in E. pachyclada habitats (14.2-17.2%). E. pachyclada soil (pH 8.4-9.2) was more alkaline than that for E. gerardiana (pH 8.5). The five ions (Cl-, SO42-, Ca2+, Mg2+, and Na+) in soil of E. pachyclada (Cl-, 0.01-18.97 mmol/100 g dry soil weight; SO42-, 1.95-83.33; Ca2+, 3.79-77.91; Mg2+, 1.28-27.9; Na+, 0.94-34.49) were markedly higher than those of E. gerardiana (Cl-, 0.18-0.29; SO42-, 0.07-0.08; Ca2+, 4.19-4.59; Mg2+, 0.22-0.58; Na+, 0.93-1.40). The main factor contributing to strongly alkali soils for each species was different between E. gerardiana and E. pachyclada: CaCO3 for E. gerardiana and CaSO4, MgSO4, NaCl, or a combination of these for E. pachyclada. The total ephedrine and pseudoephedrine content in E. gerardiana and E. pachyclada ranged from 1.67-1.88%DW and 1.95-4.80%DW, respectively. Both E. gerardiana and E. pachyclada were amenable for use a raw material source for extraction of ephedrine and pseudoephedrine, and the ephedrine content of both species showed a statistically significantly positive correlation with Mg2+ and Na+ contents of the soil.

Thiosemicarbazones as Potent Anticancer Agents and their Modes of Action.

Thiosemicarbazones (TSCs) are a class of Schiff bases usually obtained by the condensation of thiosemicarbazide with a suitable aldehyde or ketone. TSCs have been the focus of chemists and biologists due to their wide range of pharmacological effects. One of the promising areas in which these excellent metal chelators are being developed is their use against cancer. TSCs have a wide clinical antitumor spectrum with efficacy in various tumor types such as leukemia, pancreatic cancer, breast cancer, non-small cell lung cancer, cervical cancer, prostate cancer and bladder cancer. To obtain better activity, different series of TSCs have been developed by modifying the heteroaromatic system in their molecules. These compounds possessed significant antineoplastic activity when the carbonyl attachment of the side chain was located at a position α to the ring nitrogen atom, whereas attachment of the side chain ß or γ to the heterocyclic N atom resulted in inactive antitumor agents. In addition, replacement of the heterocyclic ring N with C also resulted in a biologically inactive compound suggesting that a conjugated N,N,S-tridentate donor set is essential for the biological activities of thiosemicarbazones. Several possible mechanisms have been implemented for the anticancer activity of thiosemicarbazones.

2-Pyridineformamide N(4)-ring incorporated thiosemicarbazones inhibit MCF-7 cells by inhibiting JNK pathway.

In an effort to develop a more potent anticancer therapeutic agent, a series of 2-pyridineformamide thiosemicarbazones (R = H, 4-CH3, 5-F, 6-CH3 and ) have been synthesized and evaluated for their anti-cancer activities against the cancer cells MCF-7 (breast cancer cell line), A-431 and A375 (epidermoid carcinoma cell line), and HeLa (cervical cancer cell line) using MTT assay. All these 2-pyridineformamide thiosemicarbazones exhibited anti-proliferative activities towards these cell lines. 5FAmPyrr possess most profound effects against MCF-7 cells with IC50 of 0.9 µM. In flow cytometry using Propidium Iodide, 5FAmPyrr was found to induce cell death significantly in a dose dependent manner (100 nM-3 µM) and inhibited colony formation of MCF-7 cells. This compound induced pro-apoptotic protein Bax and inhibited anti apoptotic protein Bcl-2 as well as both c-Jun and Jun N-terminal kinase (abbreviated as JNK) in concentration dependent manner. Further pro-caspase 3 and PARP were inhibited by 5FAmPyrr at concentration of 3 µM. The results suggest that 5FAmPyrr exhibit anticancer potency and induced cell death by inhibiting MAPK signaling and inducing intrinsic apoptotic pathway. All these indicate that 2-pyridineformamide thiosemicarbazones could be developed as future therapeutics agents to treat cancer.

Anticancer Activity of Chitosan, Chitosan Derivatives, and Their Mechanism of Action.

Tailoring of chitosan through the involvement of its amino, acetamido, and hydroxy groups can give derivatives of enhanced solubility and remarkable anticancer activity. The general mechanism of such activity is associated with the disturbances in normal functioning of cell cycle, interference to the central dogma of biological system from DNA to RNA to protein or enzymatic synthesis, and the disruption of hormonal path to biosynthesis to inhibit the growth of cancer cells. Both chitosan and its various derivatives have been reported to selectively permeate through the cancer cell membranes and show anticancer activity through the cellular enzymatic, antiangiogenic, immunoenhancing, antioxidant defense mechanism, and apoptotic pathways. They get sequestered from noncancer cells and provide their enhanced bioavailability in cancer cells in a sustained release manner. This review presents the putative mechanisms of anticancer activity of chitosan and mechanistic approaches of structure activity relation upon the modification of chitosan through functionalization, complex formation, and graft copolymerization to give different derivatives.

Discovery of 2-pyridineformamide thiosemicarbazones as potent antiausterity agents.

Series of 2-pyridineformamide thiosemicarbazones were synthesized. Their preferential cytotoxicity in nutrient deprived medium (NDM) was evaluated using PANC-1 human pancreatic cancer cells by employing an antiausterity strategy. 2-Pyridineformamide thiosemicarbazones induced apoptosis and exhibited preferential cytotoxic activity toward PANC-1 cells in NDM, with potencies in the submicromolar range. These compounds are potential candidates for the development of therapeutics against pancreatic cancer.

Heterologous expression and characterization of Indian Sahiwal cattle (Bos indicus) alpha inhibin.

Inhibin is a non-steroidal glycoprotein hormone of gonadal origin with major action as negative feedback control of the production of FSH by the anterior pituitary gland. The physiological role of inhibin has led to the development of inhibin immunogens for fertility enhancement in farm animals. It is envisaged that a reduction of endogenous inhibin secretion would increase FSH concentrations and thus offers a potential for increasing the number of ovulatory follicles in the ovary. The present work was carried out to produce recombinant bovine (Indian Sahiwal Cattle; Bos indicus) alpha inhibin (bINH-α) in E. coli by optimizing its expression and purification in biologically active form and to study its immunological characterization. A bacterial protein expression vector system based on the phage T(5) promoter was used. The bINH-α encoding gene was successfully cloned and expressed in E. coli and the purified recombinant bINH-α was characterized. Recombinant bINH-α (25 µg mL(-1)) immunized guinea pigs had a significant increase in litter size compared to the control group. These results indicate a role for recombinant bINH-α as a fecundity vaccine to enhance the ovulation rate and litter size in animals.

Synthesis and biological activities of 4-N-(anilinyl-n-[oxazolyl])-7-chloroquinolines (n=3' or 4') against Plasmodium falciparum in in vitro models.

The synthesis (Pd-mediated coupling strategy) and characterization (NMR, IR, elemental analysis, etc.) of a short series of quinoline-oxazole hybrid compounds has been carried out. These materials are found to be moderately active against Plasmodium falciparum in vitro, with activities in the sub-micromolar range, and to display acceptable cytotoxicity to mononuclear leukocytes. Chemical modification strategies, with the intention to increase the biological potency of this new class of anti-malarial agents, are discussed.

A Simple Method for the Efficient Isolation of Genomic DNA from Lactobacilli Isolated from Traditional Indian Fermented Milk (dahi).

A simple, inexpensive and effective genomic DNA isolation procedure for Lactobacillus isolates from traditional Indian fermented milk (dahi) is described. A total of 269 Lactobacillus isolates from fermented milk collected from four places in North and west India were tested for lysis by an initial weakening of the Gram positive cell wall with Ampicillin followed by Lysozyme treatment. The average genomic DNA yield was ~50 µg/ml log phase culture. Quality and repeatability of the method was found to be adequate for subsequent molecular applications. The quality of the genomic DNA isolated by this method was verified by restriction digestion and polymerase chain reaction (PCR). No inhibition was observed in subsequent PCR amplification and restriction digestion. The presented method is rapid, cheap and useful for routine DNA isolation from gram positive bacteria such as Lactobacillus.

Characterization of the luteinizing hormone beta (LH-beta) subunit gene in the Indian river buffalo (Bubalus bubalis).

The cDNA sequence of leuteinizing hormone (LH) beta subunit was determined to understand the molecular basis for silent oestrus behavior and poor response to superovulation in buffalo. The LH-beta cDNA contains an open reading frame 426 bp long. The deduced sequence of the LH-beta is 141 amino acids in length. The amino acid sequences of the Indian river buffalo LH-beta subunit showed overall similarity to those of other mammals. The nucleotide sequence variability of LH-beta was studied in more than approximately 350 Indian buffaloes covering five different breeds. The results of the sequence analysis showed that the buffalo LH-beta gene is not highly conserved and non-synonymous mutations are not rare, at least in the samples collected randomly from five different breeds and buffalo populations. A total of seven different variants were obtained. In spite of its crucial role in reproduction, variation of the LH-beta gene was found present in this species. The polymorphisms found were unique in the Indian river buffalo population.

Zinc(II) complexes derived from pyridine-2-carbaldehyde thiosemicarbazone and (1E)-1-pyridin-2-ylethan-1-one thiosemicarbazone. Synthesis, crystal structures and antiproliferative activity of zinc(II) complexes.

The complexes [ZnCl(2)(HFoTsc)xH(2)O], [Zn(FoTsc)(2)], [ZnCl(2)(HAcTsc)xH(2)O] and [Zn(AcTsc)(2)], where HFoTsc and HAcTsc is pyridine-2-carbaldehyde thiosemicarbazone and (1E)-1-pyridin-2-ylethan-1-one thiosemicarbazone respectively, have been prepared and structurally characterized by means vibrational, and NMR ((1)H and (13)C) spectroscopy. The crystal structures of the complexes [ZnCl(2)(HFoTsc)xH(2)O], [Zn(AcTsc)(2)] and [ZnCl(2)(HAcTsc)xH(2)O] have been determined by X-ray crystallography. The metal co-ordination geometry of [ZnCl(2)(HFoTsc)xH(2)O] and [ZnCl(2)(HAcTsc)xH(2)O] is described as distorted square pyramidal and the two complexes are self-assembled via pi-->pi stacking interactions and intermolecular hydrogen bonds. In these two cases molecular recognition of the hydrogen bonds leads to aggregation and a supramolecular assembly of infinite two-dimensional network. The metal co-ordination geometry of [Zn(AcTsc)(2)] is described as distorted octahedral configuration in a trans-N(2)-cis-N(1)-cis-S configuration. HFoTsc and HAcTsc and the zinc complexes have been evaluated for antiproliferative activity in vitro against the cells of two human cancer cell lines: MCF-7 (human breast cancer cell line), T24 (bladder cancer cell line) and a mouse fibroblast L-929 cell line. The cytotoxic activity shown by these compounds indicates that coupling of HFoTsc and HAcTsc to Zn(II) metal center result in metallic complexes with important biological properties since they display IC(50) values in a microM range similar to or better than that of the antitumor drug cis-platin and are considered as agents with potential antitumor activity candidates for further stages of screening in vitro and/or in vivo.