Sujata K. Dass

Metalloporphyrins—Applications and clinical significance

The fascinating structures of naturally occurring porphyrins and metalloporphyrins have been perfected by nature to give functional dyes par excellence. The important roles these tetrapyrrolic macrocycles play in vital biological processes, in particular photosynthesis (chlorophyll), oxygen transport (hemoglobin), oxygen activation (cytochrome), have led to their characterization as ‘pigments of life’. Because porphyrins possess extended π-electron systems and exhibit stability, they are finding use, to an increasing extent, in advanced materials, as components in organic metals, molecular wires, and other devices. In medicine, porphyrins are experiencing a renaissance due to the advent of photodynamic therapy of great promise in the treatment of cancer and dermatological diseases. The interdisciplinary interest porphyrins thus generate has provided the impetus to develop Novel-porphyrin like molecules anticipated to exhibit special properties, by structural variation of the tetrapyrrolic macrocycle, while maintaining a (4n+2)π main conjugation pathway.In addition to their esoteric application in science, porphyrins have been shown to have profound implications for therapeutic purposes. Their photosensitizing properties have led to their utilization in photodynamic therapy. Certain metalloporphyrins such as SnPP are being tested as drugs for the treatment of neonatal jaundice. Metalloporphyrins are serving as SOD mimetics to combat oxidative stress and a range of metalloporphyrin complexes have been proposed as contrast agents for magnetic resonance imaging

Implications of Nanoscale Based Drug Delivery Systems in Delivery and Targeting Tubulin Binding Agent, Noscapine in Cancer Cells

Noscapine, a tubulin binding anticancer agent undergoing Phase I/II clinical trials, inhibits tumor growth in nude mice bearing human xenografts of breast, lung, ovarian, brain, and prostrate origin. The analogues of noscapine like 9-bromonoscapine (EM011) are 5 to 10-fold more active than parent compound, noscapine. Noscapinoids inhibit the proliferation of cancer cells that are resistant to paclitaxel and epothilone. Noscapine also potentiated the anticancer activity of doxorubicin in a synergistic manner against triple negative breast cancer (TNBC). However, physicochemical and pharmacokinetic (ED50˜300-600 mg/kg bodyweight) limitations of noscapine present hurdle in development of commercial anticancer formulations. Therefore, objectives of the present review are to summarize the chemotherapeutic potential of noscapine and implications of nanoscale based drug delivery systems in enhancing the therapeutic efficacy of noscapine in cancer cells. We have constructed noscapine-enveloped gelatin nanoparticles, NPs and poly (ethylene glycol) grafted gelatin NPs as well as inclusion complex of noscapine in β-cyclodextrin (β-CD) and evaluated their physicochemical characteristics. The Fe3O4 NPs were also used to incorporate noscapine in its polymeric nanomatrix system where molecular weight of the polymer governed the encapsulation efficiency of drug. The enhanced noscapine delivery using μPAR-targeted optical-MR imaging trackable NPs offer a great potential for image directed targeted delivery of noscapine. Human Serum Albumin NPs (150-300 nm) as efficient noscapine drug delivery systems have also been developed for potential use in breast cancer.

Synthesis and electrochemical studies of charge-transfer complexes of thiazolidine-2,4-dione with σ and π acceptors

In the present work, we report the synthesis and characterization of novel charge-transfer complexes of thiazolidine-2,4-dione (TZD) with sigma acceptor (iodine) and pi acceptors (chloranil, dichlorodicyanoquinone, picric acid and duraquinone). We also evaluated their thermal and electrochemical properties and we conclude that these complexes are frequency dependent. Charge-transfer complex between thiazolidine-2,4-dione and iodine give best conductivity. In conclusion, complex with sigma acceptors are more conducting than with pi acceptors.

Ameliorating effect of phytoestrogens on CCl4-induced oxidative stress in the livers of male Wistar rats.

Glutathione-S-transferases and glutathione play a key role in the detoxification of most toxic agents. In the present study, the protective effects, if any, of isoflavone phytoestrogens—genistein and daidzein on the carbon tetrachloride (CCl4) induced changes in the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutathione S transferase (GSH) and levels of glutathione (GSH) and thiobarbituric acid reactive substances (TBARS)—were studied. The activities of ALT and AST were assayed in the serum, whereas the activity of GST and levels of GSH and TBARS were determined in the livers of rats. The current study involved the division of animals into two main groups: (i) rats pretreated with genistein and daidzein for three days; and (ii) non-pretreated rats. In the pretreated group, rats received oral doses of genistein (7.9 µmol/kg body weight) and daidzein (7.9 µmol/kg body weight) for three consecutive days (once daily) followed by oral dose of CCl4 on the 4th and the 5th day concurrently with the phytoestrogens-genistein or daidzein. In the non-pretreated group animals received oral dose of CCl4 (1 ml/kg body weight) for two consecutive days along with the phytoestrogens-genistein or daidzein. Treatment of male rats with CCl4 significantly elevated the activity of ALT and AST in serum and levels of TBARS in the liver. On the other hand, CCl4 resulted in decreased activity of GST and lowered the GSH levels. Coadministration of genistein and daidzein with CCl4 could not restore the alterations in the activity of ALT and AST caused by CCl4 to normal control levels. However, repeated dose treatments with genistein and daidzein for three days prior to the administration of CCl4 restored such alterations to normal levels. Our results indicate that genistein is more effective than daidzein in counteracting the inhibition of GST activity caused by CCl4 and restoring it to normal levels. Genistein was also more effective than daidzein restoring the induced TBARS levels caused by CCl4 to normal control levels when rats were pretreated with the isoflavone orally for three days. It has been observed that the tested isoflavonoids were able to antagonize the toxic effects of CCl4. Such counteracting effects were more pronounced for genistein and when the phytoestrogens were administered as repeated doses prior CCl4 administration.

A Review on Noscapine, and its Impact on Heme Metabolism

This review introduces the Noscapine, which is being used as an antitussive drug for a long time has been recently discovered as a novel tubulin-binding, anti-angiogenic anticancer drug that causes cell cycle arrest and induces apoptosis in cancer cells both in vitro as well as in vivo. Noscapine is a multifunctional molecule i.e. it possesses various functional moieties. We maneuvered various amenable sites and have synthesized analogs, which might prove to be more efficacious and less cytotoxic. Moreover, development of oral controlled release anticancer formulation of noscapine is severely hampered due to short biological half-life (<2-h), poor absorption, low aqueous solubility, and extensive first pass metabolism, thereby requiring large doses for effective treatment.

Modulatory influence of tin-protoporphyrin on gossypol-induced alterations of heme oxygenase activity in male wistar rats

SummaryGossypol — a male contraceptive is toxic and causes anorexia, reduction in body weight, hypokalemia etc. It prevents liberation of oxygen from oxyhemoglobin and has hemolytic effect on erythrocytes and leads to microcytic hypochromic anemia. SnPP has been shown to either competitively suppress or to significantly ameliorate a variety of naturally occuring or experimentally induced forms of jaundice in animals and man by inhibiting heme degradation. In this paper novel tissue-dependent response to differential dosing regimen of gossypol and gossypol in association with Sn-protoporphyrin (SnPP) is described. Gossypol was found to be a stimulator of heme oxygenase activity in the liver and kidney to varying degrees. This tissue response contrasted with that of the spleen, where gossypol decreased the activity of the enzyme. The increase in enzymatic activity was accompanied by a decline in the total microsomal protein content on gossypol administration. The gossypol mediated an increase of heme oxygenase activity, elevated bilirubin levels leading to hyperbilirubinemia. The stimulatory effect of gossypol was counteracted to a considerable extent when SnPP was simultaneously administered. Hence, we envision the importance of combined rather than single exposures in defining the realms of toxicology of these and other related drugs. We further envisage the existence of important gossypol-heme interactions in the regulation of heme metabolism.

Co-administration of melatonin reverses the Tinprotoporphyrin (SnPP) induced decline of Cytochrome P450 contentin vivo in rats

SummaryMelatonin (N-acetyl-5 methoxytryptamine) is a low molecular weight antioxidant and is an endogeneous defence system against the deleterious actions of the extremely reactive hydroxyl radical. Among the enzymes that participate in the antioxidant functions is cytochrome P-450, a stalwart of the detoxification system in the body. Our results revealed that tin-protoporphyrin administration brought about a marked decline in cytochrome P-450 levels. This decline was, however, reversed by the co-administration of the antioxidant, melatonin. Thus, the enhanced antioxidant status in melatonin-treated rats may act as a protective mediator of various pharmacological functions altered during tin-protoporphyrin (an antihyperbilirubemenic agent) administration to Wistar rats.

Papaverine, an opium alkaloid influences hepatic and pulmonary glutathione s-transferase activity and glutathione content in rats

SummaryThe present study evaluates the effect of oral administration of papaverine at differential dosing regimens (100 mg/kg bw and 200mg/kg bw) on the hepatic and pulmonary glutathione S-transferase (GST) activity and glutathione content (GSH) in male Wistar rats. Papaverine treatment caused a pronounced increase in GST activity and GSH content at the higher dosing level in the rat liver and lung. We conclude that papaverine, can possibly act as a chemopreventive agent against chemical carcinogenesis.

Effect of gossypol in association with chromium protoporphyrin on heme metabolic enzymes

Gossypol prevents the liberation of oxygen from oxyhemoglobin and exerts a hemolytic effect on erythrocytes. In excessive dosages of gossypol, an extreme burden is placed upon the respiratory and circulatory organs owing to the reduced oxygen carrying capacity of blood. Chromium protoporphyrin (CrPP) has been shown to either competitively suppress or to significantly ameliorate a variety of naturally occurring or experimentally induced forms of jaundice in animals and man. In this communication, a novel tissue dependent response to gossypol (50 µmol/kg bw) and gossypol in association with CrPP (50 µmol/kg bw) is described. Our results revealed that gossypol stimulated the hepatic, splenic, and renal δ-aminolevulinic acid synthase (ALA-S) activity, the heme biosynthetic enzyme, and simultaneous administration of CrPP and gossypol synergized the gossypol-mediated increase of ALA-S activity. Gossypol was found to be a potent stimulator of heme oxygenase (HMOX) activity in rat liver and kidney to varying degrees. This tissue response contrasted with that of the spleen, where gossypol decreased the activity of the enzyme. In consonance with the increased hepatic and renal HMOX activity, a marked increase was observed in total serum bilirubin concentration in gossypol treated rats. When rats were given CrPP simultaneously with gossypol, the gossypol mediated increase in hepatic and renal HMOX activity was effectively blocked. Furthermore, the increase in enzymatic activity was accomplished by a decline in the total microsomal protein content on gossypol administration. These findings emphasize the toxic effect of gossypol in eliciting increased heme degradation by stimulating HMOX activity in the liver and the kidney and the potential usefulness of CrPP in experimental and perhaps clinical conditions in which hyperbilirubinemia occurs.

Cadmium, carcinogen, co-carcinogen and anti carcinogen.

As a stress agent, inducing apoptosis and blocking it, Cd can have both helpful and harmful effects. The atmosphere is a thin envelope which makes the worid a global village. Cd is the most toxic metal in air. As both the first and second messenger of the stress response, it is synergistically toxic with all other stressors, including many other carcinogens. Elimination of Pb and its replacement with added benzene in gasoline appears to have increased the toxicity of atmospheric Cd. With scientific understanding of the molecular basis of Cds role in carcinogenesis and anti-carcinogenesis, primary cancer prevention can be practiced by reducing Cd and chemical air pollution and educating the public on smoke cessation, healthy eating habits and stress reduction. Using the existing information on Cd and its effects, determinations could be made on established cancers so that individualized treatment protocols can be developed to improve patient care.