Medicinal Chemistry - Volume 6, Issue 4, 2010

Phytosterols have been proposed to act as potent anticancer agents. However the mechanism of their action has not been elucidated yet. Thus, the aim of our study was to determine whether plant sterols and their thermal processing products (in physiological concentration range) could influence the viability of cancer cells and thus could be considered as positive diet complements. Additionally we decided to study potential specificity of those natural compounds against cells showing high multidrug resistance. In this study we show that the cytotoxic effect of β-sitosterol was observed in both, estrogen-dependent and estrogen-independent cells. It was also shown that the β-sitosterol was significantly more cytotoxic in cells with basal ABCB1 expression (MCF7) than in multidrug resistant NCI/ADR-RES. Surprisingly, 5a,6aepoxysitosterol did not decrease the viability of any investigated cells but on the contrary, it provoked their increased proliferation. It was shown that oxyphytosterols blocked the cell cycle of MCF7 cells in G0/G1 phase while did not affect NCI/ADR-RES cell cycle in physiological concentration range. We also show that PgP activity (responsible for Multidrug Resistance phenomena) is inhibited by β-sitosterol. Thus, the phytosterols are supposed to act at various mechanisms but, what is most interesting, can target cells showing high multidrug resistance potential.

Zinc(II)complex (3) {bis(3-ethoxy-2-hydroxy-benzylidene)-N,N'-bis(2,2-dimethyl-3-aminopropyl) ethylenediamine}- zinc(II); [(3-OEt-ENBDMPI)Zn(II)] was obtained in situ by a ligand exchange reaction involving zinc(II) acetylacetonate and the Schiff-base ligand obtained in situ. For assessing ability of 3 to act as a transport substrate of multidrug resistance (MDR1) P-glycoprotein (Pgp), its cytotoxic activity was evaluated in human epidermal carcinoma drug-sensitive KB 3-1 (Pgp-) and drug resistant KB 8-5 (Pgp+) cells. Compared with its cationic gallium(III) counterpart 4 showing cytotoxicity profiles consistent with its recognition as a Pgp substrate, the neutral zinc(II) complex 3 did not display cytotoxicity profiles (at pharmacologically relevant concentrations >10 μM) modified by expression of Pgp. Further, 3 was found be slightly more toxic against KB 8-5 cells compared to KB 3-1 cells at higher concentration. The neutral zinc (II) complex 3 was also found to be considerably less toxic against Pgp-lacking cells compared to its cationic gallium( III) counterpart 4. Additionally, the neutral zinc(II) complex 3 demonstrated considerably more toxicity against Pgp expressing KB 8-5 cells (< 10 μM) compared with its cationic counterpart 4 displaying minimal effect at highest concentration. The results suggest that differential cytotoxic activity of 3 and 4 in drug-resistant human epidermal carcinoma KB 8-5 (Pgp+) cells could result from variation in the overall charge of the molecules.

Interactions between pharmaceutical ingredients play an important role in the development of drug formulations. It was the aim of our present studies to investigate drug-polymer interactions. Interaction of the antiviral drug acyclovir with polyethylenimines, polyvinylamines and the non-ionic PVP was investigated using a modified equilibrium dialysis. The membrane was only permeable to free acyclovir, while polymers and acyclovir-polymer-associates did not pass through. Significant amounts of acyclovir were bound with the polyethylenimines. The formation of associates consisting of acyclovir and either PVP or polyvinylamine could not be demonstrated. In solutions of acyclovir and polyethylenimine (Mr=25000) the amount of bound drug is increased with increasing concentration of acyclovir. Between 7.9 μg and 31.7 μg take part in the formation of associates. Differences in the osmotic pressure of the solutions do not play an important role in the permeation of acyclovir. In solutions containing acyclovir and high molecular weight polyethylenimine (Mr=750000) the bound amount of drug increases with increasing acyclovir concentration up to c0=400μg/100 ml. Further addition of free drug to the solution does not change the amount of bound drug significantly, due to possible limitations in the binding capacity. Molecular modeling investigations were performed. According to the calculations, about 85% of the interactions can be attributed to electrostatic interactions.

A series of capsaicin derivatives were designed and synthesized, including 10 compounds which are the combination of capsaicin and dihydro capsaicin with ibuprofen through bridge chain. Preliminary biological tests suggested that some compounds had both anti-inflammatory activity and analgesic activity. And their pungency was lower. Based on these results, some of these molecules can be considered as lead candidates for the further development of analgesic drugs.

Six derivatives of 1-(2-(benzoyl-(substituted)-2-phenyl-1H-indole-5-carbony) hydrazinyloxy) vinyl nitrate were synthesized and tested in vivo for anti-inflammatory, analgesic, and ulcerogenic properties. Synthesized compounds shown significant anti-inflammatory activity comparable to that of Diclofenac sodium in the carrageenan-induced rat paw edema test and all of the compounds were found to be equipotent to Diclofenac sodium in the acetic acid induced writhing analgesic model. Out of six derivatives two derivatives found to produce no ulceration in stomach specimen of rats; nitric oxide seems to contribute to their excellent safety profile which supports several endogenous GIT defense mechanisms, including increase in mucus, bicarbonate secretions, increase in mucosal blood flow, and inhibition of the activation of pro-inflammatory cells by which NO-Indomethacin protects GI mucosa.

As part of a program to develop medications which can preferentially block the binding of cocaine to the dopamine transporter, yet spare dopamine, a new series of N-substituted methylphenidate derivatives was synthesized and evaluated for inhibitory potency in [3H] WIN 35,428 binding and [3H] dopamine uptake assays using rat striatal tissue. Structure-activity relationships studies associated these as potential cocaine antagonists were investigated. This series of methylphenidate analogs was developed by introducing various alkyl and aryl groups on the piperidine nitrogen. Preliminary pharmacological studies indicated that for the N-aryl group, the best activity is obtained when the piperidine nitrogen atom was alkylated with 4-chlorobenzyl group. The N-(4-chlorobenzyl) methylphenidate analog (1d) is 2-fold more potent than methylphenidate in [3H] WIN 35,428 binding and about 1.5-fold more potent in [3H] dopamine uptake assays Furthermore, compound 1d is 2-fold more potent than methylphenidate in [3H] WIN 35,428 binding and about 1.5-fold more potent in [3H] dopamine uptake assays. Compound 1c, although significantly less potent than methylphenidate in both assays, has the highest DR (8.2) in the series. Large N-aryl-substituted analogs were significantly less active than the corresponding N-benzyl analog. The data provide further evidence that N-alkylation changes aromatic ring SAR and the utility of methylphenidate derivatives in the development of site-directed treatment agents as partial agonists or antagonists of cocaine.

Background: Administration of dehydroepiandrosterone (DHEA) has been demonstrated to improve survival and cellular immune functions during systemic inflammation. Although there is evidence that the route of drug application may profoundly affect the DHEA-induced effects the impact of this parameter remains to be established. Materials and Methods: Male NMRI mice were subjected to sham-operation (laparotomy) or sepsis (cecal ligation and puncture). Animals received saline or DHEA (20 mg/kg/day) given either subcutaneously, intravenously, or intraperitoneally. Termination of animals was performed 48 hrs after induction of sepsis in order to monitor splenocyte proliferation (3H-thymidine incorporation assay), splenocyte apoptosis (Annexin V binding capacity), and cytokine release (IL-1β and IL-6, ELISA). Results: Subcutaneous DHEA administration improved the survival rate of septic mice 48 hrs after induction of CLP (75% vs. 47%). This effect was paralleled by a restoration of splenocyte proliferation, a decreased cellular apoptosis rate of splenocytes, and an attenuation of pro-inflammatory cytokine release. In contrast, no significant effects on the survival rate or cellular immune functions were observed following intravenous or intraperitoneal DHEA administration. Conclusions: Subcutaneous administration of DHEA induced an increased survival rate and improved cellular immune functions in septic mice. In contrast, no comparable effects were noticed following intravenous or intraperitoneal administration of DHEA.

A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a series of 1, 3, 4-thiadiazole derivatives reported as anticonvulsant employing self-organizing molecular field analysis (SOMFA) techniques to investigate the structural requirements for the design of novel anticonvulsant. The training set composed of twenty two 1, 3, 4-thiadiazole derivatives that exhibit a potent activity in MMS test while predictive power was evaluated using a test set of 7 molecules. Physicochemical determinants of binding, such as steric and electrostatic properties, were mapped onto the molecular structures of 1, 3, 4-thiadiazole in order to interpret graphically the SOMFA results in terms of master grids showing various field contributions. The present 3D-QSAR studies yielded stable and statistically robust models indicated by the moderate cross correlation coefficients which may prove to be a guideline for design of novel anticonvulsants.

Thionamide-derived antithyroid drugs (ATD) have been in use for over half a century and much is now known about their mechanism of action, pharmacokinetics and clinical pharmacology. Candidates for first option ATD therapy are young adults, without large goitre. The recommended initial dose for patients without big goitre and mild hyperthyroidism is 20 mg of MMI/CBZ. The recommended maintenance doses are 5-10 mg of MMI/CBZ. In cases of big goitre and/or severe hyperthyroidism the recommended initial dose is 30 to 40 mg/day. PTU use should be restricted to first trimester of pregnancy, doses should be as low as possible (150 to 200 mg/day) and then changing to MMI is recommended. Treatment Duration should be of 12-18 months. ATD plus thyroxine combination therapy have not advantage on ATD alone. ATD plus L-Thyroxine regimens should be used to avoid hypothyroidism when patients are with maintenance doses of ATD drugs in order to relax monitoring. In this case a low dose of T4 50-75 μg per day is used. Breast feeding women with hyperthyroidism can be treated with MMI/CBZ. ATD will not stop until serum stimulating TSH-receptors antibodies values are within the normal range. We are waiting for results of ongoing studies of biochemical and/or genetic markers that will permit us to predict the outcome of these patients after ATD treatment is stopped.

Oseltamivir (has known by its brand name 'Tamiflu') is a prodrug, requiring ester hydrolysis for conversion to the active form, Oseltamivir carboxylate. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed by US based Gilead Sciences and is currently marketed by F. Hoffmann-La Roche (Roche). Oseltamivir is an antiviral drug which works by blocking the function of the viral neuraminidase protein. US FDA approved Oseltamivir for prophylaxis of uncomplicated influenza A and B. Currently, Oseltamivir is the only first line defense drug available for the treatment of Swine Flu. Orally Oseltamivir is well tolerated and effective in treatment of influenza in adolescents and adults, including the elderly and patients with chronic cardiac and/or respiratory disease. Many of the pharmaceutical companies targeted Oseltamivir as a block buster molecule. In present review, we have tried to cover chemistry, mode of binding, total synthesis, current patent status, adverse effect and clinical status of Oseltamivir giving emphasis on medicinal chemistry aspect.

Recent studies indicated that andrographolide was a potential anti-HIV therapeutic agent. In the paper, the synthesis of a series of andrographolide derivatives was described and their anti-HIV activities were evaluated in vitro. As compared with TI, compounds 5c, 5d and 5i showed moderate inhibitory activities on the cytopathic effect with TI above 10. Among the derivatives, compound 5i was the best one with TI >51.