Hassan A. El-Kashef

Substituted quinazolines, part 3. Synthesis, in vitro antitumor activity and molecular modeling study of certain 2-thieno-4(3H)-quinazolinone analogs☆

The synthesis of some new 2-thieno-4(3H)-quinazolinone derivatives and their biological evaluation as antitumor agents using the National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated. Compounds 2-(2-thienylcarbonylamino)-5-iodo-N-(4-hydroxyphenyl)-benzamide (16), 2-(2-thieno)-6-iodo-3-phenylamino-3,4-dihydro-quina-zolin-4-one (26), and 2-(2-thieno)-4-[4-sulfonamidobenzylamino]-6-iodo-quinazoline (42), with GI(50) values of 12.7, 10.3, 16.9 microM, respectively, proved to be the most active members in this study, as compared to the known drug 5-FU. Conformational analysis of the most active molecules using molecular modeling and QSAR techniques enabled the understanding of the pharmacophoric requirements for 2-thieno-quinzolinone derivatives as antitumor agents. These three quinazolinone analogs (16, 26, 42) could be considered as useful templates for future development to obtain more potent antitumor agents.

Hyperglycemia increased the responsiveness of isolated rabbit's pulmonary arterial rings to serotonin.

The effect and mechanism of action of serotonin (5-HT) were studied in the pulmonary circulation of normal and diabetic rabbits. 5-HT (10, 50 and 100 nmol/l) produced a concentration-dependent increase in rabbit pulmonary arterial tension. Pulmonary arterial rings from diabetic rabbits were more responsive to 5-HT compared to those from normal rabbits. The pressor effects of 5-HT in normal and diabetic pulmonary arterial rings were totally abolished by either the 5-HT receptor antagonist, ketanserin (200 nmol/l) or the calcium channel blocker, verapamil (5.5 nmol/l). On the other hand, the cyclo-oxygenase inhibitor, indomethacin (0.4 nmol/l), significantly potentiated the pressor response of 5-HT in normal but not in diabetic pulmonary arterial rings. The lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA, 20 nmol/l), significantly enhanced the 5-HT-induced pressor response in normal rings while significantly attenuating those responses in diabetic rings. NG-nitro-L-arginine methyl ester (100 nmol/l), an inhibitor of nitric oxide synthase, significantly potentiated the contractile response of 5-HT in normal as well as diabetic pulmonary arterial rings. The results of this study indicate that 5-HT induces pulmonary hypertension in normal as well as in diabetic rabbits. In addition, experimentally induced diabetes exaggerates the pressor response of 5-HT and therefore may increase the risk of pulmonary hypertension. Furthermore, 5-HT alone or in combination with indomethacin, NDGA and a nitric oxide synthase inhibitor may be used to induce experimental pulmonary hypertension and possibly pulmonary edema.

Synthesis and biological evaluation of new curcumin derivatives as antioxidant and antitumor agents

Twenty-four new compounds were prepared, taking curcumin as a lead, in order to explore their antioxidant and antitumor properties. The capacities of these derivatives to scavenge the 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS.+), and to protect human red blood cells (RBCs) from oxidative haemolysis were investigated. In addition, the percentage viability of different cell lines (Hep G2, WI38, VERO and MCF-7) was tested. The result of the antitumor testing was generally in accordance with those of the antioxidant assays. Compounds which bear o-methoxy substitution to the 4-hydroxy function in the phenyl ring (7g, 5g and 3g) exhibited significantly higher ABTS.+-scavenging, antihaemolysis, and antitumor activities than other derivatives. In addition, molecular modelling studies were carried out for biologically active and inactive compounds, to study the structure–activity relationship, with the aim to elucidate which portions of the molecules are critical for the antioxidant and antitumor activity.

Resveratrol reverses hydrogen peroxide-induced proliferative effects in human coronary smooth muscle cells: a novel signaling mechanism.

BACKGROUNDnIn human coronary smooth muscle cells (HCSMCs), we tested the proatherogenic/proliferative potential of the reactive oxygen species (ROS), hydrogen peroxide (HP), and the ability of the polyphenol stilbene resveratrol (RSVL) to protect against such effects.nnnMETHODSnActivity for ERK1/2 and the kinase-G cascade were determined and correlated with HCSMC count before and after treatment with HP and/or RSVL.nnnRESULTSnHP evoked concentration-dependent cell proliferation and stimulated ERK1/2 phosphorylation at active sites. Pretreatment with the MEK-ERK inhibitor (PD98059) reversed these effects of HP. RSVL (1-100 microM) elicited more prominent inhibition of HP-evoked cell proliferation and ERK1/2 activation. In addition, RSVL markedly enhanced cGMP formation, a response that was insensitive to the soluble guanylyl-cyclase (sGC) inhibitor (ODQ, 10 microM) but was obliterated with the phorbol ester, (PMA, 0.1 microM), a desensitizer of the pGC enzyme. Likewise, the RSVL-evoked cytostatic and ERK inhibitory effects were significantly reversed by the kinase-G-inhibitor, KT-5823 (10 microM).nnnCONCLUSIONSnCollectively, RSVL activates the kinase-G system to counteract HP-induced ERK1/2 activation and coronary arterial proliferation. These effects for RSVL remain functional in endothelium-disrupted arteries, scenarios that commonly occur in advanced coronary heart disease.

Effect of Zinc on the Anti-Inflammatory and Ulcerogenic Activities of Indometacin and Diclofenac

In the present study, the potential anti-inflammatory activity of zinc sulfate (zinc) has been examined in rats with acute and chronic inflammation. Additionally, we studied the effect of the concurrent administration of zinc on the anti-inflammatory activity of indometacin and diclofenac and their gastric side effects. Oral or subcutaneous administration of zinc (25 and 15 mg/kg, respectively) significantly reduced carrageenan-induced paw edema. Subcutaneous co-administration of zinc (15 mg/kg) and indometacin (5 mg/kg) or diclofenac (10 mg/kg) resulted in a further reduction in paw edema which was more than either that produced by either agent alone. However, after oral co-administration of zinc and diclofenac the reduction in paw edema was not significantly different from that produced by either zinc or diclofenac alone. In rats with chronic inflammation, the administration of zinc (5 mg/kg s.c. for 7 days) proved as effective as either indometacin (3 mg/kg) or diclofenac (5 mg/kg). Co-administration of zinc with indometacin or diclofenac did not affect the level of activity of either drug. Co-administration of zinc did not affect the ulcerogenic effect of indometacin expressed as the ulcer index. In contrast to indometacin, administration of zinc markedly reduced the ulcerative action of diclofenac. In conclusion, zinc supplementation may contribute significantly to the treatment of inflammation. The combination of zinc with other anti-inflammatory drugs may provide beneficial additive effects and reduce their gastric hazards, particularly with diclofenac.

Celecoxib, a Selective Cyclooxygenase-2 Inhibitor, Attenuates Renal Injury in a Rat Model of Cisplatin-Induced Nephrotoxicity

Background: Cisplatin is an effective chemotherapeutic agent successfully used in the treatment of a wide range of tumors. Nevertheless, nephrotoxicity has restricted its clinical use. Recent studies have strongly suggested that inflammatory mechanisms may play an important role in the pathogenesis of cisplatin nephrotoxicity. Celecoxib, a selective cyclooxygenase-2 inhibitor used as anti-inflammatory, may therefore have a protective effect on cisplatin-induced renal injury. Methods: In the present study, rats were injected intraperitoneally with a single dose of cisplatin (7 mg/kg) and/or celecoxib (30 mg/kg) for 5 days. Results: Nephrotoxicity manifested biochemically by elevations in serum creatinine, blood urea nitrogen, and proteinuria, and an increase in kidney weight as a percentage of total body weight. In addition, a marked decrease in serum albumin was observed. Lipid peroxidation in the kidney was monitored by measuring the malondialdehyde level and glutathione content, which were increased and depleted, respectively. Administration of celecoxib with cisplatin attenuated cisplatin-induced changes in kidney function parameters and oxidative stress markers. Histopathological examination of the kidney confirmed these results. Conclusion: In conclusion, this study indicates that celecoxib may be a promising drug for clinical use as a nephroprotectant against cisplatin-induced nephrotoxicity.

Synthesis and biological evaluation of new curcumin analogues as antioxidant and antitumor agents: molecular modeling study.

New curcumin analogues have been synthesized and their antioxidant activities were investigated by measuring their free radical scavenging capacities. The inxa0vitro and inxa0vivo antitumor activities of the synthesized compounds on Ehrlich ascites carcinoma (EAC) cell line were evaluated. 4-(4-Chlorophenyl)-2-(5-ethyl-7-(4-methoxybenzylidene)-3-(4-methoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c] pyridin-2-yl)thiazole 7h showed excellent antineoplastic activity in both inxa0vitro and inxa0vivo studies more than that of tested compounds and reference drug, cisplatin. Different molecular modeling studies were performed, where docking of compound 7h into telomerase active site suggested that it could exert its antitumor potential by telomerase inhibition.

Modulation of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis by olmesartan and omega-3.

This study was designed to investigate the potential effects of omega-3, olmesartan and their combination on established hepatic fibrosis in the carbon tetrachloride (CCl4) rat model. Male Wistar rats received subcutaneous injections of CCl4 twice weekly for 12weeks, as well as daily oral treatments of olmesartan (1 and 3mg/kg), omega-3 (75 and 150mg/kg) and their combination during the last 4weeks of intoxication. Our results indicated that omega-3 and, to a lesser extent, olmesartan dose-dependently blunted CCl4-induced necroinflammation scoring and elevation of liver injury parameters in serum. Besides, omega-3 and, to a lesser extent, olmesartan treatments in a dose dependent manner attenuated CCl4-induced liver fibrosis, as demonstrated by hepatic histopathology scoring and 4-hydroxyproline content. The mechanisms behind these beneficial effects of both omega-3 and olmesartan were also elucidated. These include (1) counteracting hepatic oxidative stress and augmenting hepatic antioxidants; (2) preventing the activation of hepatic stellate cells (HSCs), as denoted by reducing α-smooth muscle actin (α-SMA) expression in the liver; (3) inhibiting the proliferation and chemotaxis of HSCs, as evidenced by downregulating platelet-derived growth factor receptors-β (PDGFR-β) expression in the liver; and (4) inhibiting the fibrogenesis response of HSCs, as indicated by inhibiting the secretion of transforming growth factor-β1 (TGF-β1). Unexpectedly, when olmesartan was co-administered with omega-3, it interfered with the hepatoprotective and anti-fibrotic activities of omega-3. In conclusion, this study introduces the first evidence regarding the pronounced anti-fibrotic activity of omega-3 and suggests that it may be beneficial in the treatment of hepatic fibrosis in humans.

Synthesis, Ultra-Short Acting Hypnotic Activity, and Metabolic Profile of Ethyl 8-Oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a] [1,3]diazepin-3-carboxylate (HIE-124)

The synthesis and biological evaluation of ethyl 8‐oxo‐5,6,7,8‐tetrahydro‐thiazolo[3,2‐a][1,3]diazepin‐3‐carboxylate (HIE‐124, 4), as a member of a new generation of ultra‐short acting hypnotics is described. HIE‐124 4 exhibited potent in‐vivo activity with a very rapid onset of action and a shorter duration of action with no acute tolerance or noticeable side effects than thiopental sodium. The rat in‐vivo and in‐vitro metabolic profile of 4 is also described. Urine was pooled from a number of animals and analyzed using electrospray liquid chromatography mass spectrometry (ESI LC‐MS). HIE‐124 4 was incubated with rat‐liver microsomal and rat‐liver hepatocyte preparations then similarly analyzed. The only metabolic product of both in‐vitro and in‐vivo experiments is the carboxylic acid derivative 5. HIE‐124 4 has the potential use not only as a pre‐anesthetic medication and as anesthesia inducer but also has the potential to be used with thiopental sodium to maintain anesthesia for longer duration.

Protective potential of MMR vaccine against complete Freund’s adjuvant-induced inflammation in rats

The aim of the present study was to investigate the effect of MMR vaccine on inflammation which was induced by complete Freund’s adjuvant (CFA) in male Sprague–Dawley rats. Rats were randomly divided into the control, CFA, MMR and CFAxa0+xa0MMR groups. Inflammatory symptoms such as paw oedema was measured in CFA-injected rats’ paw. Body weight changes and alterations in some haematological parameters and oxidative stress markers following CFA injection were checked. In CFA-inflammed rats, there was a significant increase in rat paw thickness and decrease in body weight increment. MMR exhibited a significant anti-inflammatory effect as manifested by reduction in paw thickness and normal gain in body weight when administered 1xa0week prior to induction of inflammation. The altered haematological parameters (TLC) and oxidative stress markers (MDA, GSH, SOD) in the inflammed rats were significantly brought back to near normal by MMR treatment. In conclusion, MMR vaccine showed a reduction in rat paw thickness and it could significantly normalize the haematological and biochemical abnormalities in CFA-induced inflammatory pain model in rats. Our data suggested that MMR could be a potential protective agent against certain types of inflammatory pain. Further histopathological and radiological studies are required to confirm the possibility of developing novel therapeutic vaccines against some forms of arthritis.